Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:19]1[CH2:24][C:23](=[O:25])[O:22][C:20]1=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[NH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][OH:33]>>[OH:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][N:26]1[C:23](=[O:25])[CH2:24][CH:19]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:20]1=[O:22]
Reactant: CCCCCCCCCCCCCCCCCCC1CC(=O)OC1=O
Reactant: NCCCCCCO
Product: CCCCCCCCCCCCCCCCCCC1CC(=O)N(CCCCCCO)C1=O
Yield: 69 %

Procedure:
A 300 mL reaction flask was charged with 63.2 g of octadecyl succinic anhydride (manufactured by Tokyo Chemical Industry Co., Ltd.) and 21.0 g of 6-amino-1-hexanol (manufactured by Tokyo Chemical Industry Co., Ltd.), and the resulting mixture was reacted at 160° C. for 3.5 hours under continuous nitrogen purging and with vigorous stirring. The reaction product was purified by silica gel column chromatography, yielding 55.87 g of N-(6-hydroxyhexyl)octadecyl succinimide (yield: 69.0%).
Reaction SMILES: [OH:1][C:2]1[CH:30]=[CH:29][C:5]([C:6]([C:8]2[CH:28]=[CH:27][C:11]([CH2:12][S:13][C:14]3[N:23]([CH3:24])[C:22](=[O:25])[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][C:20]=4[CH3:26])[N:15]=3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:31][N:32]([CH3:36])[C:33](Cl)=[O:34].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:24][N:23]1[C:22](=[O:25])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[CH3:26])[N:15]=[C:14]1[S:13][CH2:12][C:11]1[CH:27]=[CH:28][C:8]([C:6](=[O:7])[C:5]2[CH:4]=[CH:3][C:2]([O:1][C:33](=[O:34])[N:32]([CH3:36])[CH3:31])=[CH:30][CH:29]=2)=[CH:9][CH:10]=1
Reactant: Cc1cccc2nc(SCc3ccc(C(=O)c4ccc(O)cc4)cc3)n(C)c(=O)c12
Reactant: CN(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc2nc(SCc3ccc(C(=O)c4ccc(OC(=O)N(C)C)cc4)cc3)n(C)c(=O)c12

Procedure:
A solution of 2-[4-(4-hydroxybenzoyl)benzylthio]-3,5-dimethyl-4(3H)-quinazolinone (478 mg), dimethylcarbamoyl chloride (0.15 ml) and potassium carbonate (315 mg) in DMF (7 ml) was stirred at 50° C. for 48 hours. This reaction mixture was concentrated and the residue was dissolved in ethyl acetate. The solution was washed with water, dried, and concentrated. The residue was recrystallized from ethyl acetate to provide the title compound as colorless solid (346 mg).
Reaction SMILES: Cl[C:2]1[C:3]([C:12]([F:15])([F:14])[F:13])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.[F:16][C:17]([F:21])([F:20])[CH2:18][OH:19].[OH-].[K+].Cl>CS(C)=O.O>[N+:9]([C:5]1[CH:4]=[C:3]([C:12]([F:15])([F:14])[F:13])[C:2]([O:19][CH2:18][C:17]([F:21])([F:20])[F:16])=[CH:7][C:6]=1[NH2:8])([O-:11])=[O:10]
Reactant: Nc1cc(Cl)c(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: OCC(F)(F)F
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 23 °C
Reaction time: 96 h
Yield: 98 %

Procedure:
Commercially available 5-chloro-2-nitro-4-trifluoromethyl-phenylamine [CAS-No. 35375-74-7] (72.2 g, 300 mmol) was dissolved in DMSO (600 mL) and 2,2,2-trifluoroethanol (270 mL) were added at 23° C., the slightly exothermic reaction was cooled with a ice bath. KOH (85%, 99.0 g, 1500 mmol) were added slowly and the dark red reaction mixture was stirred at 23° C. for 4 days. Transferred into a 3 L flask and 1500 ml H2O were added under ice bath cooling, acidified with 3 N HCl and stirred at 23° C. for 3 h, filtered off the yellow precipitate, washed with H2O and dried in air at 60° C. to give the title compound as a yellow solid (89.47 g, 98%). MS (ISN) 303.1 [M−H].
Reaction SMILES: N[C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5].[BrH:10].N([O-])=O.[Na+]>O.C(OCC)C>[Br:10][C@@H:2]([CH2:3][C:4]([OH:6])=[O:5])[C:7]([OH:9])=[O:8]
Reactant: Br
Reactant: N[C@@H](CC(=O)O)C(=O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: O=C(O)C[C@H](Br)C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 51 %

Procedure:
To a 500 mL round bottom flask was added L-aspartic acid ((S)-aspartic acid, 25 g, 188 mmol) and 245 mL of 5 N HBr. The reaction was cooled in an ice bath to 0-50° C., followed by the dropwise addition of sodium nitrite (20.7 g, 301 mmol) in 75 mL of water over five hours. The temperature was maintained below 50° C. during the addition. After the addition was complete, the reaction was allowed to stir for 12 hours at 23-25° C. The reaction was diluted with diethyl ether (120 mL). The aqueous layer was removed and the organic phase was washed with 1 N HCl (100 mL). The combined aqueous phases were washed with EtOAc (100 ml). The combined organic extracts were dried (MgSO4), filtered and concentrated under reduced pressure to leave the product as a slightly yellow solid. The solid was recrystallized from EtOAc (˜100 mL) and hexanes (˜10 mL) to obtain the product (19.03 g, 97 mmol, 51%) as a white crystalline solid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3](O)=O.FC(F)(F)C(O)=O.[CH:15]([C@:18]1([C:24]([N:26]2[CH2:31][CH2:30][N:29]([C:32]3[CH:37]=C[CH:35]=[C:34](CC(F)(F)F)[CH:33]=3)[CH2:28][CH2:27]2)=[O:25])[CH2:22][CH2:21][C@@H:20]([NH2:23])[CH2:19]1)([CH3:17])[CH3:16].[O:43]1[CH2:48][CH2:47][C:46](=O)[CH2:45][CH2:44]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CCOC(C)=O>[CH:15]([C@:18]1([C:24]([N:26]2[CH2:31][CH2:30][N:29]([C:32]3[CH:33]=[CH:34][CH:35]=[C:3]([C:2]([F:7])([F:6])[F:1])[CH:37]=3)[CH2:28][CH2:27]2)=[O:25])[CH2:22][CH2:21][C@@H:20]([NH:23][CH:46]2[CH2:47][CH2:48][O:43][CH2:44][CH2:45]2)[CH2:19]1)([CH3:17])[CH3:16]
Reactant: CC(C)[C@]1(C(=O)N2CCN(c3cccc(CC(F)(F)F)c3)CC2)CC[C@@H](N)C1
Reactant: O=C1CCOCC1
Reactant: O=C(O)C(F)(F)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)[C@]1(C(=O)N2CCN(c3cccc(C(F)(F)F)c3)CC2)CC[C@@H](NC2CCOCC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1R,3S)-3-isopropyl-3-({4-[3-(trifluoro ethyl)phenyl]piperazin-1-yl}carbonyl)cyclopentanamine bis(trifluoroacetate) (98 mg, 0.16 mmol), tetrahydro-4H-pyran-4-one (0.044 mL, 0.48 mmol) and triethylamine (0.067 mL, 0.48 mmol) in methylene chloride (5 mL) was added sodium triacetoxyborohydride (68 mg, 0.32 mmol). After being stirred at room temperature overnight, the reaction mixture was diluted with EtOAc and washed with saturated Na2CO3. The aqueous layer was extracted with EtOAc three times. The combined organic layers were dried (MgSO4), concentrated and purified on silica gel eluting with EtOAc to 1% Et3N/EtOAc providing 63 mg (84%) of the desired product, which was further purified by HPLC to give the product as diTFA salt. MS calculated for C25H36F3N3O2: (M+H) 468; found 468.2.
Reaction SMILES: C([N:9]1[C:13](=[O:14])[C:12]([CH:16]([CH3:18])[CH3:17])([CH3:15])[N:11]=[C:10]1[C:19]1[N:28]=[CH:27][C:26]([CH2:29]Br)=[CH:25][C:20]=1[C:21](OC)=[O:22])(=O)C1C=CC=CC=1.[C-:31]#[N:32].[Na+].[OH2:34]>C(O)C>[C:31]([CH2:29][C:26]1[CH:27]=[N:28][C:19]([C:10]2[NH:9][C:13](=[O:14])[C:12]([CH:16]([CH3:17])[CH3:18])([CH3:15])[N:11]=2)=[C:20]([CH:25]=1)[C:21]([OH:22])=[O:34])#[N:32]
Reactant: COC(=O)c1cc(CBr)cnc1C1=NC(C)(C(C)C)C(=O)N1C(=O)c1ccccc1
Reactant: O
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCO
Product: CC(C)C1(C)N=C(c2ncc(CC#N)cc2C(=O)O)NC1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 1.0 g of 2-(1-benzoyl-4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)-5-bromomethyl-nicotinic acid, methyl ester, in 60 mL ethanol is added 0.24 g sodium cyanide, followed by 10 cc water. The resulting solution is stirred at room temperature for 24 hours and concentrated in vacuo. The residue is partitioned between methylene chloride and water. The aqueous phase is acidified to pH 3 and extracted with methylene chloride, and the combined organic phases are dried and concentrated in vacuo. Chromatography of the residue on silica gel using methylene chloride-methanol mixtures affords the desired product, mp 196°-200° (dec).
Reaction SMILES: [C:1]([O:7][CH2:8][CH2:9][Br:10])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[N+:11]([C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O)([O-:13])=[O:12].C(O)(=O)C.N1CCCCC1>C(O)(C)C>[N+:11]([C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=[C:2]([C:3]([CH3:5])=[O:4])[C:1]([O:7][CH2:8][CH2:9][Br:10])=[O:6])([O-:13])=[O:12]
Reactant: CC(=O)CC(=O)OCCBr
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Solvent: CC(C)O
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)OCCBr

Procedure:
405 g of 2-bromoethyl acetoacetate are dissolved in 1500 ml of isopropanol. 293 g of 3-nitrobenzaldehyde, 4.6 g of acetic acid and 6.8 g of piperidine are added while stirring. The mixture is stirred at 40° C. until a clear solution has formed. The solution is allowed to cool slowly, seeded with a few crystals of the title compound and stirred at room temperature for 48 h and then cooled, and the product is filtered off under suction, washed with cold isopropanol and dried in vacuo at 50° C. 495 g of the title compound of m.p. 94.5°-95.5° C. are obtained.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[C:4]([CH:5]=O)[C:3]=1[OH:11].CO[C:14]1[CH:19]=CC(O)=C[CH:15]=1.C1N2CC[N:23](CC2)C1>C(#N)C=C>[F:10][C:8]1[CH:7]=[C:4]2[C:3](=[C:2]([F:1])[CH:9]=1)[O:11][CH2:15][C:14]([C:19]#[N:23])=[CH:5]2
Reactant: O=Cc1cc(F)cc(F)c1O
Reactant: COc1ccc(O)cc1
Reactant: C1CN2CCN1CC2
Solvent: C=CC#N
Product: N#CC1=Cc2cc(F)cc(F)c2OC1
Temperature: 75 °C

Procedure:
84 g (0.531 mol) of 3,5-difluorosalicylaldehyde are dissolved in 850 ml of acrylonitrile, 1 g (8 mmol) of p-methoxyphenol and 18 g (0.16 mol) of DABCO are added, and the mixture is heated overnight at 75° C. The batch is evaporated, the residue is taken up in dichloromethane, and the solution is filtered through silica gel, giving 6,8-difluoro-2H-chromene-3-carbonitrile, which is sufficiently pure for further reactions.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[C:14]([CH3:18])=[CH:15][CH:16]=[CH:17][C:12]3=[N:11][C:10]=2[CH:19]([NH2:21])[CH3:20])[CH:5]=[C:6]([F:8])[CH:7]=1.Br[C:23]1[N:31]=[CH:30][N:29]=[C:28]2[C:24]=1[N:25]=[CH:26][NH:27]2.C(N(CC)C(C)C)(C)C>C(O)C.CO>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[C:14]([CH3:18])=[CH:15][CH:16]=[CH:17][C:12]3=[N:11][C:10]=2[CH:19]([NH:21][C:23]2[N:31]=[CH:30][N:29]=[C:28]3[C:24]=2[N:25]=[CH:26][NH:27]3)[CH3:20])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: Cc1cccc2nc(C(C)N)c(-c3cc(F)cc(F)c3)n12
Reactant: Brc1ncnc2[nH]cnc12
Solvent: CO
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc2nc(C(C)Nc3ncnc4[nH]cnc34)c(-c3cc(F)cc(F)c3)n12
Yield: 58.1 %

Procedure:
A solution of 1-[3-(3,5-difluorophenyl)-5-methylimidazo[1,2-a]pyridin-2-yl]ethanamine (40 mg, 0.14 mmol), 6-bromo-9H-purine [Aldrich, 104981] (33 mg, 0.17 mmol), and N,N-diisopropylethylamine (29 μL, 0.17 mmol) in ethanol (1.6 mL) was heated at 90° C. for 18 h. The reaction mixture was diluted with methanol and purified by preparative LCMS to give the desired product (33 mg, 58%) as a white solid. LCMS for C21H18F2N7 (M+H)+: m/z=406.1. 1H NMR (400 MHz, CD3OD): δ 8.12 (s, 1 H), 8.03 (br s, 1 H), 7.49 (d, J=9.0 Hz, 1 H), 7.25 (dd, J=9.0, 6.8 Hz, 1 H), 7.21-7.18 (m, 1 H), 7.00-6.94 (m, 2 H), 6.66 (d, J=6.8 Hz, 1 H), 5.44 (br s, 1 H), 2.15 (s, 3 H), 1.69 (d, J=7.0 Hz, 3 H).
Reaction SMILES: [CH2:1]([N:8]1[C@H:13]([CH3:14])[CH2:12][CH:11]([NH:15][C:16]2[C:17]([CH3:27])=[C:18]([CH:23]=[C:24]([F:26])[CH:25]=2)[C:19]([O:21][CH3:22])=[O:20])[CH2:10][C@H:9]1[CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:29](=O)[CH3:30].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C>[CH2:1]([N:8]1[C@H:13]([CH3:14])[CH2:12][CH:11]([N:15]([CH2:29][CH3:30])[C:16]2[C:17]([CH3:27])=[C:18]([CH:23]=[C:24]([F:26])[CH:25]=2)[C:19]([O:21][CH3:22])=[O:20])[CH2:10][C@H:9]1[CH3:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC=O
Reactant: COC(=O)c1cc(F)cc(NC2C[C@@H](C)N(Cc3ccccc3)[C@H](C)C2)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCN(c1cc(F)cc(C(=O)OC)c1C)C1C[C@@H](C)N(Cc2ccccc2)[C@H](C)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 95.8 %

Procedure:
To a stirred solution of methyl 3-{[(2R,6R)-1-benzyl-2,6-dimethylpiperidin-4-yl]amino}-5-fluoro-2-methylbenzoate (269 mg, 0.701 mmol) in dichloromethane (5 mL) and acetic acid (500 uL) was added acetaldehyde (124 mg, 2.80 mmol) and sodium triacetoxyborohydride (469 mg, 2.10 mmol) at 0° C. The reaction mixture was stirred at rt for 12 hours. Then the reaction mixture was quenched with aq. NaHCO3 until pH8-9. The content was extracted with ethylacetate. The organic layer was dried over MgSO4 and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (NH—SiO2; heptane/ethylacetate=5/1) to give the titled compound as a light yellow oil (277 mg, 96% yield). 1HNMR (400 MHz, CDCl3) δppm; 7.19-7.36 (m, 6H), 6.97 (dd, J=2.4, 10.4 Hz, 1H), 3.89 (s, 3H), 3.86 (d, J=10.4 Hz, 1H), 3.39 (d, J=10.4 Hz, 1H), 3.02-3.10 (m, 4H), 2.74-2.80 (m, 1H), 2.43 (s, 3H), 1.74-1.82 (m, 1H), 1.51-1.63 (m, 2H), 1.32-1.40 (m, 1H), 1.05 (d, J=6.4 Hz, 3H), 0.93 (d, J=7.2 Hz, 3H), 0.86 (t, J=6.8 Hz, 3H); MS (ES) [M+H] 413.0.
Reaction SMILES: [CH:1]([C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:10][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=O.[CH3:19][C:20]([S@@:23]([NH2:25])=[O:24])([CH3:22])[CH3:21]>C1COCC1.CCO.CCO.CCO.CCO.[Ti]>[C:20]([S@@:23](/[N:25]=[CH:1]/[C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:10][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:24])([CH3:22])([CH3:21])[CH3:19]
Reactant: CC(C)(C)[S@@](N)=O
Reactant: Cc1cccc(CCC(=O)OC(C)(C)C)c1C=O
Agent: [Ti]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cccc(CCC(=O)OC(C)(C)C)c1/C=N/[S@@](=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.8 %

Procedure:
To a solution of 305 mg of tert-butyl 3-(2-formyl-3-methylphenyl)propanoate in 3 ml of THF 3 ml were added 298 mg of (S)-2-methyl-2-propanesulfinamide and 0.62 ml of tetraethyl orthotitanate, followed by stirring at room temperature for 16 hours. The reaction mixture was poured into ice water and the insoluble material was filtered through Celite. To the filtrate was added chloroform to carry out a layer separation operation. The organic layer was washed with water and subsequentially with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 336 mg of tert-butyl 3-{2-[(E)-{[(S)-tert-butylsulfinyl]imino}methyl]-3-methylphenyl}propanoate.
Reaction SMILES: Br[C:2]1[S:6][CH:5]=[C:4]([C:7]([OH:9])=[O:8])[CH:3]=1.C([Li])CCC.CN(C)[CH:17]=[O:18]>O1CCCC1>[CH:17]([C:2]1[S:6][CH:5]=[C:4]([C:7]([OH:9])=[O:8])[CH:3]=1)=[O:18]
Reactant: CN(C)C=O
Reactant: O=C(O)c1csc(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1cc(C(=O)O)cs1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-Bromo-3-thiophenecarboxylic acid (4.14 g) was dissolved in tetrahydrofuran (50 ml), and the mixture was cooled to -78° C. n-Butyllithium (1.6M in hexane, 27.5 ml) was slowly added dropwise. The resulting mixture was stirred at the same temperature for 1 hour, and N,N-dimethylformamide (3.1 ml) was added. The mixture was warmed slowly to room temperature and concentrated under reduced pressure. The concentrate was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a crude product of 5-formyl-3-thiophenecarboxylic acid (3.12 g). 5-Formyl-3-thiophenecarboxylic acid (3.12 g) was dissolved in N,N-dimethylformamide (50 ml), and iodoethane (1.58 ml) and potassium carbonate (2.76 g) were added. The mixture was stirred at room temperature for 15 hours, poured into water and extracted with ethyl acetate. The extract was washed with 5 % potassium hydrogen sulfate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the desired fractions were concentrated under reduced pressure to give 5-formyl-3-thiophenecarboxylic acid ethyl ester (0.71 g). 5-Formyl-3-thiophenecarboxylic acid ethyl ester (1.47 g) synthesized in this manner in methylene chloride (10 ml) was slowly added dropwise to diethylaminosulfur trifluoride (DAST) (1.2 ml) in methylene chloride (10 ml) at room temperature. The mixture was stirred at room temperature for 15 hours, and saturated aqueous sodium bicarbonate was added. The organic layer was collected, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 5-difluoromethyl-3-thiophenecarboxylic acid ethyl ester (0.7 g). 5-Difluoromethyl-3-thiophenecarboxylic acid ethyl ester was dissolved in a mixture of ethanol (5 ml) and tetrahydrofuran (5 ml), and 1N aqueous sodium hydroxide (5 ml) was added. The mixture was stirred at room temperature for 1 hour and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 5-difluoromethyl-3-thiophenecarboxylic acid (0.58 g) as crystals.
Reaction SMILES: [CH:1]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH:9]=[C:10]([C:16]([OH:18])=[O:17])[NH:11]3)[CH2:4][CH2:3][CH2:2]1.[CH3:19][O:20][C:21]1C=C[C:24]2C(CCO)=[CH:26][O:27][C:23]=2[CH:22]=1.C(OC(C1NC2C(C=1)=C(O)C=CC=2)=O)C>>[CH3:26][O:27][C:23]1[CH:24]=[CH:2][C:3]2[C:4]([CH2:1][CH2:5][O:6][C:7]3[CH:15]=[CH:14][CH:13]=[C:12]4[C:8]=3[CH:9]=[C:10]([C:16]([OH:18])=[O:17])[NH:11]4)=[CH:19][O:20][C:21]=2[CH:22]=1
Reactant: COc1ccc2c(CCO)coc2c1
Reactant: O=C(O)c1cc2c(OCC3CCC3)cccc2[nH]1
Agent: CCOC(=O)c1cc2c(O)cccc2[nH]1
Product: COc1ccc2c(CCOc3cccc4[nH]c(C(=O)O)cc34)coc2c1

Procedure:
4-[2-(6-methoxy-benzofuran-3-yl)-ethoxy]-1H-indole-2-carboxylic acid (16o) is synthesized analogous to 16a from 4-[2-(6-methoxy-benzofuran-3-yl)-ethanol 21 (synthesis see below) and 4-hydroxy-1H-indole-2-carboxylic acid ethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[OH:11].C(=S)=S.[Br:15]Br>O>[Br:15][C:6]1[CH:5]=[C:4]([OH:11])[C:3]([O:2][CH3:1])=[CH:8][C:7]=1[O:9][CH3:10]
Reactant: COc1ccc(O)c(OC)c1
Reactant: BrBr
Solvent: O
Solvent: S=C=S
Product: COc1cc(OC)c(Br)cc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
To a mixed solution comprising 8.6 g of 2,4-dimethoxyphenol and 80 ml of carbon disulfide (CS2) was added dropwise 2.86 ml of bromine at 10° to 15° C. After stirring the mixture at room temperature for one hour, water was added to the reaction mixture and the reaction mixture was extracted with diethyl ether. The extract was washed and dried, and the solvent was removed under reduced pressure. Hexane was added to the obtained residue and the precipitated crystals were collected by filtration to give 12.0 g of 3-bromo-4,6-dimethoxyphenol (yield: 92%, melting point: 78°-80° C.).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:28]=[CH:29][C:30]([C:33]#[C:34][CH2:35][OH:36])=[N:31][CH:32]=2)=[CH:23][CH:22]=1.[N:37]1([CH2:42][C:43]2[CH:48]=[CH:47][C:46](O)=[CH:45][CH:44]=2)[CH2:41][CH2:40][CH2:39][CH2:38]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:28]=[CH:29][C:30]([C:33]#[C:34][CH2:35][O:36][C:46]3[CH:45]=[CH:44][C:43]([CH2:42][N:37]4[CH2:41][CH2:40][CH2:39][CH2:38]4)=[CH:48][CH:47]=3)=[N:31][CH:32]=2)=[CH:23][CH:22]=1
Reactant: OCC#Cc1ccc(-c2ccc(Cl)cc2)cn1
Reactant: Oc1ccc(CN2CCCC2)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1ccc(-c2ccc(C#CCOc3ccc(CN4CCCC4)cc3)nc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
131 mg (0.5 mmol) triphenylphosphane are added to a solution of 100 mg (0.41 mmol) 3-[5-(4-chloro-phenyl)-pyridin-2-yl]-prop-2-yn-1-ol and 88 mg (0.5 mmol) 4-pyrrolidin-1-ylmethyl-phenol in 4 mL THF. Then 0.1 mL (0.5 mmol) diisopropyl azo-dicarboxylate is slowly added dropwise and the reaction mixture is stirred for 3 h at RT. The mixture is evaporated down i. vac., the residue is taken up in 1 mL DMF and purified by HPLC. The product obtained, which still contains triphenylphosphane oxide, is again purified by chromatography (silica gel, EtOAc after EtOAc/MeOH/NH3 9:1:0.1).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([O:22][CH2:23][CH:24]=[C:25]([Cl:27])[Cl:26])[CH:19]=[C:18]([Cl:28])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=O)[CH3:16])=[CH:11][CH:10]=1.Cl.[CH2:30]([O:32][NH2:33])[CH3:31].Cl>N1C=CC=CC=1>[CH2:30]([O:32][N:33]=[C:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][CH2:5][O:4][C:3]2[C:2]([Cl:1])=[CH:21][C:20]([O:22][CH2:23][CH:24]=[C:25]([Cl:27])[Cl:26])=[CH:19][C:18]=2[Cl:28])=[CH:10][CH:11]=1)[CH3:16])[CH3:31]
Reactant: CC(=O)c1ccc(OCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1
Reactant: CCON
Agent: Cl
Solvent: c1ccncc1
Product: CCON=C(C)c1ccc(OCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 97.4 %

Procedure:
To a mixture of 0.31 g of 4′-(3-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)propyloxy)acetophenone (which had been produced in Intermediate Production Example 2 as described below) and 10 ml of pyridine was added 0.07 g of O-ethylhydroxylamine hydrochloride. After stirring at room temperature for 24 hours, the reaction mixture was poured into diluted hydrochloric acid, and extracted twice with diethyl ether. The diethyl ether layers were combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated to give a crude product. This crude product was subjected to silica gel chromatography, which afforded 0.33 g (yield, 99%) of 4′-(3-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)propyloxy)acetophenone O-ethyloxime, nD24.5 1.5948.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[F:10][C:11]1[CH:19]=[C:18]2[C:14]([C:15]([C:21]3[N:22]=[C:23]4[C:29]([C:30]([OH:32])=O)=[CH:28][N:27]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:24]4=[N:25][CH:26]=3)=[N:16][N:17]2[CH3:20])=[CH:13][CH:12]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.FC(F)(F)C(O)=O.[NH2:72][C@@H:73]1[CH2:77][CH2:76][C@H:75]([OH:78])[CH2:74]1>CN(C=O)C>[OH:78][C@@H:75]1[CH2:76][CH2:77][C@H:73]([NH:72][C:30]([C:29]2[C:23]3[C:24](=[N:25][CH:26]=[C:21]([C:15]4[C:14]5[C:18](=[CH:19][C:11]([F:10])=[CH:12][CH:13]=5)[N:17]([CH3:20])[N:16]=4)[N:22]=3)[N:27]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[CH:28]=2)=[O:32])[CH2:74]1
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Reactant: N[C@@H]1CC[C@H](O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1nc(-c2cnc3c(n2)c(C(=O)N[C@H]2CC[C@@H](O)C2)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 35 %

Procedure:
In a round-bottomed flask, cis-3-amino-cyclopentanol trifluoroacetate (crude from Step 2) was dissolved in DMF (1.2 ml) and N,N-diisopropylethylamine (0.40 ml, 2.3 mmol) was added. Then 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (120 mg, 0.27 mmol) and HATU (114 mg, 0.30 mmol) were added. The reaction mixture was stirred at room temperature overnight then quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then concentrated. The residue was absorbed on silica gel and chromatographed with MeOH/CH2Cl2/0.5% NH4OH (gradient 0-4% MeOH) to afford 50 mg (35%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (cis-3-hydroxy-cyclopentyl)-amide as a light yellow solid.