Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[C:8]([O:18]C(=O)C)=[CH:7][N:6]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3)(OC)=[O:2].[H-].C([Al+]CC(C)C)C(C)C.O>O1CCCC1>[OH:2][CH2:1][C:5]1[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[C:8]([OH:18])=[CH:7][N:6]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3
Reactant: COC(=O)c1ncc(OC(C)=O)c2c1[nH]c1ccccc12
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: OCc1ncc(O)c2c1[nH]c1ccccc12
Reaction time: 2 h

Procedure:
In 30 ml of dry tetrahydrofuran were dissolved 70 mg of the product of 1-carbomethoxy-4-acetoxy-9H-pyrido[3,4-b]indole. With ice-cooling, 4.0 ml of diisobutylaluminum hydride were added. The reaction mixture was allowed to stand for 2 hours, after which the unreacted reagent was decomposed with a small amount of water. The mixture was then extracted with ethyl acetate. The organic layers were pooled and concentrated and the resultant crystals were recrystallized from ethyl acetate to yield 16 mg of the title compound as white needles melting at 148°-150°0 C. (decomp.). The IR absorption spectrum shows absorption at 1680 cm-1 has disappeared. An intense absorption was observed at 1620 cm-1. Mol. wt. (based on mass spectrum) 214.
Reaction SMILES: Cl[CH:2]1[O:6][C:5]2[CH:7]=[CH:8][C:9]3[C:14]([C:4]=2[C:3]1([CH3:24])[CH3:23])=[CH:13][C:12]([CH2:15][N:16]1[CH:20]=[N:19][CH:18]=[N:17]1)=[C:11]([C:21]#[N:22])[CH:10]=3.C(N(CC)CC)C.[CH2:32]([OH:34])[CH3:33]>>[CH2:32]([O:34][CH:2]1[O:6][C:5]2[CH:7]=[CH:8][C:9]3[C:14]([C:4]=2[C:3]1([CH3:24])[CH3:23])=[CH:13][C:12]([CH2:15][N:16]1[CH:20]=[N:19][CH:18]=[N:17]1)=[C:11]([C:21]#[N:22])[CH:10]=3)[CH3:33]
Reactant: CCO
Reactant: CC1(C)c2c(ccc3cc(C#N)c(Cn4cncn4)cc23)OC1Cl
Solvent: CCN(CC)CC
Product: CCOC1Oc2ccc3cc(C#N)c(Cn4cncn4)cc3c2C1(C)C
Reaction time: 3 h

Procedure:
A solution of 2-chloro-1,2-dihydro-1,1-dimethyl-8-(1H-1,2,4-triazol-1-ylmethyl)naphtho[2,1-b]furan-7-carbonitrile in ethanol (5 ml) was treated with triethylamine (0.06 ml), and the mixture was kept at room temperature for 3 h and then evaporated to dryness under reduced pressure. The residue was purified by flash chromatography, using methanol:dichloromethane, 1:200 v/v as eluant, to give 2-ethoxy-1,2-dihydro-1,1-dimethyl-8-(1H-1,2,4-triazol-1-ylmethyl)naphtho[2,1-b]-furan-7-carbonitrile, m.p. 128°-129°.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:10]=[CH:9][S:8][C:7]=1[C:11]([O:13][CH3:14])=[O:12])(=O)C.C(=O)([O-])[O-].[K+].[K+].P([O-])([O-])([O-])=O>CO>[OH:4][CH2:5][C:6]1[CH:10]=[CH:9][S:8][C:7]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1sccc1COC(C)=O
Agent: O=C([O-])[O-]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)c1sccc1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.4 %

Procedure:
To a solution of methyl 3-(acetoxymethyl)-2-thenoate (4.89 g, 22.8 mmol) obtained from Example 37-(1) in methanol (60 ml) was added potassium carbonate (157.7 mg, 1.14 mmol), and the mixture was stirred at room temperature for 1 hour. A phosphate buffer solution (pH 7, 20 ml) was added to the reaction mixture, and the methanol was evaporated under reduced pressure. The product was extracted with ethyl acetate, and then the solvent was evaporated under reduced pressure. The obtained oily residue was subjected to chromatography on a silica gel (90 g) column (eluent; ethyl acetate:hexane=1:2) to give the title compound (3.94 g, quantitative yield) as needle crystals (mp. 35-36° C.).
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[C:12]([F:13])=[CH:11][C:10]([F:14])=[C:9]([F:15])[CH:8]=1.[C:16](=[O:18])=[O:17].Cl>O1CCCC1.O>[F:6][C:7]1[C:12]([F:13])=[CH:11][C:10]([F:14])=[C:9]([F:15])[C:8]=1[C:16]([OH:18])=[O:17]
Reactant: Fc1cc(F)c(F)cc1F
Reactant: O=C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1c(F)c(F)cc(F)c1F
Temperature: -70 °C
Reaction time: 1 h

Procedure:
n-Butyllithium (2.7M solution in n-hexane, 148 cm3) was added dropwise over a period of one hour to a stirred solution of 2,3,5,6-tetrafluorobenzene (60 g) in dry tetrahydrofuran (200 cm3) maintained at -70° C. under a nitrogen atmosphere, after which the mixture was stirred at -70° C. for a further one hour. Carbon dioxide gas was passed into the mixture over a period of 4 hours during which time the temperature was allowed to warm up to the ambient value (ca. 22° C.). After adding water and acidifying with dilute hydrochloric acid, the mixture was extracted with diethyl ether and the extracts dried over anhydrous magnesium sulphate. The product was obtained by removal of the solvent by evaporation under reduced pressure to give 2,3,5,6-tetrafluorobenzoic acid (42.5 g), mp. 152°-154° C.
Reaction SMILES: [CH2:1]([OH:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].[C:9]([N:12]1[C:16](=[O:17])[CH:15]=[CH:14][C:13]1=[O:18])(=[O:11])[NH2:10]>C(#N)C.[Cl-].[Zn+2].[Cl-]>[C:16]([O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][O:8][C:16](=[O:17])/[CH:15]=[CH:14]\[C:13](=[O:18])[NH:12][C:9](=[O:11])[NH2:10])(=[O:17])/[CH:15]=[CH:14]\[C:13](=[O:18])[NH:12][C:9](=[O:11])[NH2:10]
Reactant: NC(=O)N1C(=O)C=CC1=O
Reactant: OCCCCCCO
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC#N
Product: NC(=O)NC(=O)/C=C\C(=O)OCCCCCCOC(=O)/C=C\C(=O)NC(N)=O
Reaction time: 3 h
Yield: 70.6 %

Procedure:
A mixture of 5.66 g of 1,6-hexanediol (0.048 moles), 12 g of N-carbamylmaleimide (0.086 moles) and 0.3 g of zinc chloride (0.0022 moles) in 70 mL of acetonitrile was heated to reflux. After 3 hours, a lot of solid material had been produced from the mixture. The mixture was filtered and the solids washed with acetonitrile and dried to afford 12.1 g of 1,6-hexanediol bismaleurate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[F:9].[N+]([C:13]1[CH:18]=CC=C[CH:14]=1)([O-])=O.S(=O)(=O)(O)O>OCC(CO)O>[Br:1][C:2]1[C:3]([F:9])=[C:4]2[C:5](=[CH:6][CH:7]=1)[N:8]=[CH:18][CH:13]=[CH:14]2
Reactant: O=[N+]([O-])c1ccccc1
Reactant: Nc1ccc(Br)c(F)c1
Agent: O=S(=O)(O)O
Solvent: OCC(O)CO
Product: Fc1c(Br)ccc2ncccc12
Temperature: 25 °C

Procedure:
A mixture of 4-bromo-3-fluoro-phenylamine (100 g, 526 mmol), ferrous sulfate (30 g), glycerol (200 g), nitrobenzene (40 g) and concentrated sulfuric acid (100 mL) were heated gently. After the first vigorous reaction, the mixture was heated to reflux for 5 hours. Nitrobenzene was evaporated in vacuo. The aqueous solution was acidified with glacial acetic acid and dark brown precipitate separated, which was purified by flash chromatography (silica gel, petroleum/ethyl acetate=12/1) to return a mixture of 6-bromo-5-fluoro-quinoline and 6-bromo-7-fluoro-quinoline as a white solid (80 g, 68%). This mixture was heated to reflux in petroleum ether. The solution was cooled to r.t., filtered and dried to return 6-bromo-7-fluoro-quinoline as a white solid. To the solution was added HCl/MeOH, and a white solid precipitated from the solution. The solid was filtered and basified. The resulting precipitate was collected by filtration and dried to obtain 6-bromo-5-fluoro-quinoline as white solid. 1H-NMR (DMSO-d6, 300 MHz): 9.0 (d, 1H), 8.5 (d, 1H), 8.0 (m, 1H), 7.8 (d, 1H), 7.7 (m, 1H); MS: m/z 228 [M+H+]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]12[CH2:13][CH2:12]1.C([O-])(=O)C.[Na+].[Br:19]Br>C(Cl)Cl.CCOCC>[Br:19][C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([F:1])[CH:3]=1)[NH:9][C:8](=[O:11])[C:7]12[CH2:13][CH2:12]1
Reactant: BrBr
Reactant: O=C1Nc2c(F)cccc2C12CC2
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: O=C1Nc2c(F)cc(Br)cc2C12CC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.9 %

Procedure:
7′-Fluorospiro[cyclopropane-1,3′-indol]-2′(1′H)-one (0.54 g, 3.05 mmol) was dissolved in 20 mL of CH2Cl2 and sodium acetate (0.28 g, 3.36 mmol) was added followed by bromine (0.173 mL, 3.36 mmol). The mixture was stirred at 25° C. for 16 h then diluted with ether and washed with Na2S3O3, sodium bicarbonate, water, brine, dried over MgSO4, and concentrated. Purification by flash chromatography (15% acetone/hexane) afforded 5′-Bromo-7′-fluorospiro[cyclopropane-1,3′-indol]-2′(1′H)-one (0.64 g, 82%) as a white solid:
Reaction SMILES: [OH-].[Na+].C([O:6][C:7]1[CH:24]=[CH:23][C:10]2[O:11][CH2:12][C:13]3[CH:20]=[C:19]([C:21]#[N:22])[CH:18]=[CH:17][C:14]=3[C:15](=[O:16])[C:9]=2[CH:8]=1)(=O)C>CO>[C:21]([C:19]1[CH:18]=[CH:17][C:14]2[C:15](=[O:16])[C:9]3[CH:8]=[C:7]([OH:6])[CH:24]=[CH:23][C:10]=3[O:11][CH2:12][C:13]=2[CH:20]=1)#[N:22]
Reactant: CC(=O)Oc1ccc2c(c1)C(=O)c1ccc(C#N)cc1CO2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N#Cc1ccc2c(c1)COc1ccc(O)cc1C2=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
6 ml of a 3N-sodium hydroxide aqueous solution was added to 2.8 g of 2-acetoxy-8-cyano-11-oxo-6,11-dihydrodibenz[b,e]oxepine obtained in Reference example 25 dissolved in 30 ml of methanol and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the solvent was removed under reduced pressure, water was added to the residue and the mixture was adjusted to about pH 2 with conc. hydrochloric acid. Crystals precipitated were collected by filtration and dissolved in ethyl acetate and the organic layer was washed with a saturated saline solution and then dried over anhydrous sodium sulfate. The solvent was removed from the solution to obtain 2.35 g of the title compound.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12](O)=O)[CH:10]=2)[NH:5][C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:3]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH2:54]([O:56][C:57](=[O:72])[C:58]1[CH:63]=[CH:62][C:61]([NH:64][CH:65]2[CH2:70][CH2:69][CH2:68][CH2:67][CH2:66]2)=[C:60]([NH2:71])[CH:59]=1)[CH3:55]>CN(C=O)C>[CH2:54]([O:56][C:57]([C:58]1[CH:63]=[CH:62][C:61]2[N:64]([CH:65]3[CH2:66][CH2:67][CH2:68][CH2:69][CH2:70]3)[C:12]([C:9]3[CH:10]=[C:11]4[C:6](=[CH:7][CH:8]=3)[NH:5][C:4]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:3][C:2]4=[O:1])=[N:71][C:60]=2[CH:59]=1)=[O:72])[CH3:55]
Reactant: CCOC(=O)c1ccc(NC2CCCCC2)c(N)c1
Reactant: O=C(O)c1ccc2[nH]c(-c3ccccc3)cc(=O)c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1ccc2c(c1)nc(-c1ccc3[nH]c(-c4ccccc4)cc(=O)c3c1)n2C1CCCCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 800.1 %

Procedure:
4-Oxo-2-phenyl-1,4-dihydro-quinoline-6-carboxylic acid (2.78 g, 1.05 mmol) was dissolved in DMF (50 mL), and HATU (1.1 eq.) and diisopropyl ethylamine (2.2 eq, 402 μL) were added. After stirring at room temperature for 15 minutes, 3-amino-4-cyclohexylamino-benzoic acid ethyl ester (2.89 g, 1.1 eq.) dissolved in 20 mL DMF was added. After stirring overnight, the reaction was evaporated, dissolved in ethyl acetate and washed with water and brine, dried with sodium sulfate, evaporated and dried overnight. The product was then refluxed in acetic acid for 4 hr, evaporated to dryness, and coevaporated 2 more times with toluene. The product was recrystallized from methanol to give 4.13 g of product.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.C(OCC)(=O)C.[C:18]1([CH3:24])[CH:23]=CC=C[CH:19]=1>CCCCCC>[C:18]([O:10][C:9](=[O:11])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1)([CH3:24])([CH3:23])[CH3:19]
Reactant: O=C(O)Cc1ccc(O)cc1
Reactant: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)Cc1ccc(O)cc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
A stirred suspension of 4-hydroxy-phenyl acetic acid (0.152 g, 1 mmol) in anhydrous toluene (5 mL) was heated at 80° C. and N,N-dimethyl formamide-di-ti-butyl acetal (1 mL, 4.17mmol) was added when the solution became homogenous. After 0.5 h, the reaction mixture was cooled to ambient temperature and the volatiles were distilled off in vacuo. The residue was diluted with water and extracted with diethyl ether (×2). The combined organic extract was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to afford an oil which was subjected to flash column chromatography over silica gel (230-400 mesh) using 16% ethyl acetate in hexane as the eluent to afford the title compound as a solid (0.11 g, 56%).
Reaction SMILES: [CH3:1]OC1C=CC(C)=CC=1C.[F:11][C:12]([F:29])([F:28])[C:13](=[O:27])[CH2:14][C:15]([C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:19]=1[O:25][CH3:26])([CH3:17])[CH3:16]>>[F:11][C:12]([F:28])([F:29])[C:13](=[O:27])[CH2:14][C:15]([C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([CH3:1])[C:19]=1[O:25][CH3:26])([CH3:17])[CH3:16]
Reactant: COc1ccc(C)cc1C(C)(C)CC(=O)C(F)(F)F
Reactant: COc1ccc(C)cc1C
Product: COc1c(C)cc(C)cc1C(C)(C)CC(=O)C(F)(F)F

Procedure:
The title product was prepared from 1-methoxy-2,4-dimethylbenzene according to the same procedure described in the synthesis of 1,1,1-trifluoro-4-(2-methoxy-5-methylphenyl)-4-methylpentan-2-one.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[CH2:9][CH:10]=[O:11])=[CH:4][CH:3]=1.[F:14][C:15](C[SiH](C1C=CC=CC=1)C1C=CC=CC=1)=[CH2:16].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[F:14][C:15]([CH:10]([OH:11])[CH2:9][C:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)([CH3:13])[CH3:12])=[CH2:16]
Reactant: C=C(F)C[SiH](c1ccccc1)c1ccccc1
Reactant: CC(C)(CC=O)c1ccc(F)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C=C(F)C(O)CC(C)(C)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 3-(4-fluorophenyl)-3-methylbutyraldehyde (1.2 g, 6.6 mmol) and (1-fluorovinyl)methyldiphenylsilane in 5 mL of THF cooled on ice under nitrogen gas was added 1 mL of TBAF (1 M in THF). The mixture was allowed to warm to room temperature and left overnight. The solvent was evaporated and the residue was taken up in hexanes. The hexane soluble material was fractionated over silica gel (eluent: hexanes to hexanes-ethyl acetate (98:2)) to give a fraction (3.1 g) containing silylated product along with other silanes. This fraction was dissolved in 5 mL of THF and 10 mL of TBAF solution (1 M in THF) was added. The mixture was left at room temperature for 20 minutes, diluted with hexanes-ethyl acetate, and washed with water, dried, filtered, and concentrated in vacuo. Fractionation of the residue over silica gel (eluent: hexanes-ethyl acetate (99:1 to 9:1 gradient)) gave 1.73 g of the crude 2-fluoro-5-(4-fluorophenyl)-5-methylhex-1-en-3-ol as an oil which was used without additional purification.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[O-:23][S:24]([O-:26])=[O:25].[Na+:27].[Na+].CCO>O>[Na+:27].[CH2:16]([O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][S:24]([O-:26])(=[O:25])=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCCCCCCCc1ccccc1OCc1ccccc1
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=S(=O)([O-])CCCCCCCc1ccccc1OCc1ccccc1

Procedure:
Following the procedure described for 11.1 using 10.3 (0.231 g, 0.64 mmol), Na2SO3 (0.11 g, 0.89 mmol) and EtOH (8 mL)/H2O (4 ml) mixture, the crude 11.3 was obtained and used in the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].[CH3:14][NH:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:21]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH3:28].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:14][N:15]([C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:21]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH3:28])[C:6](=[O:7])[C:5]1[CH:9]=[CH:10][CH:11]=[C:3]([C:2]([F:13])([F:12])[F:1])[CH:4]=1
Reactant: CNc1cnccc1-c1ccccc1C
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccccc1-c1ccncc1N(C)C(=O)c1cccc(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
3-Trifluoromethylbenzoyl chloride (30 mg, 0.14 mmol, CAS RN 2251-65-2) was added to a solution of methyl-(4-o-tolyl-pyridin-3-yl)-amine (20 mg, 0.10 mmol, example 1, intermediate a) and DIPEA (30 μL, 0.17 mmol) in CH2Cl2 (1 mL). The reaction mixture was stirred overnight and then loaded directly onto a silica gel column and eluted with 50% EtOAc in n-hexane to yield the desired product as a waxy solid (17 mg, 46%). MS (ESI): m/z=371.0 [M+H]+.
Reaction SMILES: N#N.Br[C:4]1[CH:9]=[C:8]([C:10]2([CH3:15])[O:14][CH2:13][CH2:12][O:11]2)[CH:7]=[CH:6][N:5]=1.[Li]CCCC.CN([CH:24]=[O:25])C.[NH4+].[Cl-]>CCOCC>[CH3:15][C:10]1([C:8]2[CH:7]=[CH:6][N:5]=[C:4]([CH:24]=[O:25])[CH:9]=2)[O:14][CH2:13][CH2:12][O:11]1
Reactant: CN(C)C=O
Reactant: CC1(c2ccnc(Br)c2)OCCO1
Agent: N#N
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC1(c2ccnc(C=O)c2)OCCO1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of 2-bromo-4-(2-methyl-[1,3]dioxolan-2-yl)-pyridine (1950 mg, 7.99 mmol) in dry Et2O (40 mL) was added n-BuLi (3.60 mL of a 2.5M solution in hexanes, 8.79 mmol) at −78° C. The reaction mixture was then stirred for 30 min at −78° C. before DMF (0.75 mL, 9.69 mmol) was added dropwise. The reaction mixture was allowed to warm up to rt and stirred at this temperature for 10 min. Sat. aq. NH4Cl (30 mL) was added, the layers separated and the aq. layer extracted with Et2O (3×30 mL). The combined org. extracts were dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (10:1 to 2:1 hept-EA) gave the title compound as a pale yellow oil. TLC:rf (1:1 hept-EA)=0.40.
Reaction SMILES: Br[C:2]([F:20])([F:19])[C:3]([CH:6]1[CH2:10][CH:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][CH:7]1[C:15]([O:17][CH3:18])=[O:16])([F:5])[F:4].C(=O)(O)[O-].[Na+:25].[S:26](S([O-])=O)([O-:28])=[O:27].[Na+].[Na+].C(#N)C>O>[CH3:18][O:17][C:15]([CH:7]1[CH2:8][CH:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:10][CH:6]1[C:3]([F:5])([F:4])[C:2]([F:20])([F:19])[S:26]([O-:28])=[O:27])=[O:16].[Na+:25]
Reactant: O=S([O-])S(=O)[O-]
Reactant: COC(=O)C1CC(C(=O)OC)C(C(F)(F)C(F)(F)Br)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COC(=O)C1CC(C(=O)OC)C(C(F)(F)C(F)(F)S(=O)[O-])C1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Into a glass flask equipped with a thermometer and a capacitor were charged 2.00 g (5.49 mmol) of dimethyl 4-(2-bromo-1,1,2,2-tetrafluoroethyl)cyclopentane-1,3-dicarboxylate, 0.920 g (11.0 mmol) of sodium bicarbonate, 1.62 g (9.30 mmol) of sodium dithionite, 15 mL of acetonitrile and 15 mL of water, and the mixture was stirred at 50° C. for 8 hrs. The disappearance of the raw material was confirmed by 19F-NMR to decide completion of the reaction. Thereafter, acetonitrile was distilled off in vacuo to obtain an aqueous solution of crude sodium 2-(2,4-bis(methoxycarbonyl)cyclopentyl)-1,1,2,2-tetrafluoroethanesulfinate (precursor compound (a-4)) represented by the following formula (a-4) without carrying out further purification, which was used for the following reaction.
Reaction SMILES: [C:1]([NH:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([Cl:16])[CH:10]=1)=S)([CH3:4])([CH3:3])[CH3:2].C1CCC(N=C=NC2CCCCC2)CC1.C(N(CC)CC)C>C1COCC1>[C:1]([N:5]=[C:6]=[N:8][C:9]1[CH:10]=[C:11]([Cl:16])[CH:12]=[C:13]([Cl:15])[CH:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=S)Nc1cc(Cl)cc(Cl)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)N=C=Nc1cc(Cl)cc(Cl)c1

Procedure:
To a solution of 21.0 g of N-t-butyl-N'-(3,5-dichlorophenyl)thiourea produced in Example A-1 in 200 ml of THF were added 21.4 g of DCC and 0.73 g of triethylamine. The mixture was refluxed for 3 hours and evaporated in vacuo. The residue was extracted with petroleum ether. The extract was evaporated in vacuo to give N-t-butyl-N'-(3,5-dichlorophenyl)carbodiimide as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[C:4]([F:9])[C:3]=1[C:10]#[N:11].[CH2:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]#[CH:22])=[CH:17][CH:16]=1)[CH2:13][CH3:14].Cl>CN(C)C=O.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:12]([C:15]1[CH:16]=[CH:17][C:18]([C:21]#[C:22][C:6]2[CH:7]=[C:2]([F:1])[C:3]([C:10]#[N:11])=[C:4]([F:9])[CH:5]=2)=[CH:19][CH:20]=1)[CH2:13][CH3:14]
Reactant: C#Cc1ccc(CCC)cc1
Reactant: N#Cc1c(F)cc(I)cc1F
Agent: Cl[Pd]Cl
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCCc1ccc(C#Cc2cc(F)c(C#N)c(F)c2)cc1
Yield: 27.3 %

Procedure:
5.6 g of this 1,3-difluoro-2-cyano-5-iodobenzene was dissolved in 35 ml of N,N-dimethylformamide, to which was added 7.3 mg of bis(triphenylphosphine) palladium (II) chloride and 34 m of cuprous iodide. Next, 3 g of the 4-propylphenylacetylene obtained in Step 2 was added and allowed to react at 50° to 60° C. for 0.5 hour. After completion of the reaction, 35 ml of 9% hydrochloric acid was added to the reaction solution. After being extracted with chloroform, the crystals were washed with water three times to distill off the chloroform. The residue was purified by silica gel-chloroform column chromatography, followed by recrystallization with a mixed solvent of acetone and methanol to obtain 1.6 g of 4-propyl-3',5'-difluoro-4'-cyanotolan. The melting (C-I) point of this compound was 83.3° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[CH2:22][CH2:21][N:20]([C:23]4[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=4)[C:10]=3[N:11]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:13]=2)[CH:5]=[CH:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[CH2:38]([N:40]=[C:41]=[O:42])[CH3:39]>CN(C)C=O>[CH2:38]([NH:40][C:41]([O:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[CH2:22][CH2:21][N:20]([C:23]4[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=4)[C:10]=3[N:11]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:13]=2)[CH:5]=[CH:6][CH:7]=1)=[O:42])[CH3:39]
Reactant: Oc1cccc(-c2nc(N3CCOCC3)nc3c2CCN3c2ccncc2)c1
Reactant: CCN=C=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)Oc1cccc(-c2nc(N3CCOCC3)nc3c2CCN3c2ccncc2)c1
Temperature: 60 °C
Reaction time: 12 h
Yield: 55 %

Procedure:
Compound A-09 (4-(3-hydroxyphenyl)-2-(morpholin-4-yl)-7-(pyridin-4-yl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine (34 mg, 0.09 mmol) obtained in Example 1-A-09 was dissolved in dimethylformamide (1 mL), and diisopropylethylamine (32 μL) and ethyl isocyanate (32 μL) were added, followed by stirring at 60° C. for 12 hours. The reaction mixture was poured onto water, followed by extraction with dichloromethane, and the organic layer was dried over sodium sulfate. After the drying agent was filtered off, followed by concentration under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane/methanol), to obtain the desired compound (colorless powder, 22 mg, 55%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:11][CH2:12][NH2:13])=[CH:7][NH:8]2)=[CH:4][C:3]=1[CH3:14].[F:15][C:16]1[CH:17]=[C:18]([CH:29]=[CH:30][CH:31]=1)[CH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:11][CH2:12][NH:13][C:24](=[O:25])[C:23]3[CH:22]=[CH:21][C:20]([CH2:19][C:18]4[CH:29]=[CH:30][CH:31]=[C:16]([F:15])[CH:17]=4)=[CH:28][CH:27]=3)=[CH:7][NH:8]2)=[CH:4][C:3]=1[CH3:14]
Reactant: Cc1cc2c(CCN)c[nH]c2cc1Cl
Reactant: O=C(O)c1ccc(Cc2cccc(F)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc2c(CCNC(=O)c3ccc(Cc4cccc(F)c4)cc3)c[nH]c2cc1Cl
Yield: 14.1 %

Procedure:
N-(2-(6-Chloro-5-methyl-1H-indol-3-yl)ethyl)-4-(3-fluorobenzyl)benzamide was prepared according to Method A starting from 2-(6-chloro-5-methyl-1H-indol-3-yl)ethanamine (0.172 g; 0.825 mmol), 4-(3-fluorobenzyl)benzoic acid (0.190 g, 0.825 mmol), HATU (0.313 g; 0.825 mmol) and N,N-diisopropylethylamine (0.355 mL; 2.06 mmol) in DMF (5 mL). The crude material was purified by preparative HPLC (method 2) to afford 0.049 g (14%) of the title compound as a white solid.