Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH2:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)(=[O:5])=[O:4].[NH2:13][NH2:14].O.Cl.CO>CN(C=O)C>[ClH:12].[F:1][CH2:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([NH:13][NH2:14])=[CH:8][CH:7]=1)(=[O:5])=[O:4]
Reactant: NN
Reactant: O=S(=O)(CF)c1ccc(Cl)cc1
Agent: Cl
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: NNc1ccc(S(=O)(=O)CF)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 49.4 %

Procedure:
A mixture of 4-chlorophenyl fluoromethyl sulfone (1.97 g, 9.44 mmol. prepared according to the method of Ukrainskill Khimicheskill Zhurnal, 1972, 38. 1034) and hydrazine anhydrous (1.84 g, 57.5 mmol) in DMF (30 mL) was heated to 120° C. for 16 hours, and cooled down to room temperature. The reaction mixture was poured into water (150 mL) and the whole was extracted with ethyl acetate/hexane/ether (2/1/1, 60 mL×3). The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo. The resulting solid (1.56 g, 7.64 mmol) was added HCl-MeOH reagent 10 (10 mL) at room temperature and stirred for 10 minutes. The mixture was concentrated in vacuo to give the subtitle compound (0.91 g, 49.4% yield).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:4]=1)=O.[C:19]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)(=[O:21])[CH3:20].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CC(O)=O.C(Cl)Cl>[C:19]([N:22]1[CH2:27][CH2:26][N:25]([CH2:1][C:3]2[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:4]=2)[CH2:24][CH2:23]1)(=[O:21])[CH3:20]
Reactant: COc1cc(C=O)cc(NC(=O)OC(C)(C)C)n1
Reactant: CC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1cc(CN2CCN(C(C)=O)CC2)cc(NC(=O)OC(C)(C)C)n1

Procedure:
To a solution of tert-butyl 4-formyl-6-methoxypyridin-2-ylcarbamate (15-3, 292 mg, 1.16 mmole) and 1-acetylpiperazine (178 mg, 1.39 mmole) in 2% glacial HOAc in CH2Cl2 (5 mL) was added NaBH(OAc)3 (270 mg, 1.27 mmole) at RT. After 1.5 hr the mixture was quenched with saturated NaHCO3 and extracted with CH2Cl2 (3×). The combined organic layers were dried (MgSO4), filtered, and concentrated. Flash column chromatography (gradient, 0-5% EtOH/EtOAc) gave the titled compound as a white foam. 1H-NMR (500 MHz, CDCl3) δ7.41 (s, 1H), 7.00 (bs, 1H), 6.43 (s, 1H), 3.83 (s, 3H), 3.63 (bs, 2H), 3.46 (bs, 4H), 2.41 (m, 4H), 2.08 (s, 3H), 1.52 (s, 9H); MS (ES) (M+H)+365.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][CH:13]([CH:16]([CH3:18])[CH3:17])[C:14]#[N:15].Cl.[CH3:20][OH:21]>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][CH:13]([CH:16]([CH3:18])[CH3:17])[C:14](=[NH:15])[O:21][CH3:20]
Reactant: CO
Reactant: CC(C)C(C#N)Nc1ccc(C(F)(F)F)cc1Cl
Agent: Cl
Product: COC(=N)C(Nc1ccc(C(F)(F)F)cc1Cl)C(C)C

Procedure:
Following the procedure described in Example 6, 2-(2-chloro-4-trifluoromethylphenylamino)-3-methylbutyronitrile is reacted with methanol and hydrogen chloride to give methyl 2-(2-chloro-4-trifluoromethylphenylamino)-3-methylbutanimidate, which is then reacted with 3-phenoxybenzyl alcohol, yielding the desired compound 3-phenoxybenzyl 2-(2-chloro-4-trifluoromethylphenylamino)-3-methylbutanimidate.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5](Br)=[CH:4][C:3]=1[CH3:10].[C:11]([Cu])#[N:12].[CH3:14][N:15](C)C=O.N>O>[CH3:10][C:3]1[CH:4]=[C:5]([C:11]#[N:12])[C:6]([CH3:8])=[CH:7][C:2]=1[C:14]#[N:15]
Reactant: CN(C)C=O
Reactant: N#C[Cu]
Reactant: Cc1cc(Br)c(C)cc1Br
Agent: N
Solvent: O
Product: Cc1cc(C#N)c(C)cc1C#N
Reaction time: 12 h
Yield: 56 %

Procedure:
60 g of 2,5-Dibromo-p-xylene (0.227 mole), 42.4 g of CuCN (0.568 mole) and 300 ml of dimethylformamide were added into a round-bottom flask, and then the reaction was performed at 130° C. for 12 hours. After completion of the reaction, the reaction mixture was added to the mixing solution of 300 ml of water and 300 ml of aqueous ammonia, and extracted crystal therefrom was filtered. Then, the crystal was added again to the mixing solution of 100 ml of water and 300 ml of aqueous ammonia, mixed and filtered. The obtained crystal was added to 2,000 ml of toluene, heated to dissolve, and treated with active carbon. The filtrate was evaporated in vacuum, and then 300 ml of hexane was added thereto to obtain 20 g of white crystal (0.128 mole, yield: 56%).
Reaction SMILES: COC(=O)C1C=CC=C(CN2[CH2:16][CH2:15][CH:14]([C:17]3[C:25]4[C:20](=[N:21][CH:22]=[CH:23][CH:24]=4)[N:19]([CH2:26][CH2:27][O:28][CH2:29][CH3:30])[CH:18]=3)CC2)C=1.[OH-:32].[Na+].[CH2:34]([OH:36])[CH3:35]>>[CH2:29]([O:28][CH2:27][CH2:26][N:19]1[C:20]2=[N:21][CH:22]=[CH:23][CH:24]=[C:25]2[C:17]([CH:14]([C:15]2[CH:16]=[CH:17][CH:14]=[CH:15][C:35]=2[C:34]([OH:32])=[O:36])[N:21]2[CH2:22][CH2:23][CH2:24][CH2:25][CH2:20]2)=[CH:18]1)[CH3:30]
Reactant: CCOCCn1cc(C2CCN(Cc3cccc(C(=O)OC)c3)CC2)c2cccnc21
Reactant: CCO
Reactant: [OH-]
Agent: [Na+]
Product: CCOCCn1cc(C(c2ccccc2C(=O)O)N2CCCCC2)c2cccnc21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
0.58 g (1.28 mmol) of 3-{4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-ylmethyl}-benzoic acid methyl ester were dissolved in 5 ml of ethyl alcohol and 1.93 ml of 2 N sodium hydroxide were added. After stirring at room temperature for 20 hours, the solvent was evaporated under reduced pressure and the residue dissolved in water. The mixture was neutralised with 2 N hydrochloric acid and extracted twice with dichloromethane. The organic phase was washed with water and brine, dried with magnesium sulphate, filtrated and evaporated. The crude material weighed 0.65 g and was purified by flash chromatography over silica gel affording 0.3 g (54% of yield) of the expected product.
Reaction SMILES: [CH2:1]([N:4]([C:8]1[C:9]([I:32])=[C:10]([C:24]([NH:26][CH2:27][CH:28]([OH:31])[CH2:29][OH:30])=[O:25])[C:11]([I:23])=[C:12]([C:21]=1[I:22])[C:13]([NH:15][CH2:16][CH:17]([OH:20])[CH2:18][OH:19])=[O:14])[C:5](=[O:7])[CH3:6])[CH:2]=[CH2:3].[I-].[K+].II.[OH:37][CH:38]([CH2:63][OH:64])[CH2:39][NH:40][C:41](=[O:62])[C:42]1[C:55]([I:56])=[C:54]([NH:57][CH:58]=[O:59])[C:53]([I:60])=[C:44]([C:45]([NH:47][CH2:48][CH:49]([OH:52])[CH2:50][OH:51])=[O:46])[C:43]=1[I:61].[OH-:65].[K+]>O.CO>[OH:20][CH:17]([CH2:18][OH:19])[CH2:16][NH:15][C:13]([C:12]1[C:21]([I:22])=[C:8]([N:4]([CH2:1][CH:2]([OH:65])[CH2:3][N:57]([C:54]2[C:53]([I:60])=[C:44]([C:45]([NH:47][CH2:48][CH:49]([OH:52])[CH2:50][OH:51])=[O:46])[C:43]([I:61])=[C:42]([C:55]=2[I:56])[C:41]([NH:40][CH2:39][CH:38]([OH:37])[CH2:63][OH:64])=[O:62])[CH:58]=[O:59])[C:5](=[O:7])[CH3:6])[C:9]([I:32])=[C:10]([C:24](=[O:25])[NH:26][CH2:27][CH:28]([OH:31])[CH2:29][OH:30])[C:11]=1[I:23])=[O:14]
Reactant: [OH-]
Reactant: O=CNc1c(I)c(C(=O)NCC(O)CO)c(I)c(C(=O)NCC(O)CO)c1I
Reactant: C=CCN(C(C)=O)c1c(I)c(C(=O)NCC(O)CO)c(I)c(C(=O)NCC(O)CO)c1I
Agent: II
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(=O)N(CC(O)CN(C=O)c1c(I)c(C(=O)NCC(O)CO)c(I)c(C(=O)NCC(O)CO)c1I)c1c(I)c(C(=O)NCC(O)CO)c(I)c(C(=O)NCC(O)CO)c1I
Temperature: 10 °C
Reaction time: 1 h

Procedure:
To a stirred solution of water (10 ml) and methanol (7 ml) is added 5-(N-allylacetamido)-N1,N3-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide (5.0 g 6.35 mmol). pH is adjusted to pH 2 and a solution of potassium iodide (1.05 g, 6.35 mmol) and iodine 1.61 g, 6.35 mmol) in water (5 ml) and methanol (5 ml) is added drop wise at 50° C. The mixture is stirred over night. The solution is cooled to 10° C. and N,N′-Bis-(2,3-dihydroxy-propyl)-5-formylamino-2,4,6-triiodo-isophthalamide (Example 1a)(4.65 g 6.35 mmol) is added. Potassium hydroxide (10 M) is added drop wise to maintain a stable pH of 11.6 and the mixture is stirred for 24 hours. The solution is diluted with water (50 ml) and treated with ion exchangers (AMB200C, 20 ml) and (IRA67, 20 ml). The resins are filtered off and rinsed with water. The combined aqueous phases are reduced in vacuo and the crude product is purified by preparative HPLC (column Phenomenex Luna C18 10 μm 250×50.0 mm, solvents: A=water and B=acetonitrile; gradient 0-10% B over 60 min; flow 50.0 ml/min.
Reaction SMILES: Cl.[CH2:2]([N:9]([S:15]([C:18]1[CH:27]=[C:26]2[C:21]([C:22]([Cl:32])=[CH:23][N:24]=[C:25]2[NH:28][C:29]([NH2:31])=[NH:30])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:10]([C:12]([OH:14])=[O:13])[CH3:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.NC(N)=N.[C:38](OC(=O)[C@H](C)N(CC1C=CC=CC=1)S(C1C=C2C(C(Cl)=CN=C2Cl)=CC=1)(=O)=O)([CH3:41])([CH3:40])[CH3:39]>COCCOC>[C:38]([O:13][C:12](=[O:14])[C@H:10]([CH3:11])[N:9]([CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[S:15]([C:18]1[CH:27]=[C:26]2[C:21]([C:22]([Cl:32])=[CH:23][N:24]=[C:25]2[NH:28][C:29]([NH2:31])=[NH:30])=[CH:20][CH:19]=1)(=[O:17])=[O:16])([CH3:41])([CH3:40])[CH3:39]
Reactant: C[C@@H](C(=O)O)N(Cc1ccccc1)S(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Reactant: C[C@@H](C(=O)OC(C)(C)C)N(Cc1ccccc1)S(=O)(=O)c1ccc2c(Cl)cnc(Cl)c2c1
Agent: Cl
Agent: N=C(N)N
Solvent: COCCOC
Product: C[C@@H](C(=O)OC(C)(C)C)N(Cc1ccccc1)S(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Temperature: 60 °C
Yield: 56.3 %

Procedure:
N-Benzyl-N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-L-alanine hydrochloride ##STR30## NaH (30 mg, 80% dispersion by wt in mineral oil, 1.01 mmol) was added in one portion to a stirred suspension of guanidine hydrochloride (154 mg, 1.61 mmol) in DME (5.0 mL) and the mixture was heated at 60° C. under N2 for 45 min. A solution of N-benzyl-N-[(1,4-dichloro-7-isoquinolinyl)sulphonyl]-L-alanine t-butyl ester (200 mg, 0.40 mmol) in DME (2.0 mL) was added and the mixture heated at 95° C. for 4 h. The solvents were evaporated in vacuo and the residue was purified by column chromatography upon silica gel using pentane-EtOAc (50:50 to 20:80) as eluant to give N-benzyl-N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-L-alanine t-butyl ester (120 mg, 0.225 mmol) as pale yellow foam after repeated evaporation from CH2Cl2,
Reaction SMILES: [Br:1][C:2]1[C:3]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[C:15]([N+:22]([O-])=O)[CH:14]=2)=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:9])[F:8].C(N(CC)CC)C.[CH3:32][CH:33](N)[CH2:34][OH:35].C(OCC)C>CN(C)C=O>[Br:1][C:2]1[C:3]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[C:15]([NH:22][CH:33]([CH3:32])[CH2:34][OH:35])[CH:14]=2)=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:9])([F:8])[F:10]
Reactant: CC(N)CO
Reactant: Cn1nc(Oc2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)c(Br)c1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(CO)Nc1cc(Oc2nn(C)c(C(F)(F)F)c2Br)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 21 h
Yield: 95.1 %

Procedure:
The dinitrobenzene obtained in Step A (10.0 g, 24.3 mmol) was dissolved in N,N-dimethylformamide (60 cm 3). Triethylamine (5.1 cm3, 36.5 mmol) and DL 2-aminopropanol 2.9 cm3, 36.5 mmol) were added, and the mixture was stirred at room temperature for 21 hours, and then heated at 70° C. for a further 3 hours. The mixture was cooled to room temperature, poured into diethyl ether (500 cm3) and washed with water (3×300 cm3). The organic layer was dried (MgSO4), filtered and evaporated under reduced pressure to give DL 2-[5-(4-bromo-1-methyl-5-trifluoromethyl-1H-pyrazol -3-yloxy)-2-nitrophenylamino]propan-1-ol (10.15 g) as an orange solid m.p 116°-118° C.
Reaction SMILES: [OH:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:16][CH2:17][CH2:18][N:19]=2)=[CH:11][CH:10]=1.[N:20]([O-])=O.[Na+].[CH2:24]1[C:32]2[C:27](=[CH:28][C:29]([N:33]3[C:37](=[O:38])[CH2:36][C:35]([CH3:39])=[N:34]3)=[CH:30][CH:31]=2)[CH2:26][CH2:25]1.C(=O)(O)[O-].[Na+]>Cl.C(O)C>[NH:19]1[CH2:18][CH2:17][N:16]=[C:15]1[C:12]1[CH:11]=[CH:10][C:9]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([NH:8][N:20]=[C:36]3[C:35]([CH3:39])=[N:34][N:33]([C:29]4[CH:28]=[C:27]5[C:32](=[CH:31][CH:30]=4)[CH2:24][CH2:25][CH2:26]5)[C:37]3=[O:38])[C:2]=2[OH:1])=[CH:14][CH:13]=1
Reactant: CC1=NN(c2ccc3c(c2)CCC3)C(=O)C1
Reactant: O=N[O-]
Reactant: Nc1cccc(-c2ccc(C3=NCCN3)cc2)c1O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC1=NN(c2ccc3c(c2)CCC3)C(=O)C1=NNc1cccc(-c2ccc(C3=NCCN3)cc2)c1O
Yield: 30.3 %

Procedure:
2-(2′-Hydroxy-3′-amino-biphenyl-4-yl-4,5-dihydro-1H-imidazol 32d (334 mg, 1.11 mmol) was dissolved in hydrochloric acid (3.7 mL, 1 mol/L) upon cooling by an ice-water bath, followed by dropwise addition of 1.5 mL of aqueous sodium nitrite (85 mg, 1.22 mmol). After the mixture was reacted for 20 minutes, 2-indan-5-yl-5-methyl-2,4-dihydro-pyrazol-3-one 1i (214 mg, 1 mmol) was added. The mixture was adjusted to pH 8 with saturated aqueous sodium bicarbonate, followed by addition of 5 mL of ethanol. The reaction mixture was reacted overnight at room temperature. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was filtered and 30 mL of water was added to the filter cake. After mixing well, the mixture was adjusted to pH 4 with concentrated hydrochloric acid to form precipitates. The mixture was filtered and the filter cake was purified by silica gel column chromatography to obtain the title compound 4-{[4′-(4,5-dihydro-1H-imidazol-2-yl)-2-hydroxy-biphenyl-3-yl]-hydrazono}-2-indan-5-yl-5-methyl-2,4-dihydro-pyrazol-3-one 32 (145 mg, yield 30.3%) as a red solid.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2([CH3:19])[O:18][CH2:17][CH2:16][O:15]2)[CH2:9]1)C1C=CC=CC=1.[H][H].Cl[C:23]([O:25][CH2:26][CH:27]=[CH2:28])=[O:24].[OH-].[Na+]>CO.O.O1CCCC1.[OH-].[OH-].[Pd+2]>[CH2:26]([O:25][C:23]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2([CH3:19])[O:15][CH2:16][CH2:17][O:18]2)[CH2:9]1)=[O:24])[CH:27]=[CH2:28]
Reactant: [H][H]
Reactant: CC1(C2CN(Cc3ccccc3)CCO2)OCCO1
Reactant: C=CCOC(=O)Cl
Agent: [Pd+2]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: C=CCOC(=O)N1CCOC(C2(C)OCCO2)C1

Procedure:
A solution of 4-benzyl-2-(2-methyl-1,3-dioxolan-2-yl)morpholine (4.25 g) in methanol (42 ml) was hydrogenated under atmospheric pressure of hydrogen over 20% palladium hydroxide on carbon (1.0 g) for 30 hours at ambient temperature. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to give an oil. To a solution of the oil in a mixture of water (50 ml) and tetrahydrofuran (50 ml) was added a solution of allyl chloroformate (1.8 ml) in tetrahydrofuran (4 ml) under ice-cooling with stirring, while keeping the pH between 8.5 and 9.5 with 4N aqueous sodium hydroxide. After stirring for one hour, the mixture was extracted with ethyl acetate (100 ml), washed with brine (50 ml), dried over magnesium sulfate, and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (50 g) and eluted with a mixture of methanol and chloroform (2:98, V/V) to give 4-allyloxycarbonyl-2-(2-methyl-1,3-dioxolan-2-yl)morpholine (2.26 g) as a syrup.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=O.[CH2:13]([CH2:15][NH2:16])[OH:14]>C(O)C>[F:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH2:4][NH:16][CH2:15][CH2:13][OH:14]
Reactant: O=Cc1cc([N+](=O)[O-])ccc1F
Reactant: NCCO
Solvent: CCO
Product: O=[N+]([O-])c1ccc(F)c(CNCCO)c1
Reaction time: 48 h
Yield: 56.7 %

Procedure:
To 2-fluoro-5-nitrobenzaldehyde (52.4 g, 0.31 mol) in absolute ethanol (500 ml) was added ethanolamine (18.93 g, 0.31 mol) and borane-pyridine complex (31.31 ml, 0.31 mol). The mixture was stirred for 48 h and then evaporated. The residue was acidified with 2.5N hydrochloric acid, extracted with methylene chloride (3×150 ml), and the extracts were discarded. The aqueous phase was basified with 25% aqueous sodium hydroxide and extracted with methylene chloride (4×200 ml). These extracts were washed with saturated brine solution, dried over magnesium sulfate and evaporated to give yellow crystals (37.67 g, 57%), m.p. 98.5-99.5° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[OH:7].C([O:10][C:11]([CH2:13][CH:14]=[C:15]1CCP(C2C=CC=CC=2)C1(C1C=CC=CC=1)C1C=CC=CC=1)=O)C.[CH:38]1C=CC=CC=1>>[OH:10][CH2:11][CH2:13][CH2:14][CH2:15]/[CH:4]=[C:3](\[CH3:38])/[C:2]([O:1][CH2:6][CH3:5])=[O:7]
Reactant: CCOC(=O)CC=C1CCP(c2ccccc2)C1(c1ccccc1)c1ccccc1
Reactant: OC1CCCCO1
Reactant: c1ccccc1
Product: CCOC(=O)/C(C)=C/CCCCO
Temperature: 90 °C

Procedure:
Tetrahydropyran-2-ol (2) (14.03 g; 0.138 mol) is added to a benzene solution (300 ml) of (ethoxycarbonylethylidene) triphenylphospholane (64.40 g; 0.178 mol) and the whole is refluxed at 90° C. for 1.5 hours. After the temperature is returned to room temperature, the solvent is then distilled off under reduced pressure, and the residue is separated and purified by column chromatography (developing solution, ethyl acetate:hexane=1:5) to produce Ester 3 (25.15 g; 0.135 mol) of 98% in yield.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:11]=[C:12]([NH:16][C:17](=[O:21])[CH:18]([CH3:20])[CH3:19])[CH:13]=[CH:14][CH:15]=2)[CH2:6][CH2:5]1.[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[C:32](Cl)=[O:33]>C1COCC1>[C:17]([NH:16][C:12]1[CH:11]=[C:10]([CH:7]2[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][NH:1][C:32]([C:23]3[CH:24]=[CH:25][C:26]4[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:22]=3)=[O:33])[CH2:5][CH2:6]2)[CH:15]=[CH:14][CH:13]=1)(=[O:21])[CH:18]([CH3:19])[CH3:20]
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCN)CC2)c1
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCNC(=O)c3ccc4ccccc4c3)CC2)c1

Procedure:
Prepared by Procedure Q1 (THF) and Scheme AT using N-(3-[1-(2-aminoethyl)-4-piperidinyl]phenyl)-2-methylpropanamide and 2-naphthoyl chloride: ESMS m/e: 444. 2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[Na].[C:10]1([SH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)C.C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]([S:16][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: Sc1ccccc1
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Clc1nccc(Sc2ccccc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.3 %

Procedure:
To a stirred solution of 2,4-dichloropyrimidine (1.00 g, 6.71 mmol) in absolute ethanol (10 mL), was added sodium salt of benzenethiol (0.89 g, 6.73 mmol) in small portions. The mixture was stirred at room temperature for 2 hours, then at 40° C. for 16 hours. It was diluted with ethyl acetate (20 mL), and filtered. The filtrate was concentrated in vacuo, and the residue was flash chromatographed on silica gel using ethyl acetate:petroleum ether (1:99→25:75) as eluant to give the desired product (498 mg, 36%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1[OH:10])[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O.O>[CH2:18]([O:10][C:9]1[C:2]([F:1])=[CH:3][C:4]([CH:5]=[O:6])=[CH:7][C:8]=1[F:11])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: ClCc1ccccc1
Reactant: O=Cc1cc(F)c(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cc(F)c(OCc2ccccc2)c(F)c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a mixture of 3,5-difluoro-4-hydroxybenzaldehyde (6) (8.26 g, 52.2 mmol), and potassium carbonate (14.4 g, 104.4 mmol) in dimethylformamide (100 mL) was added benzyl chloride (7.2 mL, 62.7 mmol) and stirred overnight at 50° C. The reaction was diluted with water and extracted with ethyl acetate (3×75 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (0-100% EtOAc in hexanes) to afford 4-(benzyloxy)-3,5-difluorobenzaldehyde (7).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:34](=[O:40])OC(Cl)(Cl)Cl)Cl.[NH2:42][C@H:43]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH2:45][CH2:44]1>C(Cl)(Cl)Cl>[C@H:43]1([NH:42][C:34]([NH:20][C:19]2[CH:21]=[CH:22][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:17][CH:18]=2)=[O:40])[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH2:45][CH2:44]1
Reactant: N[C@@H]1CCc2ccccc21
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)N[C@@H]4CCc5ccccc54)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 69.1 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (70 mg) was dissolved in chloroform (1 ml) and triethylamine (0.1 ml) to prepare a solution. A solution of triphosgene (33 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred at room temperature for 75 min. Next, a solution of (R)-1-aminoindane (31 mg) in chloroform (0.2 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (35 mg, yield 32%).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:16])[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10](I)=[CH:9][CH:8]=3.C1COCC1.CCN(CC)CC.[CH3:29][Si:30]([C:33]#[CH:34])([CH3:32])[CH3:31]>CCOCC.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>[CH3:29][Si:30]([C:33]#[C:34][C:4]1[C:5]2[N:6]([CH3:16])[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:13]=2[CH:14]=[CH:2][CH:3]=1)([CH3:32])[CH3:31]
Reactant: Cn1c2ccc(I)cc2c2cc(I)ccc21
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cn1c2ccccc2c2cccc(C#C[Si](C)(C)C)c21
Yield: 135.6 %

Procedure:
Firstly, a mixture of PdCl2(PPh3)2 (13 mg, 0.018 mmol), CuI (3.5 mg, 0.018 mmol) and 3,6-diiodo-9-methylcarbazole (200 mg, 0.46 mmol) was added with dist. THF (3 mL), dist. Et3N (1.5 mL) and trimethylsilylacetylene (653 μL, 4.6 mmol). The resultant mixture was stirred under a nitrogen atmosphere at room temperature for 3 hours to obtain a reaction mixture. Then, the reaction mixture was diluted with ether. After that, an organic layer was washed with dist. H2O and sat. NaCl, and was dried with MgSO4. The dried organic layer was filtered and concentrated to obtain a crude product. Subsequently, the obtained crude product was separated and purified by silica gel column chromatography (hexane/EtOAc=5/1) to obtain 3,6-bis[(trimethylsilylethynyl)-9-methylcarbazole (173 mg, 100% yield).