Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li].[CH2:11]([O:13][C:14]1[CH:29]=[CH:28][C:17]([CH2:18][O:19][C:20]2[CH:21]=[C:22]([C:26]#[CH:27])[CH:23]=[CH:24][CH:25]=2)=[CH:16][CH:15]=1)[CH3:12].CON(C)[C:33](=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>O1CCCC1>[C:34]1([C:33](=[O:40])[C:27]#[C:26][C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([O:19][CH2:18][C:17]3[CH:28]=[CH:29][C:14]([O:13][CH2:11][CH3:12])=[CH:15][CH:16]=3)[CH:21]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: C#Cc1cccc(OCc2ccc(OCC)cc2)c1
Reactant: CON(C)C(=O)c1ccccc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Product: CCOc1ccc(COc2cccc(C#CC(=O)c3ccccc3)c2)cc1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
Place lithium hexamethyldisilazane (2 mL of a 1M solution in tetrahydrofuran, 2 mmol) and tetrahydrofuran (8 mL) under an argon atmosphere and cool to 0° C. Add a solution of 3-(4ethoxybenzyloxy)phenylacetylene (0.51 g, 2 mmol) in tetrahydrofuran and stir the solution for 45 minutes at 0° C. Add N-methoxy-N-methylbenzamide (0.4 g, 2.4 mmol), remove the cooling bath andstir at room temperature for 1 hour. Partition the mixture between ethyl ether and water, separate the organic phase and dry (MgSO4). Filter and evaporate the solvent in vacuo to yield an oil. Filter through silica gel and elute with 10% ethyl acetate/hexane to yield a crude solid. Purifyby silica gel chromatography to give the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6]>C1COCC1>[Br:1][C:2]1[C:3]([CH3:11])=[C:4]([CH2:5][OH:6])[CH:8]=[CH:9][CH:10]=1
Reactant: Cc1c(Br)cccc1C(=O)O
Solvent: C1CCOC1
Product: Cc1c(Br)cccc1CO
Reaction time: 24 h

Procedure:
To a solution of 3-bromo-2-methyl benzoic acid (35 g, 163 mmol) in THF (200 mL) was added Borane THF Complex (1.0 M, 212 mL, 212 mmol). The mixture was allowed to stir for 24 h. TLC showed one single product spot. The reaction was quenched with water. The solvent THF was removed under reduced pressure. The resulting solid was dissolved in ethyl acetate (500 mL), washed with 1N HCl, sodium carbonate, and brine. The organic layer was dried over sodium sulfate and concentrated to afford (3-bromo-2-methylphenyl)methanol. 1H NMR (500 MHz, CDCl3) δ 7.76 (d, J=8.0 Hz, 1H), 7.63 (d, J=8.0 Hz, 1H), 5.30 (s, 2H), 2.42 (s, 3H).
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[C:12](#[N:16])[CH2:13][C:14]#[N:15].Br[C:18]([C:25]1[N:29]=[C:28]([CH3:30])[O:27][N:26]=1)([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20]>C1COCC1>[C:14]([CH:13]([C:12]#[N:16])[C:18]([CH3:24])([C:25]1[N:29]=[C:28]([CH3:30])[O:27][N:26]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])#[N:15]
Reactant: N#CCC#N
Reactant: CCOC(=O)C(C)(Br)c1noc(C)n1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(c1noc(C)n1)C(C#N)C#N
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
DBU (2.56 mL, 8.1 mmol) was added dropwise to a −78° C. THF (20 mL) solution of malononitrile (1.12 g, 17 mmol) and the intermediate from Step C (1.49 g, 5.66 mmol). The reaction solution was stirred at −78° C. for 15 minutes and then at room temperature for 1 hour. The solution was then concentrated and the residue purified by silica gel chromatography using a hexanes/EtOAc gradient to give the indicated product. 1H NMR δ (ppm) (CHCl3-d): 4.79 (1H, s), 4.30 (2H, dd, J=7.1, 2.6 Hz), 2.64 (3H, s), 2.02 (3H, s), 1.31-1.25 (3H, m).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:9]([NH:11][C@H:12]([C:21]([NH:23][C@H:24]([C:26](O)=[O:27])[CH3:25])=[O:22])[CH2:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:10])[CH2:3][O:4][C:5]([CH3:8])([CH3:7])[CH3:6].O1CCOCC1.[OH:42][N:43]1[C:48](=[O:49])[CH2:47][CH2:46][C:44]1=[O:45].C1CCC(N=C=NC2CCCCC2)CC1>CCOC(C)=O>[NH2:1][C@H:2]([C:9]([NH:11][C@H:12]([C:21]([NH:23][C@H:24]([C:26]([O:42][N:43]1[C:48](=[O:49])[CH2:47][CH2:46][C:44]1=[O:45])=[O:27])[CH3:25])=[O:22])[CH2:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:10])[CH2:3][O:4][C:5]([CH3:7])([CH3:8])[CH3:6]
Reactant: O=C1CCC(=O)N1O
Reactant: C[C@H](NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)[C@H](COC(C)(C)C)NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C[C@H](NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)[C@@H](N)COC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Reaction time: 48 h

Procedure:
A solution of Boc-Ser(tBu)-Asp(OtBu)-Ala-OH.CHA (1.205 g, 2.0 mmol) was extracted with a mixture of EtOAc: 0.5N H2SO4 (10 mL-10 mL). The organic layer was retained, washed with saturated NaCl, dried (MgSO4) and evaporated in vacuo. The resultant free acid in EtOAc:dioxane (5 mL-10 mL) was treated with HOSu (230 mg, 2.0 mmol, 1 eq) and cooled to 0°. To the cold stirring solution DCC (412 mg, 2.0 mm, 1 eq) was added portionwise and stirring proceeded at 0° for 1 hr and at 25° for 48 hr. The reaction mixture was filtered and the filtrate evaporated to dryness and crystallized from isopropanol-petroleum ether. Yield: 631 mg (52.5%); mp 129°-136°; [α]D25 -32.74° (c 1, MeOH); Rf 0.86 (CHCl3 :MeOH:AcOH; 85-10-5); Rf 0.79 (CHCl3 :MeOH:AcOH; 80-5-2). Anal. calc. for C27H44N4O11 (600.67): C, 53.99; H, 7.38; N, 9.33. Found C, 53.85; H, 7.50; N, 9.29.
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH:20]=3)[CH:12]=2)[CH2:5][C:6]([O:8]CC)=[O:7])[CH2:3][CH2:2]1.[OH-].[Na+]>C1COCC1.CO>[CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH:20]=3)[CH:12]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:2][CH2:3]1
Reactant: CCOC(=O)CC(c1cccc(COc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)c1)C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(F)c(-c2ccc(OCc3cccc(C(CC(=O)O)C4CC4)c3)cc2CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.7 %

Procedure:
To a solution of ethyl 3-cyclopropyl-3-(3-(((2′-fluoro-5′-methoxy-2-neopentyl-[1,1′-biphenyl]-4-yl)oxy)methyl)phenyl)propanoate (305 mg) in THF (6.0 mL) and methanol (12 mL) was added 1N aqueous sodium hydroxide solution (5.9 mL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (282 mg) as a pale-yellow oil.
Reaction SMILES: [CH2:1](N(CC)CC)C.[CH2:8]=[C:9]([C:14]([O:17]S(F)(=O)=O)([F:16])[F:15])[C:10]([F:13])([F:12])[F:11].O>CO>[F:15][C:14]([F:16])([O:17][CH3:1])[C:9]([C:10]([F:13])([F:12])[F:11])=[CH2:8]
Reactant: CCN(CC)CC
Reactant: C=C(C(F)(F)F)C(F)(F)OS(=O)(=O)F
Solvent: CO
Solvent: O
Product: C=C(C(F)(F)F)C(F)(F)OC
Yield: 51.1 %

Procedure:
Triethylamine (2.5 g, 0.02 mole) is added gradually to CH2═C(CF3)CF2OSO2F (5 g, 0.02 mole) in dry methanol (10 ml) at 10° C. After 20 minutes the reaction mixture is poured into water. The organic layer is separated, washed in turn in dilute aqueous HCl, water, sodium bicarbonate solution, and water, and then dried over MgSO4. Distillation of the dried mixture gives 3,3-difluoro-3-methoxy-2-trifluoromethylpropene (1.8 g, 50% yield). The isomer 1,1-difluoro-2-trifluoromethyl-3-methoxypropene (about 1%) and CH2═C(CF3)COOCH3 (about 3%) are also detected by gas chromatography-mass spectrometry (GC-MS).
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[In].[OH:12][C:13]1[C:14](=[O:24])[C:15]2[C:20]([C:21](=[O:23])[CH:22]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2>CN(C)C=O>[OH:24][C:14]1([CH2:1]/[CH:2]=[CH:3]/[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21]([OH:23])=[CH:22][C:13]1=[O:12]
Reactant: BrCC=Cc1ccccc1
Reactant: O=C1C=C(O)C(=O)c2ccccc21
Agent: [In]
Solvent: CN(C)C=O
Product: O=C1C=C(O)c2ccccc2C1(O)C/C=C/c1ccccc1
Yield: 9.1 %

Procedure:
Cinnamyl bromide (0.43 g, 2.2 mmol) was added to a suspension of indium metal (0.17 g, 1.5 mmol) in N,N-dimethylformamide (1 mL) at 25° C. for 0.5 h causing dissolution of the metal. 2-Hydroxy-1,4-naphthoquinone (0.25 g, 1.5 mmol) was dissolved in N,N-dimethylformamide (1 mL) and added to the mixture. After 0.5 h the mixture was partitioned between 1% HCl and ethyl acetate. The orgamic layer was separated, washed with water, brine, dried over sodium sulfate and the solvents were evaporated. The crude residue was purified using BioTage 12L column and 5% methanol/dichloromethane to give the title compound (40 mg, 10% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[S:13][C:14]2[C:20]([CH3:21])=[CH:19][CH:18]=[C:17]([CH3:22])[C:15]=2[N:16]=1)[CH2:9][C:10]#[CH:11]>>[CH3:22][C:17]1[C:15]2[N:16]=[C:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[S:13][C:14]=2[C:20]([CH3:21])=[CH:19][CH:18]=1.[S:13]1[C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=[CH:12]1
Reactant: C#CCCc1nc2c(C)ccc(C)c2s1
Reactant: Brc1ccccn1
Product: Cc1ccc(C)c2sc(CCC#Cc3ccccn3)nc12
Product: c1ccc2scnc2c1

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (46 mg, 0.29 mmol) and 2-but-3-ynyl-4,7-dimethyl-benzo[d]thiazole (63 mg, 0.29° mmol). The crude residue was purified by flash chromatography (CM/MeOH 99:1 to 98:2) to yield 15 mg (52 mmol, 18%) of 4,7-dimethyl-2-(4-pyridin-2-yl)but-3-ynyl)benzo[d]thiazole as a yellow solid.
Reaction SMILES: [C@@H:1]1([N:9]2[C:18]3[N:17]=[CH:16][N:15]=[C:13](O)[C:12]=3[N:11]=[CH:10]2)[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[N+:55]([C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=1[CH:64]([NH2:66])[CH3:65])([O-:57])=[O:56]>CN(C=O)C>[N+:55]([C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=1[CH:64]([NH:66][C:13]1[C:12]2[N:11]=[CH:10][N:9]([C:18]=2[N:17]=[CH:16][N:15]=1)[C@@H:1]1[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1)[CH3:65])([O-:57])=[O:56]
Reactant: OC[C@H]1O[C@@H](n2cnc3c(O)ncnc32)C[C@@H]1O
Reactant: CC(N)c1ccccc1[N+](=O)[O-]
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(Nc1ncnc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 64 h

Procedure:
To a suspension of 2′-deoxyinosine (100 mg, 0.4 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP, 210 mg, 0.48 mmol) in anhydrous DMF (1 mL), N,N-diisopropylethylamine (100 μL, 0.6 mmol) was added followed by the addition of a solution of 1-(2-nitrophenyl)ethylamine (250 mg, 1.51 mmol) in DMF (1 μL). The reaction was stirred at room temperature for 64 hours. Silica gel 60 (1 g, 60-200 mesh) was added, and the mixture was evaporated in vacuo to dryness. The residue was purified by silica gel column chromatography to yield N6-[1-(2-nitrophenyl)ethyl]-2′-deoxyadenosine dA.19 (67 mg, 42%, 1:1 mixture of diastereomers) as a white foam.
Reaction SMILES: C[Si](C=[N+]=[N-])(C)C.[I:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][C:16]([OH:18])=[O:17].[CH3:19]O>C(Cl)Cl>[CH3:19][O:17][C:16](=[O:18])[CH2:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[I:8]
Reactant: O=C(O)Cc1ccccc1I
Reactant: CO
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: ClCCl
Product: COC(=O)Cc1ccccc1I
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
Trimethylsilyl diazomethane (15.3 ml, 30.6 mmol, 2.0 M in diethyl ether) was added dropwise to a stirred, cooled 0° C. solution of (2-iodophenyl)acetic acid (4.0 g, 15.3 mmol) and MeOH (10 ml) in CH2Cl2 (50 ml) and the solution was stirred at 0° C. for 1 hour. The yellow solution was purged with nitrogen for 10 minutes. The solvent removed in vacuo and the residue was azeotroped with THF (3×25 ml) to afford 4.2 g, 100% of 23-1 as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].Br[CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH3:21].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH3:21])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccc(O)c(F)c1
Reactant: CCOCCOCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOCCOCCOc1ccc(C(=O)OC)cc1F
Yield: 89.1 %

Procedure:
Into a 500-ml, round-bottom flask equipped with a magnetic stirrer, heating mantle and condenser were placed 5.7 g (33.5 mmol) methyl 3-fluoro-4-hydroxybenzoate, 8.5 g (43.2 mmol) 1-bromo-2-(2-ethoxyethoxy)-ethane, 23.2 g of powdered anhydrous potassium carbonate and 350 ml acetonitrile. After stirring the reaction mixture under reflux for four hours, TLC analysis showed that none of the phenolic starting material remained. Three hundred ml of the acetonitrile was then distilled off and 300 ml dichloromethane was added. The reaction mixture was filtered through Celite and the solids were washed thoroughly with dichloromethane. Evaporation of the filtrate yielded product in the form of a yellow oil. Purification by flash chromatography on silica gel with 4% ethyl ether in dichloromethane, followed by low temperature recrystallization from pentane, yielded 8.55 g of white crystals, 89%, m.p. 33°-36.5° C. The structure was confirmed by infrared, nuclear magnetic resonance and mass spectral analyses. ##STR32##
Reaction SMILES: FC1C=C(F)C(F)=CC=1C(O)=O.[Cl:13][C:14]1[C:15]([F:25])=[C:16]([CH:20]=[C:21]([F:24])[C:22]=1[F:23])[C:17](O)=[O:18].S(Cl)([Cl:28])=O>>[Cl:13][C:14]1[C:15]([F:25])=[C:16]([CH:20]=[C:21]([F:24])[C:22]=1[F:23])[C:17]([Cl:28])=[O:18]
Reactant: O=C(O)c1cc(F)c(F)c(Cl)c1F
Reactant: O=S(Cl)Cl
Agent: O=C(O)c1cc(F)c(F)cc1F
Product: O=C(Cl)c1cc(F)c(F)c(Cl)c1F

Procedure:
Chlorination of 2,4,5-trifluorobenzoic acid in chlorosulphonic acid leads to 3-chloro-2,4,5-trifluorobenzoic acid, which is reacted as the crude product with thionyl chloride to give 3-chloro-2,4,5-trifluorobenzoyl chloride (boiling point 94°/18 mbar; nD20 =1.5164): ##STR15##
Reaction SMILES: [S:1]1[C:5]2[C:6]([SH:10])=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.[CH2:11]([N:18]([CH3:29])[CH2:19][CH2:20][CH:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[I-].C(C[P+](C)(C)C)#N.C(N(C(C)C)CC)(C)C>C(#N)CC>[S:1]1[C:5]2[C:6]([S:10][CH:19]([N:18]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH3:29])[CH2:20][CH2:21][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: CN(CCC(O)c1ccccc1)Cc1ccccc1
Reactant: Sc1cccc2ccsc12
Agent: C[P+](C)(C)CC#N
Agent: [I-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: CN(Cc1ccccc1)C(CCc1ccccc1)Sc1cccc2ccsc12
Temperature: 25 °C

Procedure:
A solution of 1-benzothiophene-7-thiol (0.32 g, 1.96 mmol), 3-[benzyl(methyl)amino]-1-phenyl-1-propanol (0.5 g, 1.96 mmol), (cyanomethyl) trimethylphosphonium iodide (Ref Tetrahedron, 2001, 57, 5451–5454) (0.714 g, 2.94 mmol), diisopropylethylamine (0.379 g, 2.94 mmol) in propionitrile (5 mL) was stirred at 90° C. in a reacti-vial for 72 h. After this time the reaction was allowed to cool to room temperature. The reaction mixture was purified by an SCX-2 column eluting with methanol followed by ammonia:methanol solution (7 N). The organics were then evaporated and the compound taken directly onto the next step without any further purification LCMS determined successful product formation (M+H+1 [404]).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][CH2:30][CH3:31])=[O:28])=[C:22]([Cl:32])[CH:21]=3)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[C:33]#[N:34])[C:2]1C=CC=C[CH:3]=1.FC(F)(F)C(O)=[O:38].C1(SC)C=CC=CC=1>>[Cl:32][C:22]1[CH:21]=[C:20]([O:19][C:13]2[C:12]3[C:17](=[CH:18][C:9]([O:8][CH2:1][C@H:2]4[CH2:3][O:38]4)=[C:10]([C:33]#[N:34])[CH:11]=3)[N:16]=[CH:15][CH:14]=2)[CH:25]=[CH:24][C:23]=1[NH:26][C:27]([NH:29][CH2:30][CH3:31])=[O:28]
Reactant: CCNC(=O)Nc1ccc(Oc2ccnc3cc(OCc4ccccc4)c(C#N)cc23)cc1Cl
Reactant: O=C(O)C(F)(F)F
Solvent: CSc1ccccc1
Product: CCNC(=O)Nc1ccc(Oc2ccnc3cc(OC[C@H]4CO4)c(C#N)cc23)cc1Cl

Procedure:
1-(4-(7-Benzyloxy-6-cyanoquinolin-4-yloxy)-2-chloro-phenyl)-3-ethylurea (1 g) was treated with trifluoroacetic acid and thioanisole for deprotection in the same manner as Production Example 21, and the obtained hydroxy compound (0.48 g) was treated in the same manner as Example 543 to obtain the title compound (0.31 g) as a solid.
Reaction SMILES: [Mg].[Cl:2][C:3]1[CH:8]=[CH:7][C:6](Br)=[CH:5][CH:4]=1.[C:10]([C:12]1[N:13]=[CH:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2)#[N:11].[Cl-].[NH4+]>CCOCC>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:10](=[NH:11])[C:12]2[N:13]=[CH:14][C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:5][CH:4]=1
Reactant: Clc1ccc(Br)cc1
Reactant: N#Cc1cc2ccccc2cn1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: N=C(c1ccc(Cl)cc1)c1cc2ccccc2cn1
Temperature: 25 °C
Yield: 60 %

Procedure:
The starting substance is prepared as follows: To a mixture of 0.62 g (26 millimoles) of metallic magnesium and 8 ml of anhydrous ether a solution of 5.0 g (26 millimoles) of 4-chloro-bromobenzene in ether is dropwise added, the Grignard solution thus-obtained is admixed with 3.1 g (20 millimoles) of 3-cyano-isoquinoline, and the reaction mixture is stirred at room temperature for an hour. The Grignard complex is decomposed with an ammonium chloride solution, the solvent is distilled off and the residue is recrystallized from ethanol. 3.2 g (60%) of 3-(4-chlorobenzoyl)-isoquinoline imine are obtained.
Reaction SMILES: C([O:8][N:9]([C:16](=[O:56])[CH2:17][CH2:18][CH2:19][CH2:20][N:21]([O:48]CC1C=CC=CC=1)[C:22](=[O:47])[CH2:23][CH2:24][CH2:25][CH2:26][N:27]([O:39]CC1C=CC=CC=1)[C:28](=[O:38])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[N:15])C1C=CC=CC=1.[ClH:57]>CO.[Pd]>[ClH:57].[OH:8][N:9]([C:16](=[O:56])[CH2:17][CH2:18][CH2:19][CH2:20][N:21]([OH:48])[C:22](=[O:47])[CH2:23][CH2:24][CH2:25][CH2:26][N:27]([OH:39])[C:28](=[O:38])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH2:15]
Reactant: CCCCCCCCCC(=O)N(CCCCC(=O)N(CCCCC(=O)N(CCCCC#N)OCc1ccccc1)OCc1ccccc1)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCCCCCCCCC(=O)N(O)CCCCC(=O)N(O)CCCCC(=O)N(O)CCCCCN

Procedure:
Compound (10) (1.13 g, 1.47 mmol) was hydrogenated in CH3OH (150 mL) and 0.1N HCl (16.2 mL, 1.62 mmol) with 10% Pd-C. (0.6 g) by the procedure used for [A]. Purification by Sephadex LH-20 column chromatography with 20% EtCH/toluene as the eluant produced 0.508 g (64%) of [A] as a colorless solid: NMR (CD3OD) δ 0.90 (t, 3 H, J=6), 1.17-1.87 (m, 28 H), 2.33-2.63 (m, 6 H), 2.92 (t, 2 H, J=6), 3.60 (t, 6 H, J=6 ). Anal. (C25H51ClN4O6) C, H, N.
Reaction SMILES: [CH3:1][CH2:2][Mg+].[Br-].C1COCC1.[Si:10]([O:17][CH2:18][CH:19]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)[C:20]#[N:21])([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].[OH-].[Na+]>CCOCC.C(Cl)Cl>[Si:10]([O:17][CH2:18][CH:19]([C:20]1([NH2:21])[CH2:2][CH2:1]1)[CH2:22][C:23]1[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)OCC(C#N)Cc1ccc(Cl)cc1
Reactant: CC[Mg+]
Agent: [Br-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCC(Cc1ccc(Cl)cc1)C1(N)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
A solution of EtMgBr in THF (3.0M, 8.0 mL, 24 mmol) was added dropwise at room temperature to a stirred solution of 3-(tert-butyldimethylsilyloxy)-2-(4-chlorobenzyl)propanenitrile (3.7 g, 12 mmol) and Ti(i-PrO)4 (3.9 mL, 13 mmol) in Et2O (50 mL). After the mixture was stirred at room temperature for 1 hour, BF3OEt (3.0 mL, 24 mmol) was added at once. The mixture was stirred for an additional 1 hour. A solution of 10% NaOH (10 mL) was added, followed by DCM (300 mL). The resulting precipitate was filtered and washed with DCM. The combined filtrates were dried and concentrated. The residue was purified by column chromatography (30:1 DCM:MeOH) to give 1-(1-(tert-butyldimethylsilyloxy)-3-(4-chlorophenyl)propan-2-yl)cyclopropanamine (2.6 g, 64%) as a colorless oil. LCMS: 340.2 (M+H)+ (APCI+); Rf: 3.17 min.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[CH2:8]([OH:12])[CH2:9][CH2:10][OH:11].S(O[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[C:20]=1[N+:27]([O-:29])=[O:28])(C)(=O)=O>CCCCCC.O>[OH:11][CH2:10][CH2:9][CH2:8][O:12][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[C:20]=1[N+:27]([O-:29])=[O:28]
Reactant: CSc1cccc(COS(C)(=O)=O)c1[N+](=O)[O-]
Reactant: OCCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: O
Product: CSc1cccc(COCCCO)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74 %

Procedure:
33 mg (0.76 mmol) of sodium hydride (as a 55% w/w suspension in mineral oil) were washed twice with hexane, and then 1 ml of dimethylformamide was added to the suspension. The resulting suspension was cooled in an ice bath, and then 0.8 ml (11 mmol) of 1,3-propanediol was added. The mixture was then stirred for 30 minutes at this temperature and then for 30 minutes at room temperature. 1 ml of a dimethylformamide solution containing the whole of the 2-mesyloxymethyl-6-methylthio-1-nitrobenzene prepared as described in step (i) above was then added to the resulting solution, whilst ice-cooling, and the mixture was stirred for 2 hours at the ice-cooling temperature and then for 1.5 hours at room temperature. At the end of this time, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic extract was washed with water several times, and then the solvent was removed by distillation under reduced pressure. The resulting residue was subjected to column chromatography through 10 g of silica gel using mixtures of methylene chloride and ethyl acetate in ratios ranging from 10:1 to 8:1 by volume as the eluent, to obtain 95 mg (yield 74%) of the title compound as an oily substance.
Reaction SMILES: C(OC([CH:6]1[CH:14]2[C:9]3([CH:18]=[CH:17][CH:16]=[CH:15][C:10]3=[N:11][CH2:12][CH2:13]2)[S:8][CH2:7]1)=O)C.[C:19]([O:23][C:24](SC1N=C(C)C=C(C)N=1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>C(Cl)(Cl)Cl>[CH2:19]([O:23][C:24]([C:7]1([C:24]([O:23][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:25])[S:8][C:9]23[CH:18]=[CH:17][CH:16]=[CH:15][C:10]2=[N:11][CH2:12][CH2:13][CH:14]3[CH2:6]1)=[O:25])[CH3:20]
Reactant: Cc1cc(C)nc(SC(=O)OC(C)(C)C)n1
Reactant: CCOC(=O)C1CSC23C=CC=CC2=NCCC13
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1(C(=O)OC(C)(C)C)CC2CCN=C3C=CC=CC32S1
Yield: 123.3 %

Procedure:
In 20 ml of desiccated chloroform were dissolved 6 g of 1,2,3,4-tetrahydro-benzo[b]thieno[2,3-c]pyridinecarboxylic acid ethyl ester synthesized in Example 1 and 6.63 g of 2-(tertiary-butoxycarbonylthio)-4,6-dimethylpyrimidine, and the solution was refluxed for 30 minutes. After distilling off chloroform under reduced pressure, the residue was dissolved in 300 ml of ethyl acetate and the solution was washed thrice with 50 ml of an aqueous 5% sodium hydrogencarbonate, twice with an aqueous 5% citric acid solution, and then twice with a saturated aqueous sodium chloride solution and thereafter dried with sodium sulfate. Ethyl acetate was distilled off under reduced pressure and the residue was recrystallized from a mixture of chloroform and petroleum ether to provide 6.18 g (yield of 76%) of 2 -tert-butoxycarbonyl-1,2,3,4-tetrahydro-benzo[b]thieno[2,3-c]pyridine-carboxylic acid ethyl ester.