Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:13])[CH2:9][C:10]([OH:12])=O)=[CH:3][CH:2]=1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl.FC(F)(F)C(O)=O.[Br:58][C:59]1[CH:72]=[CH:71][CH:70]=[CH:69][C:60]=1[O:61][CH:62]1[CH2:67][CH2:66][N:65](N)[CH2:64][CH2:63]1>CN(C=O)C.O>[C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:2]=[CH:3][C:4]([NH:7][C:8](=[O:13])[CH2:9][C:10]([N:65]2[CH2:64][CH2:63][CH:62]([O:61][C:60]3[CH:69]=[CH:70][CH:71]=[CH:72][C:59]=3[Br:58])[CH2:67][CH2:66]2)=[O:12])=[CH:5][CH:6]=1
Reactant: NN1CCC(Oc2ccccc2Br)CC1
Reactant: O=C(O)CC(=O)Nc1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC(=O)N1CCC(Oc2ccccc2Br)CC1)Nc1ccc(-c2ccccc2)cc1
Temperature: 10 °C
Reaction time: 8 h
Yield: 31.5 %

Procedure:
To a stirred solution of N-biphenyl-4-yl-malonamic acid (0.075 g, 0.00029 mole) in DMF (2.0 mL) was added HOBt (0.042 g, 0.00031 mole) and DIPEA (0.083 g, 0.00065 mole). The mixture was cooled to 10° C. and EDCI.HCl (0.060 g, 0.00031 mole) followed by 4-(2-bromo-phenoxy)-piperidin-1-ylamine trifluoroacetate (0.106 g, 0.00029 mole) were added. The mixture was stirred at the ambient temperature overnight. The mixture was then diluted with water and the product was extracted with ethyl acetate. The organic layer was washed with brine and concentrated. The resulting residue was purified by column chromatography using silica gel 60-120 mesh (40% ethyl acetate in hexane) to afford 0.045 g (31%) of N-biphenyl-4-yl-3-[4-(2-bromo-phenoxy)-piperidin-1-yl]-3-oxo-propionamide. LCMS: 493 (M+1)+, 94.19%, 1H NMR (CDCl3): δ 10.0 (s, 1H), 7.66 (d, 2H), 7.58 (m, 5H), 7.44 (t, 2H), 7.32 (m, 1H), 6.9 (m, 2H), 4.52 (m, 1H), 4.15 (m, 1H), 3.56 (m, 1H), 3.54 (m, 2H), 3.51 (d, 2H), 2.0 (m, 2H), 1.8 (m, 2H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14](=[O:35])[NH:15][CH:16]([CH2:26][CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[C:20]1([CH2:19][CH2:18][CH2:17][CH:16]([NH:15][C:14]([CH:10]2[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]2)=[O:35])[CH2:26][CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)NC(CCCc2ccccc2)CCCc2ccccc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCCNC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92.5 %

Procedure:
3-[4-Phenyl-1-(3-phenyl-propyl)-butylcarbamoyl]-piperidine-1-carboxylic acid tert-butyl ester (12) (0.202 g; 0.42 mmol) is dissolved in methylene chloride (5 mL) at ambient temperature. Trifluoroacetic acid (5 mL) is added in a slow stream, and the solution is stirred for 90 minutes at ambient temperature. The solution is concentrated in vacuo at 40° C. The residue is slurried in a mixture of methylene chloride (10 mL) and water (100 mL), then potassium carbonate is added until the slurry is alkaline. The slurry is diluted with water (50 mL) then extracted with methylene chloride (3×50 mL). The organic extracts are dried over MgSO4, filtered, and concentrated in vacuo affording the desired product (0.147 g) as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.N[C:11]1C=CC(Cl)=NC=1>>[CH3:9][O:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][CH3:11])=[CH:7][N:6]=1
Reactant: COc1ccc(N)cn1
Reactant: Nc1ccc(Cl)nc1
Product: CNc1ccc(OC)nc1

Procedure:
The reaction procedure of Reference Example 24 was repeated except that 5-amino-2-methoxypyridine was used in lieu of 5-amino-2-chloropyridine to give the title compound as a yellow oil.
Reaction SMILES: C(OC([NH:11][C@:12]1([PH:20]([NH:22][C:23](=[O:31])[NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:21])[CH2:17][CH2:16][CH2:15][N:14]([NH2:18])[C:13]1=[O:19])=O)C1C=CC=CC=1>C(O)C.[Pd]>[NH2:11][C:12]1([PH:20]([NH:22][C:23](=[O:31])[NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:21])[CH2:17][CH2:16][CH2:15][N:14]([NH2:18])[C:13]1=[O:19]
Reactant: NN1CCC[C@](NC(=O)OCc2ccccc2)([PH](=O)NC(=O)Nc2ccccc2)C1=O
Agent: [Pd]
Solvent: CCO
Product: NN1CCCC(N)([PH](=O)NC(=O)Nc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Palladium black (5 mg) was added to a solution of (3S)-3-benzyloxycarbonylamino-1-amino(phenylcarbamoylamino)phosphinyl-2-piperidone (30 mg, 0.067 mmol) in ethanol (10 mL), and the resulting mixture was stirred at room temperature for 24 hours under a hydrogen atmosphere.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1(C2OC3C=CC=CC=3C=2)[CH2:10][CH:9]1CO)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:23][C:24]1[O:25][C:26]2[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=2[CH:28]=1.C(OC(C1([Li])CC1)=O)(C)(C)C>>[C:1]([O:5][C:6]([C:8]1([CH2:23][C:24]2[O:25][C:26]3[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=3[CH:28]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)C1(c2cc3ccccc3o2)CC1CO
Reactant: BrCc1cc2ccccc2o1
Agent: [Li]C1(C(=O)OC(C)(C)C)CC1
Product: CC(C)(C)OC(=O)C1(Cc2cc3ccccc3o2)CC1

Procedure:
An appropriately substituted bromobenzofuran is converted to the corresponding aldehyde as described supra. This aldehyde is then reacted with 1-tert-butoxycarbonylcyclopropyllithium essentially as described by Haener et al. (Helvetica Chimica Acta, 69, 1655–65 (1986)) to provide the corresponding 1-tert-butoxycarbonyl-1-(benzofuryl)hydroxymethylcyclopropane. The alcohol is reduced to methylene by treating the corresponding acetate with samarium(II) iodide as described supra. The resulting tertbutyl ester is subjected to standard Curtius rearrangement conditions to provide the corresponding N-tert-butoxycarbonyl 1-amino-1-(benzofuryl)methylcyclopropane. This compound is deprotected by treatment with acid to provide the compounds of the present invention. If necessary or desired, the starting aldehyde may be reduced to the corresponding alcohol and then converted to the corresponding bromomethylbenzofuran. This reagent is then reacted with 1-tert-butoxycarbonylcyclopropyllithium essentially as described by Haener, to provide 1-tert-butoxycarbonyl-1-(benzofuryl)methylcyclopropane which is then subjected to the Curtius rearrangement/deprotection sequence described supra to provide the compounds of the present invention.
Reaction SMILES: [CH3:1][N:2]1[C@@H:7]2[CH2:8][C:9]([CH2:11][C@H:3]1[CH2:4][CH2:5][CH2:6]2)=O.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>C1(C)C=CC=CC=1.Cl[Ti](Cl)(Cl)Cl>[CH3:1][N:2]1[CH:3]2[CH2:4][CH2:5][CH2:6][CH:7]1[CH2:8][C:9]([N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)=[CH:11]2
Reactant: CN1[C@@H]2CCC[C@H]1CC(=O)C2
Reactant: C1CCNC1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CN1C2C=C(N3CCCC3)CC1CCC2
Temperature: 25 °C
Reaction time: 48 h
Yield: 98.9 %

Procedure:
To pseudo-pelletierine (1.5 g, 9.8 mmol) in toluene (75 mL) was added pyrrolidine (4.9 mL, 58.75 mmol). TiCl4 (0.66 mL, 6.0 mmol) in toluene (10 mL) was then added to the mixture at −5° C. The reaction mixture was left to warm up to rt and stirred for 2 days. The mixture was filtered and the filtrate was concentrated to a residue and toluene (100 mL) was added and the mixture was filtered again. The filtrate was concentrated to a residue to afford the product (2.0 g, 100%) as yellow oil.
Reaction SMILES: [C:1]([C:3]1[C:4]([N:10]=[CH:11][N:12](C)C)=[N:5][C:6]([CH3:9])=[CH:7][CH:8]=1)#[N:2].[Br:15][C:16]1[CH:17]=[CH:18][C:19]([S:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:20](N)[CH:21]=1>C(O)(=O)C>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([S:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:18]([NH:2][C:1]2[C:3]3[CH:8]=[CH:7][C:6]([CH3:9])=[N:5][C:4]=3[N:10]=[CH:11][N:12]=2)[CH:17]=1
Reactant: Nc1cc(Br)ccc1Sc1ccccc1
Reactant: Cc1ccc(C#N)c(N=CN(C)C)n1
Solvent: CC(=O)O
Product: Cc1ccc2c(Nc3cc(Br)ccc3Sc3ccccc3)ncnc2n1
Temperature: 130 °C
Yield: 65.2 %

Procedure:
A mixture of the product from Example 10B (0.188 g, 1.0 mmol) and 5-bromo-2-(phenylthio)benzenamine (0.280 g, 1.0 mmol) in glacial acetic acid (2 mL) was heated in a 130° C. oil bath for 30 min. The reaction mixture was then cooled to room temperature and the solvent evaporated under reduced pressure. The residue was triturated with methanol, and the resulting solid isolated by vacuum filtration and dried to provide the title compound (0.276 g, 65% yield) as a beige solid.
Reaction SMILES: C(OC[O:5][CH:6]1[CH2:24][CH:23]2[N:8]([C:9](=[O:45])[N:10](CC3C=CC(OC)=CC=3)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]=[CH:17][CH:18]3[C:20]([C:26]([NH:28][S:29]([C:32]4(C)[CH2:34][CH2:33]4)(=[O:31])=[O:30])=[O:27])([NH:21][C:22]2=[O:25])[CH2:19]3)[CH2:7]1)C.Cl.C(=O)([O-])O.[Na+]>C1COCC1.CO>[OH:5][CH:6]1[CH2:24][CH:23]2[N:8]([C:9](=[O:45])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]=[CH:17][CH:18]3[C:20]([C:26]([NH:28][S:29]([CH:32]4[CH2:33][CH2:34]4)(=[O:31])=[O:30])=[O:27])([NH:21][C:22]2=[O:25])[CH2:19]3)[CH2:7]1
Reactant: CCOCOC1CC2C(=O)NC3(C(=O)NS(=O)(=O)C4(C)CC4)CC3C=CCCCCCN(Cc3ccc(OC)cc3)C(=O)N2C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C1NC2(C(=O)NS(=O)(=O)C3CC3)CC2C=CCCCCCNC(=O)N2CC(O)CC12
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.3 %

Procedure:
A solution of the acetal 139 (0.038 g, 0.06 mmol) in 1:1:1 THF-methanol-2 M aq. hydrochloric acid (1.5 ml) was stirred at rt for 30 min, then additional conc. hydrochloric acid (0.1 ml) was added and then stirred at rt overnight. The reaction mixture was then neutralized using aq. saturated sodium hydrogen carbonate, then concentrated onto silica. Flash chromatography of the residue using 9:1 ethyl acetate-methanol gave a colorless foam (0.020 g, 73%). LR-MS: Calcd for C20H29N4O6S: 453. Found: 453 [M−H].
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.[CH3:11]O>>[CH3:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1
Reactant: CO
Reactant: Cc1cnc(C(=O)O)cn1
Product: COC(=O)c1cnc(C)cn1
Reaction time: 8 h
Yield: 93 %

Procedure:
The reaction was carried out, under nitrogen, in a 1 L×4 neck flask equipped with a mechanical stirrer, water condenser (with gas inlet), and a thermocouple. The reactor was charged with 5-methylpyrazinecarboxylic acid (100 g), and acidic cation exchange resin (20 g), and methanol (300 g). The mixture was stirred at reflux for about 20 h. After the reaction was complete (analyze with GC or GC/MS), the resin was removed by pressure filtration. The resin was rinsed with methanol and about 75% of the solvent was removed under reduced pressure. The resulting suspension was allowed to stand at room temperature overnight, and then in an ice-bath for 3 h. The solid was collected by filtration and washed with ice-cold methanol (2×80 g). Drying under vacuum at room temperature (25 inches of Hg) yielded 102.4 g (93%) of 5-methyl-2-pyrazinecarboxylic acid, methyl ester that was suitable for further use.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[NH2:9][CH2:10][CH2:11][CH2:12][NH2:13]>N1C=CC=CC=1>[NH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1
Reactant: NCCCN
Reactant: Cc1ccc(Br)nc1
Solvent: c1ccncc1
Product: Cc1ccc(NCCCN)nc1

Procedure:
2-Bromo-5-methylpyridine (17.2 g), 1,3-diaminopropane (37 g) and pyridine (10 ml) were heated together under reflux for 6 hr. The mixture was stripped to remove excess diaminopropane and the residue taken up in water. The pH was adjusted to 7.5 with conc. hydrochloric acid and extracted with chloroform. The aqueous solution was basified with conc. sodium hydroxide to pH 14 and extracted again with chloroform. The extracts were dried (K2CO3) and stripped to give 2-(3-aminopropylamino)-5-methylpyridine as an oil (9.95 g; 60%) which was used without further purification.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]2[C:14](=[O:22])[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:16][N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][N:6]3[CH3:23].[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>CCOCC>[F:1][C:2]1[C:11]([F:12])=[C:10]([NH:31][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:9]2[C:14](=[O:22])[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:16][N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][N:6]3[CH3:23]
Reactant: NCc1ccccc1
Reactant: CCOC(=O)c1cn2c3c(c(F)c(F)c(F)c3c1=O)CCN2C
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: CCOC(=O)c1cn2c3c(c(F)c(F)c(NCc4ccccc4)c3c1=O)CCN2C
Temperature: 80 °C
Yield: 75.1 %

Procedure:
62 mg of the compound (198) obtained in Example 69 and 50 mg of benzylamine were added to 2 ml of toluene, and the solution was heated at 80° C. for 24 hours. The reaction solution was added to chloroform and was washed with aqueous 5% citric acid solution. After drying over magnesium sulfate, the solvent was removed by distillation. Obtained solids were dispersed in ether and filtered off to obtain 59 mg of the subject compound (200) in a 74% yield.
Reaction SMILES: [N+:1]([C:4]1[C:5]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[CH:6][C:7]([NH2:23])=[C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:9]=1)([O-])=O>C(O)C.[Ni]>[NH2:23][C:7]1[CH:6]=[C:5]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:4]([NH2:1])=[CH:9][C:8]=1[O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCCCOc1cc([N+](=O)[O-])c(OCCCCCCCCCCCC)cc1N
Agent: [Ni]
Solvent: CCO
Product: CCCCCCCCCCCCOc1cc(N)c(OCCCCCCCCCCCC)cc1N
Yield: 74.4 %

Procedure:
The product of Stage 5 (4.0 g) is dissolved with heating in 250 ml of ethanol and catalytically hydrogenated with Raney nickel at 50° C./50 atms pressure. Concentration of the hydrogenation solution after the nickel has been filtered off under suction gives 2.8 g of a product melting at 75°-76° C.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH2:11])[N:10]=2)[CH:5]=[CH:6][N:7]=1.[IH:12].[OH-].[Na+]>O>[I:12][C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH2:11])[N:10]=2)[CH:5]=[CH:6][N:7]=1
Reactant: I
Reactant: Nc1nc2c(Cl)nccn2n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1nc2c(I)nccn2n1
Temperature: 50 °C
Reaction time: 16 h
Yield: 92.7 %

Procedure:
8-Chloro-[1,2,4]triazolo[1,5-a]pyrazin-2-ylamine (5.500 g; 32.43 mmol) is suspended in water (40.0 ml) before HI (67%, 21.855 ml; 194 mmol) is added. The mixture is stirred at 50° C. for 16 h and monitored by HPLC. The mixture is cooled to Rt, diluted with water. After adding NaOH till pH 14 is reached, the resulting suspension is cooled to 0° C. and all solids are filtered off giving 8-Iodo-[1,2,4]triazolo[1,5-a]pyrazin-2-ylamine (7.850 g; 30.074 mmol) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][CH2:7][C:8]3[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=3[CH:10]([C:11](O)=[O:12])[C:4]=2[CH:3]=1.[Cl:20][C:21]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:22]=1[NH2:23]>>[Br:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][CH2:7][C:8]3[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=3[CH:10]([C:11]([NH:23][C:22]3[C:21]([Cl:20])=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:28])=[O:12])[C:4]=2[CH:3]=1
Reactant: Nc1c(Cl)cccc1Cl
Reactant: O=C(O)C1c2ccccc2COc2ccc(Br)cc21
Product: O=C(Nc1c(Cl)cccc1Cl)C1c2ccccc2COc2ccc(Br)cc21
Yield: 18.4 %

Procedure:
The similar procedures as in Example 1 were repeated except using 1.67 g of 2-bromo-6,11-dihydrodibenz[b,e]oxepin-11-carboxylic acid obtained in Example 46 (Compound H) in place of Compound A and 0.76 g of 2,6-dichloroaniline in place of aniline to obtain 0.40 g of Compound 39.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([OH:9])=[O:8].OS(O)(=O)=O.[CH3:15]O>>[CH3:15][O:8][C:7]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][N:1]=1)=[O:9]
Reactant: O=C(O)c1cnccn1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cnccn1
Yield: 59 %

Procedure:
A solution of 2-pyrazinecarboxylic acid (2.00 g, 16.1 mmol) and H2SO4 (catalytic) in MeOH (50 mL) was heated at reflux for 45 minutes, then concentrated in vacuo. The residue was partitioned between EtOAc (40 mL) and saturated NaHCO3(aq) (20 mL). The organic phase was washed with saturated NaHCO3(aq) (20 mL) and brine (10 mL), then dried (MgSO4) and concentrated in vacuo to give colourless crystals (1.32 g, 59%). 1H NMR (CDCl3) □ 4.04 (s, 3H), 8.72 (dd, 1H, J=2.4, 1.2 Hz), 8.77 (d, 1H, J=2.4 Hz), 9.32 (d, 1H, J=1.2 Hz).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[CH:5]2.[CH2:17]([OH:20])[C:18]#[CH:19]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C(N(CC)CC)C>[O:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH:11]1[N:7]1[C:8]2[C:4](=[CH:3][C:2]([C:19]#[C:18][CH2:17][OH:20])=[CH:10][CH:9]=2)[CH:5]=[N:6]1
Reactant: C#CCO
Reactant: Brc1ccc2c(cnn2C2CCCCO2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: OCC#Cc1ccc2c(cnn2C2CCCCO2)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 86.6 %

Procedure:
A 500 mL three-necked round bottom flask was charged with 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (14.0 g, 50 mmol; Intermediate 1) and triethylamine (300 mL). The flask was degassed with 3 cycles of vacuum/N2, followed by the addition of Pd(PPh3)2Cl2 (3.5 g, 5 mmol) and CuI (0.95 g, 5 mmol) under N2 atmosphere. The flask was again degassed with 3 cycles of vacuum/N2. Prop-2-yn-1-ol (8.4 g, 150 mmol) was added via syringe and the reaction mixture was stirred at 80° C. for 16 hours. Upon completion, the solvent was evaporated. The residue was diluted with dichloromethane (400 mL), washed with water (3×200 mL) and brine (200 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was further purified on silica gel column (1:100-1:20 EtOAc/petroleum ether) affording the title compound (11.1 g). 1H NMR (400 MHz, DMSO-d6): δ 8.13 (s, 1H), 7.90 (s, 1H), 7.75 (d, 1H), 7.44 (d, 1H), 5.86 (dd, 1H), 5.33 (t, 1H), 4.33 (d, 2H), 3.89-3.86 (m, 1H), 3.79-3.73 (m, 1H), 2.45-2.35 (m, 1H), 2.05-1.95 (m, 2H), 1.80-1.70 (m, 1H), 1.60-1.56 (m, 2H); LCMS: 257 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:9][CH2:8][C:7]([CH2:11][OH:12])([CH3:10])[C:6]1=[O:13])=[O:4].C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31].O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)[CH2:9][CH2:8][C:7]([CH2:11][O:12][S:30]([CH3:29])(=[O:32])=[O:31])([CH3:10])[C:6]1=[O:13])=[O:4]
Reactant: COC(=O)C1(Cc2ccc(Cl)cc2)CCC(C)(CO)C1=O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)C1(Cc2ccc(Cl)cc2)CCC(C)(COS(C)(=O)=O)C1=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
In 20 ml of methylene chloride, 1.00 g of Compound 2-1 obtained in Production Example 1 was dissolved. To the solution thus obtained, 0.68 ml of triethylamine and 0.324 ml of methanesulfonyl chloride were added. Thereafter, the resulting mixture was stirred at room temperature for 1.5 hours. After the reaction, water was added to the reaction solution thus obtained, and extraction with ethyl acetate was then carried out. The organic layer thus extracted was washed with an aqueous solution of sodium hydrogen carbonate and saturated brine and then dried over anhydrous sodium sulfate. The solvent was distilled away, and the residue was then purified by silica gel column chromatography to obtain 1.141 g of Compound 3-1-1.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:13])[NH:7]2.[H-].[Na+].[CH2:16](I)[CH:17]=[CH2:18].O>CN(C=O)C>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:13])[N:7]2[CH2:18][CH:17]=[CH2:16]
Reactant: C=CCI
Reactant: O=c1ccc2c(F)cc(F)cc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCn1c(=O)ccc2c(F)cc(F)cc21
Temperature: 25 °C
Yield: 44.7 %

Procedure:
A suspension of 5,7-difluoro-2(1H)-quinolinone (640 mg, 3.54 mmol) in DMF (15 ml) under argon at 0° C. was treated with sodium hydride (60% in mineral oil, 312 mg, 7.8 mmol) and then it was warmed up at rt. After 0.5 h at rt allyl iodide (0.72 mL, 7.8 mmol) was added. After 0.5 h sodium hydride (60% in mineral oil, 200 mg, 5 mmol) and allyl iodide (0.35 ml, 3.8 mmol) were added. Water (15 ml) was added and the aqueous was extracted using DCM (3×50 ml). The combined organic phases were dried, evaporated and the residue was chromatographed on silica gel, eluting with 0-4% MeOH-DCM to afford 350 mg of the desired compound (45%).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[O:3][C:4]1[CH:25]=[CH:24][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:20](=[O:21])[CH:19]=[C:18]([CH3:22])O[C:16]=3[CH3:23])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1.[NH3:28]>C(O)C>[F:1][C:2]([F:27])([F:26])[O:3][C:4]1[CH:25]=[CH:24][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:20](=[O:21])[CH:19]=[C:18]([CH3:22])[NH:28][C:16]=3[CH3:23])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1
Reactant: N
Reactant: Cc1cc(=O)c(-c2ccc(Oc3ccc(OC(F)(F)F)cc3)cc2)c(C)o1
Solvent: CCO
Product: Cc1cc(=O)c(-c2ccc(Oc3ccc(OC(F)(F)F)cc3)cc2)c(C)[nH]1

Procedure:
3-(4-(4-Trifluoromethoxyphenoxy)phenyl)-2,6-dimethylpyran-4-one (4.1 g) was dissolved in ethanol (10 ml) and heated in a stainless steel autoclave with 0.880 ammonia (35 ml) at 150° for 24 hr. After cooling the crystalline precipitate was filtered off, washed with ethyl acetate and dried in vacuo to afford the title compound (2.78 g), m.p. 244°-248°, NMR δH (d6 -DMSO) 11.1 (1H, br. s) 7.4 (2H, m), 7.1-7.3 (4H, m), 7.02 (2H, m), 5.95 (1H, s), 2.2 (3H, s), 2.08 (3H, s).
Reaction SMILES: FC(F)(F)C1C=CC=C(C(F)(F)F)C=1.[F:15][C:16]([F:27])([F:26])[C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1.[H][H]>O>[F:15][C:16]([F:26])([F:27])[C:17]1[CH:25]=[CH:24][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=1
Reactant: [H][H]
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Agent: FC(F)(F)c1cccc(C(F)(F)F)c1
Solvent: O
Product: O=Cc1ccc(C(F)(F)F)cc1
Temperature: 105 °C
Yield: 54 %

Procedure:
1 g of 5% palladium on barium sulfate (recovered from Example 1) and 100 g of 4-trifluoromethylbenzoyl chloride were placed in a reaction vessel at room temperature with exclusion of water. A gentle stream of hydrogen gas was then introduced at atmospheric pressure. The mixture was subsequently heated to 100-110° C. and hydrogen gas was introduced continuously at atmospheric pressure. After liberation of acidic offgases had ceased (6.5 hours), the mixture was cooled to room temperature, the catalyst was removed by filtration, and the filtrate was distilled at 33 mbar. At a boiling point of 82-86° C., 4-trifluoromethylbenzaldehyde was obtained in a yield of 45.9 g. This corresponds to a yield of 54% of theory.