Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH:13]=[O:14])=[CH:5]1)[CH:2]=[CH2:3].B1C2CCCC1CCC2.[OH-:24].[Na+]>C1COCC1.C(OCC)C>[OH:24][CH2:3][CH2:2][CH2:1][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH:13]=[O:14])=[CH:5]1
Reactant: C=CCn1cc(C=O)c2ccccc21
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=Cc1cn(CCCO)c2ccccc12

Procedure:
In a 10 mL round-bottom flask, 1-Allyl-1H-indole-3-carbaldehyde (169 mg, 0.91 mmol) is dissolved in 0.5 mL of anhydrous THF. To this solution is added 0.5 M of 9-BBN in THF (2 mL, 1.0 mmol). The reaction is allowed to stir at room temperature for 1 hr, whereupon a 1M solution of NaOH (2.5 mL) is added. The organic layer is diluted with 10 mL of diethyl ether and the aqueous layer is removed. The organic layer is washed 3×10 mL with 1M NaOH, followed by 2×10 mL water and 2×10 mL saturated NaCl solutions. The organic layer is then dried over Na2SO4 and the solvent is removed under reduced pressure to afford 1-(3-hydroxy-propyl)-1H-indole-3-carbaldehyde.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:11]3[CH2:19][CH2:18][NH:17][CH2:16][C:12]=3[N:13]=[CH:14][N:15]=2)=[CH:5][CH:4]=1.Cl[C:23]1[C:28]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:26]=[CH:25][N:24]=1.C(N(CC)C(C)C)(C)C>>[F:21][C:2]([F:1])([F:20])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]2[C:11]3[CH2:19][CH2:18][N:17]([C:23]4[C:28]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:26]=[CH:25][N:24]=4)[CH2:16][C:12]=3[N:13]=[CH:14][N:15]=2)=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1ccc(Nc2ncnc3c2CCNC3)cc1
Reactant: FC(F)(F)c1cccnc1Cl
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)c1ccc(Nc2ncnc3c2CCN(c2ncccc2C(F)(F)F)C3)cc1
Temperature: 180 °C

Procedure:
The title compound was prepared according to the procedure given for Example 9 using N-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine (0.150 g, 0.51 mmol), 2-chloro-3-(trifluoromethyl)pyridine (0.185 g, 0.10 mmol), N,N-diisopropylethylamine (0.133 mL, 0.76 mmol) and heating the reaction mixture 6 h at 180° C. to obtain 0.130 g of a light yellow solid.
Reaction SMILES: Cl[CH2:2][C:3]([CH2:5]Cl)=O.[F:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([NH2:17])=[S:16])=[CH:10][CH:9]=1.[NH2:18][C:19]1[C:24]([C:25]#[N:26])=[C:23]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][OH:36])=[CH:29][CH:28]=2)[C:22]([C:37]#[N:38])=[C:21]([SH:39])[N:20]=1.C(=O)(O)[O-].[Na+]>C(O)C.O>[NH2:18][C:19]1[C:24]([C:25]#[N:26])=[C:23]([C:27]2[CH:28]=[CH:29][C:30]([O:33][CH2:34][CH2:35][OH:36])=[CH:31][CH:32]=2)[C:22]([C:37]#[N:38])=[C:21]([S:39][CH2:5][C:3]2[N:17]=[C:15]([NH:14][C:11]3[CH:10]=[CH:9][C:8]([F:7])=[CH:13][CH:12]=3)[S:16][CH:2]=2)[N:20]=1
Reactant: O=C(CCl)CCl
Reactant: N#Cc1c(N)nc(S)c(C#N)c1-c1ccc(OCCO)cc1
Reactant: NC(=S)Nc1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#Cc1c(N)nc(SCc2csc(Nc3ccc(F)cc3)n2)c(C#N)c1-c1ccc(OCCO)cc1

Procedure:
244 mg (1.92 mmol) of 1,3-dichloroacetone are added to a solution of 327 mg (1.92 mmol) of 4-fluorophenylthiourea in 8 ml of ethanol, and the mixture is stirred under reflux for 1 h. The mixture is concentrated, the residue is dissolved in 4 ml of DMF, 429 mg (1.37 mmol) of 2-amino-4-[4-(2-hydroxyethoxy)phenyl]-6-mercaptopyridine-3,5-dicarbonitrile (preparation see WO 03/053441, Example 6/Method 1, Step 1) and 346 mg (4.1 mmol) of sodium bicarbonate are added and the mixture is stirred at RT overnight. After addition of water, the precipitate is decanted off and the residue is triturated with dichloromethane. After chromatography on silica gel (mobile phase dichloromethane/methanol 50:1), the title compound is obtained as a yellowish solid.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:11][O:10][C:9](=[O:12])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].CCC[CH2-].[F:18][C:19]([F:32])([F:31])[C:20]1[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28](Cl)=[O:29])=[CH:22][CH:21]=1>C1COCC1>[C:1]1([C@@H:7]2[CH2:11][O:10][C:9](=[O:12])[N:8]2[C:28](=[O:29])/[CH:27]=[CH:26]/[C:23]2[CH:22]=[CH:21][C:20]([C:19]([F:31])([F:32])[F:18])=[CH:25][CH:24]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cl)/C=C/c1ccc(C(F)(F)F)cc1
Reactant: O=C1N[C@H](c2ccccc2)CO1
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(/C=C/c1ccc(C(F)(F)F)cc1)N1C(=O)OC[C@H]1c1ccccc1
Temperature: -78 °C
Yield: 100.2 %

Procedure:
To a 500 mL round-bottomed flask was added (R)-4-phenyloxazolidin-2-one (19 g, 116.00 mmol) and THF (464 mL, 116 mmol). The solution was cooled to −78° C. N-butyllithium (46 mL, 116 mmol) was then added slowly, and the reaction was stirred for about 15 minutes before the addition of a THF solution of (E)-3-(4-(trifluoromethyl)phenyl)acryloyl chloride (27 g, 116 mmol). The cold bath was removed, the reaction was allowed to warm to room temperature, and the progress of the reaction was checked by LCMS. After LCMS indicated that the reaction was complete, the reaction was quenched with water, and the organics were washed with saturated sodium bicarbonate and brine, dried over sodium sulfate, filtered, and reduced to give an orange solid, (R,E)-4-phenyl-3-(3-(4-(trifluoromethyl)phenyl)acryloyl)oxazolidin-2-one (42 g, 100% yield).
Reaction SMILES: [OH:1][C@H:2]1[C@@H:9]2[C@@H:5]([CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8]2)[CH2:4][CH2:3]1.[Cl:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21](O)=[CH:20][CH:19]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(OCC)(=O)C.C1CCCCC1>[Cl:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([O:1][C@@H:2]2[C@@H:9]3[C@@H:5]([CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8]3)[CH2:4][CH2:3]2)=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CC[C@@H](O)[C@H]2C1
Reactant: Oc1ccc(Cl)c2ccccc12
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C[C@H]2CC[C@H](Oc3ccc(Cl)c4ccccc34)[C@H]2C1
Yield: 30.1 %

Procedure:
The process is performed according to the procedure described in Example 11, step 11.1. Starting with 0.15 g (0.66 mmol) of tert-butyl (3aR,4R,6aS)-4-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate, obtained in step 13.1., 0.130 g (0.73 mmol) of 4-chloro-1-naphthol, 0.160 g (0.79 mmol) of diisopropyl azodicarboxylate and 0.206 g (0.659 mmol) of resin-supported triphenylphosphine (triphenylphosphine, polymer-supported, 3.2 mmol/g on polystyrene), and after chromatography on silica gel, eluting with a 95/5 and then a 90/10 mixture of cyclohexane and ethyl acetate, 0.077 g (30%) of expected product is obtained.
Reaction SMILES: [Zn:1].II.[Br:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.C[Si](Cl)(C)C>O1CCCC1>[Br-:4].[F:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][Zn+:1])=[CH:7][CH:8]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: [Zn]
Agent: C[Si](C)(C)Cl
Agent: II
Solvent: C1CCOC1
Product: Fc1ccc(C[Zn+])cc1
Product: [Br-]
Temperature: 25 °C

Procedure:
To a stirred mixture of Zn metal (18.5 g, 289.06 mmol, 1.09 equiv), I2 (500 mg, 1.97 mmol, 0.01 equiv) and 1-(bromomethyl)-4-fluorobenzene (5 g, 0.10 equiv) in anhydrous tetrahydrofuran (50 mL) maintained under nitrogen at room temperature was added dropwise a solution of 1-(bromomethyl)-4-fluorobenzene (45 g, 211.6 mmol, 0.90 equiv) in tetrahydrofuran (200 mL). TMSCl (500 mg, 4.60 mmol, 0.02 equiv) was then added dropwise to the reaction. The resulting mixture was refluxed for 10 h. The solution was cooled to 0° C. and used in the next step immediately.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([N+:12]([O-:14])=[O:13])=[CH:6][C:5]=1[Cl:15].C([N:18]([CH2:21]C)[CH2:19]C)C.[F:23][C:24]1[CH:31]=CC(CN)=[CH:26][CH:25]=1.O>CS(C)=O>[Cl:15][C:5]1[CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[C:8]([O:10][CH3:11])=[CH:9][C:4]=1[C:3]1[CH:31]=[C:24]([F:23])[CH:25]=[CH:26][C:2]=1[CH2:21][NH:18][CH3:19]
Reactant: COc1cc(CCBr)c(Cl)cc1[N+](=O)[O-]
Reactant: CCN(CC)CC
Reactant: NCc1ccc(F)cc1
Solvent: O
Solvent: CS(C)=O
Product: CNCc1ccc(F)cc1-c1cc(OC)c([N+](=O)[O-])cc1Cl
Reaction time: 5 h
Yield: 19.5 %

Procedure:
To a solution of 1-(2-bromoethyl)-2-chloro-5-methoxy-4-nitrobenzene (7.0 g, 23.7 mmol) in DMSO (100 mL), triethylamine (8.25 mL, 59.2 mmol) and 4-fluorobenzylamine (3.56 g, 28.5 mmol) were added at room temperature and the mixture stirred for 5 hours. After completion of the reaction, water (500 mL) was added and the mixture was extracted with EtOAc (2×150 mL). The combined organic extracts were washed with water (100 mL), brine (100 mL), dried (Na2SO4) and concentrated under reduced pressure. The crude product was purified by column chromatography on neutral silica gel using 15-20% EtOAc in hexane to give the title compound (1.5 g, 19%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:32][CH2:33][C:34]([F:37])([F:36])[F:35]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[C:14](=[O:17])[N:15]([CH2:32][CH2:33][C:34]([F:37])([F:36])[F:35])[N:16]=[C:10]3[C:9]=2[C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[CH:4][CH:3]=1
Reactant: FC(F)(F)CCBr
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)ccn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1n(CCC(F)(F)F)nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)ccn12
Temperature: 80 °C
Yield: 58.6 %

Procedure:
To a stirring mixture of 7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (50 mg, 0.14 mmol) and K2CO3 (40 mg, 0.28 mmol) in DMF (0.47 mL) at 20° C. was added 3-bromo-1,1,1-trifluoropropane (50 mg, 0.28 mmol). The resulting reaction mixture was heated at 80° C. for 60 min. Analysis by HPLC/MS indicated that starting material had been consumed. The reaction mixture was brought to room temperature, diluted with water, and extracted twice with diethyl ether. The combined organic extract was washed with saturated aqueous NaHCO3 solution, then brine, then dried (MgSO4), filtered, and concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC (acetonitrile-water-TFA) to isolate the title compound (37 mg, 0.082 mmol) as a yellow oil. MS: [M+H]+=452.
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.[CH3:27][CH:28]([CH3:33])[CH2:29][CH2:30][CH2:31][OH:32]>>[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:32][CH2:31][CH2:30][CH2:29][CH:28]([CH3:33])[CH3:27])[CH:7]=1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3F)n2)c1
Reactant: CC(C)CCCO
Product: CC(C)CCCOc1cc(F)ccc1-c1ncnc(Nc2cccc(CS(C)(=O)=O)c2)n1

Procedure:
Starting with 4-(2,4-difluorophenyl)-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine (75 mg; 0.19 mmol), intermediate 42.1, and 4-methylpentan-1-ol (100 μl; 0.789 mmol), example 47 was prepared analogously to the procedure for the preparation of example 42.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:14])[C:5]2[C:10]([C:11](=[O:13])[CH:12]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[H][H]>O1CCCC1.[Pd]>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([OH:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[OH:14]
Reactant: COC1=CC(=O)c2ccccc2C1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: COc1cc(O)c2ccccc2c1O

Procedure:
A solution of 2-methoxy-1,4-naphthoquinone (20.0 g) in tetrahydrofuran (150 mL) was hydrogenated at atmospheric pressure over Pd-C (10%, 0.5 g) until the calculated amount of hydrogen was absorbed, approximately 4 hours. Filtering off the catalyst under an atmosphere of nitrogen gave a solution of the desired product, which was used as such without isolation of the product as the starting material in Examples 1, 2 and 3, infra. Alternatively, the solvent is removed under reduced pressure and the residue recrystallized from diethyl ether/pentane, affording 2-methoxy-1,4-dihydroxynaphthalene.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[CH:14][CH:13]=1.[CH2:21]([O:23][CH:24]([O:30][CH2:31][CH3:32])[C:25](OCC)=[O:26])[CH3:22].Cl>O1CCCC1>[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH2:19][C:25](=[O:26])[CH:24]([O:30][CH2:31][CH3:32])[O:23][CH2:21][CH3:22])=[CH:14][CH:13]=1
Reactant: CC(=O)c1ccc(C)cc1
Reactant: CCOC(=O)C(OCC)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(OCC)C(=O)CC(=O)c1ccc(C)cc1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
A 1.0 M solution of lithium hexamethyldisilazide in THF (310 mmol, 310 mL) was diluted with 20 mL of THF and cooled to -70° C. (internal temperature) with an acetone/dry ice bath under N2. A solution of 4'-methylacetophenone (150 mmol, 20.1 g, 20 mL) in 50 mL of tetrahydrofuran (THF) was added dropwise over a 15 min period, keeping the internal temperature below -60° C. After 1 h, the cooling bath was removed and the temperature was allowed to rise to -25° C. The reaction flask was immersed in an ice/acetone bath and a solution of ethyl diethoxyacetate (160 mmol, 28 g, 28.6 mL) in 20 mL of THF was added dropwise; during the addition, the internal temperature was kept below 0° C. The brown-red solution was stirred for 24 h and was re-cooled to 0° C. Aqueous HCl (3N, 618 mmol, 206 mL) was added carefully (temperature kept below 20° C.) to bring the pH to 3-4. The layers were separated and the aqueous layer was extracted with 200 mL of ether. The combined organic layers were washed twice with brine, dried over Na2SO4, and concentrated to give 40.3 g (100%) Cpd. 46 as an orange oil; 1H NMR (CDCl3, 300 MHz) 1.30 (t, 6H, J=7), 2.42 (s, 3H), 3.5-3.8 (complex, 4H), 4.90 (s, 1H), 6.58 (s, 1H), 7.28 (d, 2H, J=8), 7.74 (d, 2H, J=8), 15.8 (broad s, 1H)
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[NH:13]([C:15]([C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][N:18]=1)=[O:16])[NH2:14]>C(O)(=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:14][NH:13][C:15]([C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][N:18]=1)=[O:16]
Reactant: O=C1Nc2ccc(I)cc2C1=O
Reactant: COC(=O)c1ccc(C(=O)NN)nc1
Solvent: CC(=O)O
Product: COC(=O)c1ccc(C(=O)NN=C2C(=O)Nc3ccc(I)cc32)nc1
Temperature: 100 °C
Yield: 73 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added methyl 6-(hydrazinocarbonyl)nicotinate. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 33 mg of the title compound (73%) as a yellow solid in 89.7% purity by HPLC (Rt: 4.44, gradient of 8 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: CO[C:3](=[O:22])[CH2:4][C:5]1[N:9]2[CH:10]=[C:11]([CH3:14])[CH:12]=[CH:13][C:8]2=[N:7][C:6]=1[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1.[CH3:23][N:24]1[C:28](C(Cl)=O)=[CH:27][N:26]=[CH:25]1>>[CH3:23][N:24]1[C:28]([C:3](=[O:22])[CH2:4][C:5]2[N:9]3[CH:10]=[C:11]([CH3:14])[CH:12]=[CH:13][C:8]3=[N:7][C:6]=2[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[CH:27][N:26]=[CH:25]1
Reactant: COC(=O)Cc1c(-c2ccc(C)cc2)nc2ccc(C)cn12
Reactant: Cn1cncc1C(=O)Cl
Product: Cc1ccc(-c2nc3ccc(C)cn3c2CC(=O)c2cncn2C)cc1

Procedure:
Prepared from (6-methyl-2-p-tolyl-imidazo[1,2-a]pyridin-3-yl)-acetic acid methyl ester 35a and 3-methyl-3H-imidazole-4-carbonyl chloride using the procedure of Method C described above. 1H NMR (400 MHz, CDCl3) 2.34 (s, 3H), 2.39 (s, 3H), 3.91 (s, 3H), 4.52 (s, 2H), 7.05 (dd, J=1.1, 9.1 Hz, 1H), 7.26 (m, 2H), 7.57 (m, 4H), 7.74 (s, 1H), 7.80 (s, 1H). Mass spectrum (m/e) 345 (M+).
Reaction SMILES: Cl[CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:3]1=2.[C:19]([Cu])#[N:20]>C1C=CC=CC=1.CCCCCC>[C:19]([CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:3]1=2)#[N:20]
Reactant: N#C[Cu]
Reactant: COc1ccc2c(c1)C(Cl)c1ccccc1CO2
Solvent: CCCCCC
Solvent: c1ccccc1
Product: COc1ccc2c(c1)C(C#N)c1ccccc1CO2

Procedure:
11-Chloro-2-methoxy-6,11-dihydrodibenz[b,e]oxepin (10.1 g; 0.038 mole) of Example 24A is dissolved in dry benzene (170 ml) and placed under a dry nitrogen atmosphere. To this solution is added in one portion, CuCN (8.5 g; 0.095 mole). The reaction is brought to reflux (twenty minutes), filtered while hot and the salts are washed with benzene. Removal of the solvent in vacuo yields an oil. The oil is dissolved in a minimal amount of benzene and hexane is added with cooling. The resulting solid is filtered and recrystallized from ethanol to give a solid of 11-cyano-2-methoxy-6,11-dihydrodibenz[b,e]oxepin, m.p. 120°-122° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[F:8].[N:12]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.O.[C:26]([OH:30])(=[O:29])[CH:27]=O>C(Cl)Cl>[C:21]([O:20][C:18]([N:12]1[CH2:17][CH2:16][N:15]([CH:27]([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=2)[C:26]([OH:30])=[O:29])[CH2:14][CH2:13]1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: O=CC(=O)O
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(C(C(=O)O)c2ccc(F)c(Cl)c2)CC1

Procedure:
The requisite [4-(tert-butoxycarbonyl)piperazin-1-yl](3-chloro-4-fluorophenyl)acetic acid was synthesized using the following method. (3-Chloro-4-fluorophenyl)boronic acid (440 mg, 2.52 mmol), tert-butyl piperazine-1-carboxylate (469 mg, 2.52 mmol) and glyoxylic acid monohydrate (232 mg, 2.52 mmol) were reacted together in DCM (10 mL) at reflux overnight. The volatiles were removed under reduced pressure. Chromatography of the residue on SiO2 (0-10% MeOH:DCM) afforded the title compound (767 mg, 82%). MS m/z 373.1 (M+H)+, 317.1 (M+H-t-butyl). 1H NMR (300.1 MHz, DMSO) δ12.80 (s, 0.6H), 7.59(d, J=7.2 Hz, 1H), 7.42 (d, J=7.2 Hz, 2H), 4.09(s, 1H), 3.30 (s, 2H), 3.16 (s, 2H), 2.35 (m, 4H), 1.38 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5](C(OCC)=O)[N:4]([C:12]2[C:21]([F:22])=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)[N:3]=1.O[Li].[OH2:25].[OH2:26].[CH3:27]O>>[CH3:27][C:2]1([C:1]([OH:26])=[O:25])[CH:6]=[CH:5][N:4]([C:12]2[C:21]([F:22])=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)[NH:3]1
Reactant: O
Reactant: CCOC(=O)c1cc(C)nn1-c1cc2ccccc2cc1F
Reactant: CO
Agent: [Li]O
Product: CC1(C(=O)O)C=CN(c2cc3ccccc3cc2F)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
The preparation of ethyl 3-methyl-1-(3-fluoro-2-naphthyl)-1H-pyrazole-5-carboxylate was the same as that in Step 3 for Example 3. This ester (13.2 g, 44 mmol) was dissolved in 80 mL methanol. To it were added LiOH.H2O (3.7 g, 49 mmol) and 40 mL water. The mixture was stirred for overnight at room temperature. It was evaporated in vacuuo to remove methanol. The residue was acidified with 1N HCl till pH 1. The mixture was extracted with EtOAc (×4). The organic extracts were combined, dried, evaporated and pumped to dryness to afford 3-methyl-1-(3-fluoro-2-naphthyl)-1H-pyrazolecarboxylic acid in over 90% yield. ES-MS: (M+H)+ 271.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11][OH:12])[N:10]=2)[N:7]=1.[OH:13][C:14]1[CH:15]=[C:16]([NH:20][C:21]([C:23]2[N:27]([CH3:28])[N:26]=[C:25]([CH3:29])[CH:24]=2)=[O:22])[CH:17]=[CH:18][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[OH:12][CH2:11][C:9]1[N:10]=[C:5]2[CH:4]=[CH:3][C:2]([O:13][C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:27]([CH3:28])[N:26]=[C:25]([CH3:29])[CH:24]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[N:7][N:6]2[CH:8]=1
Reactant: Cc1cc(C(=O)Nc2cccc(O)c2)n(C)n1
Reactant: OCc1cn2nc(I)ccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C(=O)Nc2cccc(Oc3ccc4nc(CO)cn4n3)c2)n(C)n1
Temperature: 150 °C
Reaction time: 16 h
Yield: 12.8 %

Procedure:
To a solution of (6-iodoimidazo[1,2-b]pyridazin-2-yl)methanol (400 mg, 1.45 mmol) in N,N-dimethylformamide (4.0 mL) were added N-(3-hydroxyphenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide (504 mg, 2.18 mmol) and potassium carbonate (402 mg, 2.91 mmol), and the mixture was stirred at 150° C. for 16 hr. After cooling the mixture to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate/tetrahydrofuran, washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/ethanol=100/0→10/1) to give the title compound (70 mg, 13%) as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6](=[O:12])[NH:7][CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.Cl.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([NH2:34])[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([NH:34][C:9]([CH2:8][NH:7][C:6](=[O:12])[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:14][CH:13]=2)=[O:11])[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:33])[F:31])[CH:25]=2)=[CH:19][CH:18]=1
Reactant: NC(c1ccc(Cl)cc1)c1cccc(C(F)(F)F)c1
Reactant: O=C(O)CNC(=O)c1ccc(F)cc1
Agent: Cl
Product: O=C(CNC(=O)c1ccc(F)cc1)NC(c1ccc(Cl)cc1)c1cccc(C(F)(F)F)c1

Procedure:
Prepared in analogy to example 1.1 from 4-fluoro-hippuric acid (CA [366-79-0]) and rac-C-(4-chloro-phenyl)-C-(3-trifluoromethyl-phenyl)-methylamine hydrochloride (CA [49703-70-0]).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[O:8].[C:14]1([Mg]Br)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1.CCOC(C)=O>[C:14]1([CH:7]([C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([O:3][C:2]([F:12])([F:13])[F:1])[CH:5]=2)[OH:8])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1cccc(OC(F)(F)F)c1
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OC(c1ccccc1)c1cccc(OC(F)(F)F)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 74.1 %

Procedure:
To a solution of 3-(trifluoromethoxy)benzaldehyde (1.30 g, 6.84 mmol) in anhydrous THF (50 mL) was added phenylmagnesium bromide (1.0 M, 17 mL, 17 mmol) dropwise at 0° C. The resulting mixture was stirred at 80° C. for 3 h. The mixture was cooled to room temperature and diluted with EtOAc (100 mL). The organic layer was washed with saturated NH4Cl (50 mL) and brine (50×2 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by reverse phase Combiflash (50%-55% MeCN in 0.5% NH4HCO3) to give target product (1.36 g, 74%) as a pale yellow oil. LCMS (ESI) m/z: 267.1 [M−H]. 1H-NMR (500 MHz, DMSO-d6): δ 7.44-7.40 (m, 5H), 7.33-7.30 (m, 2H), 7.23-7.18 (m, 2H), 6.13 (d, J=4.0 Hz, 1H), 5.79 (d, J=4.0 Hz, 1H).
Reaction SMILES: O[CH2:2][C:3]1[N:7]([CH:8]([CH3:10])[CH3:9])[CH:6]=[N:5][CH:4]=1.S(Cl)([Cl:13])=O>>[ClH:13].[Cl:13][CH2:2][C:3]1[N:7]([CH:8]([CH3:10])[CH3:9])[CH:6]=[N:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: CC(C)n1cncc1CO
Product: CC(C)n1cncc1CCl
Product: Cl
Temperature: 90 °C

Procedure:
To 5-hydroxymethyl-1-isopropylimidazole (4.5 g), thionyl chloride (20 ml) was added by portions at 0° C., and the mixture was heated for 30 minutes under nitrogen atmosphere at 90° C. The mixture was allowed to be at room temperature. The solvent was distilled off under reduced pressure and the obtained residue was dissolved in methanol and the solvent was distilled off again under reduced pressure. The obtained solid was recrystallized from ethyl acetate, to give 5-chloromethyl-1-isopropylimidazole hydrochloride (6.2 g) as colorless crystals.