Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.C(O[C:13](=O)[N:14]([C@@H:16]([C:30](=[O:40])[N:31]([CH3:39])[CH2:32][CH2:33][C:34]1[S:35][CH:36]=[CH:37][CH:38]=1)[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)C)(C)(C)C.C(=O)([O-])O.[Na+].O>ClCCl>[C:21]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:20]=[CH:19][C:18]([CH2:17][C@@H:16]([NH:14][CH3:13])[C:30]([N:31]([CH3:39])[CH2:32][CH2:33][C:34]2[S:35][CH:36]=[CH:37][CH:38]=2)=[O:40])=[CH:23][CH:22]=1
Reactant: CN(CCc1cccs1)C(=O)[C@@H](Cc1ccc(-c2ccccc2)cc1)N(C)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@H](Cc1ccc(-c2ccccc2)cc1)C(=O)N(C)CCc1cccs1
Temperature: 0 °C
Reaction time: 3 h
Yield: 93.7 %

Procedure:
At 0° C., trifluoroacetic acid (4 ml) was added to a solution of N-((1R)-2-(biphenyl-4-yl)-1-(N-methyl-N-(2-(2-thienyl)ethyl)carbamoyl)ethyl)-N-methylcarbamic acid tert-butyl ester (910 mg, 1.90 mmol) in dichloromethane (4 ml). The reaction mixture was stirred for 3 h at 0° C. A saturated solution of sodium hydrogen carbonate (8 ml) was added. Solid sodium hydrogen carbonate was added, until pH 7 was obtained. Water was added, until a clear solution was obtained. The phases were separated. The aqueous phase was extracted with dichloromethane (2×30 ml). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo. The crude produduct was purified by flash chromatogrphy on silica (60 g), using dichloromethane/methanol/25% aqueous ammonia (100:10:1) as eluent, to give 674 mg of (2R)-3-(biphenyl-4-yl)-N-methyl-2-(methylamino)-N-(2-(2-thienyl)ethyl)propionamide.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11](N)=[O:12])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.[OH-].[Na+].S(=O)(=O)(O)[OH:19]>C(O)C>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:19])=[O:12])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1
Reactant: NC(=O)c1ccc(-c2ccncc2)cc1
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(-c2ccncc2)cc1
Temperature: 25 °C

Procedure:
4-(4-Pyridyl)benzamide (0.35 g, 1.8 mmol) was suspended in ethanol (5 mL). 10% w/w aqueous sodium hydroxide solution was added and the reaction mixture refluxed for two hours then allowed to cool to room temperature. The reaction mixture was adjusted to pH 7 with concentrated sulphuric acid. A white precipitate formed which was isolated by filtration to give 4-(4-pyridyl)benzoic acid (238 mg).
Reaction SMILES: C([Li])CCC.[CH:6]([C@H:9]1[N:14]=[C:13]([O:15][CH2:16][CH3:17])[CH2:12][N:11]=[C:10]1[O:18][CH2:19][CH3:20])([CH3:8])[CH3:7].[CH2:21]([C:24]1[CH:34]=[CH:33][C:27]([CH:28](Br)[SiH:29]([CH3:31])[CH3:30])=[CH:26][CH:25]=1)[CH:22]=[CH2:23].[NH4+].[Cl-]>C1COCC1>[CH2:21]([C:24]1[CH:34]=[CH:33][C:27]([CH:28]([SiH:29]([CH3:30])[CH3:31])[C@H:12]2[N:11]=[C:10]([O:18][CH2:19][CH3:20])[C@@H:9]([CH:6]([CH3:7])[CH3:8])[N:14]=[C:13]2[O:15][CH2:16][CH3:17])=[CH:26][CH:25]=1)[CH:22]=[CH2:23]
Reactant: C=CCc1ccc(C(Br)[SiH](C)C)cc1
Reactant: CCOC1=N[C@H](C(C)C)C(OCC)=NC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CCc1ccc(C([C@H]2N=C(OCC)[C@@H](C(C)C)N=C2OCC)[SiH](C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
n-Butyllithium (10.2 mL, 1.6 M solution in hexanes, 16.5 mmol) was injected into a solution of (3R)-3-isopropyl-2,5-diethoxy-3,6-dihydropyrazine (3.5 g, 16.5 mmol) in THF (70 mL) at −78° C. After 30 min of further stirring, 4-allyldimethylsilylbenzyl bromide (1 Scheme 2, 4.4 g, 16.5 mmol) in dry THF (30 mL) was added to the reaction mixture over a period of 1 h. After 1 h, saturated NH4Cl (1 mL) was added and the reaction mixture was allowed to warm to room temperature. The reaction mixture was concentrated, diluted with ethyl acetate (100 mL), and extracted with brine (20 mL×2). The organic layer was concentrated and the residue was purified by column chromatography (1:25 ethyl acetate/hexanes) to afford a colorless oil (4.7 g, 71%); 1H NMR (300 MHz, CDCl3) δ 0.28 (s; 6 H), 0.65 (d, J=6.75 Hz, 3 H), 0.96 (d, J=6.75 Hz, 3 H), 1.29 (t, J=7.05 Hz, 3 H), 1.35 (t) J=7.09 Hz, 3 H), 1.74 (d, J=8.05 Hz, 2 H), 2.19 (quintet of d, J=6.87, 3.21 Hz, 1 H), 3.10 (d, J=4.92 Hz, 2 H), 3.28 (m, 1 H), 4.07-4.24 (4 H), 4.31 (app q, J=4.50 Hz, 1 H), 4.83 (s, 1 H), 4.87 (m, 1 H), 5.77 (ddt, J=15.87, 11.13, 8.08 Hz, 1 H), 7.14 (d, J=7.98 Hz, 2 H), 7.38 (d, J=7.98 Hz, 2 H); 13C NMR (75 MHz, CDCl3) −3.4 −3.3, 14.5, 16.6, 19.1, 23.9, 31.3, 40.2, 56.7, 60.2, 60.4, 60.5, 113.3, 129.5 (2C), 133.2 (2C), 134.7, 135.9, 138.5, 162.2, 163.5; HRMS calcd for C23H36N2O2Si 400.2546, found 400.2543.
Reaction SMILES: C1(O[C:8](=[O:27])[NH:9][C:10]2[CH:15]=[C:14]([O:16][C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:18]=3[F:26])[N:13]=[CH:12][N:11]=2)C=CC=CC=1.[NH2:28][CH:29]1[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]1>CN(C)C=O>[F:26][C:18]1[CH:19]=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=[CH:22][C:17]=1[O:16][C:14]1[N:13]=[CH:12][N:11]=[C:10]([NH:9][C:8]([NH:28][CH:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[O:27])[CH:15]=1
Reactant: CN1CCC(N)CC1
Reactant: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ncn1)Oc1ccccc1
Solvent: CN(C)C=O
Product: CN1CCC(NC(=O)Nc2cc(Oc3ccc([N+](=O)[O-])cc3F)ncn2)CC1
Reaction time: 4 h
Yield: 99.8 %

Procedure:
[6-(2-Fluoro-4-nitrophenoxy)pyrimidin-4-yl]carbamic acid phenyl ester (190 mg) was dissolved in N,N-dimethylformamide (2 ml), and then 4-amino-1-methylpiperidine (176 mg)-N,N-dimethylformamide (3 ml) was added thereto, followed by stirring for 4 hrs. The reaction mixture was partitioned between ethyl acetate (30 ml) and a saturated aqueous solution of sodium hydrogencarbonate (20 ml). The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (20 ml), water (20 ml) and brine (20 ml), and dried over anhydrous sodium sulfate. The solvent was evaporated to give a crude product of 1-[6-(2-fluoro-4-nitrophenoxy)pyrimidin-4-yl]-3-(1-methylpiperidin-4-yl)urea (200 mg). The crude product (200 mg) was dissolved in methanol (5 ml)-tetrahydrofuran (5 ml), and then 10% palladium carbon (109 mg) was added thereto under a nitrogen atmosphere, followed by replacing with hydrogen inside the system and stirring overnight. After replacing with nitrogen inside the system, the catalyst was filtered, and washed with ethanol. The filtrate was concentrated under a reduced pressure to give a residue, to which diethyl ether (2.5 ml)-hexane (5.0 ml) was added to suspend. The solid was filtered off, and dried under aeration to provide a crude product of 1-[6-(4-amino-2-fluorophenoxy)pyrimidin-4-yl]-3-(1-methylpiperidin-4-yl)urea (183 mg).
Reaction SMILES: [N+](C1C=CC(C[O:11][C:12]([C:14]2[N:15]3[CH:18]([CH:19]([CH3:29])[C:20]=2[S:21][CH:22]2[CH2:26][CH:25]([CH2:27]I)[O:24][CH2:23]2)[CH:17]([CH:30]([OH:32])[CH3:31])[C:16]3=[O:33])=[O:13])=CC=1)([O-])=O.C(=O)(O)[O-].[Na+:38].O>[Pd].O1CCOCC1>[Na+:38].[OH:32][CH:30]([CH:17]1[C:16](=[O:33])[N:15]2[CH:18]1[CH:19]([CH3:29])[C:20]([S:21][CH:22]1[CH2:26][CH:25]([CH3:27])[O:24][CH2:23]1)=[C:14]2[C:12]([O-:13])=[O:11])[CH3:31]
Reactant: CC(O)C1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3COC(CI)C3)C(C)C12
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC1CC(SC2=C(C(=O)[O-])N3C(=O)C(C(C)O)C3C2C)CO1
Yield: 36.2 %

Procedure:
The title compound is prepared by the procedure of Example 18 using 0.450 g of product from Example 58, 0.230 g of 10% palladium/carbon, 0.161 g of sodium bicarbonate, 5 ml of water, and 12 ml of dioxane to give 0.0967 g of the desired product.
Reaction SMILES: [C:1]([C:5]1[N:6]([C:18]([OH:20])=[O:19])[C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([Br:14])=[C:9]([Cl:15])[C:8]=2[CH2:16]Br)([CH3:4])([CH3:3])[CH3:2].C[N+]1([O-])CC[O:25]CC1>C(#N)C>[C:1]([C:5]1[N:6]([C:18]([OH:20])=[O:19])[C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([Br:14])=[C:9]([Cl:15])[C:8]=2[CH:16]=[O:25])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc2cc(Br)c(Cl)c(CBr)c2n1C(=O)O
Reactant: C[N+]1([O-])CCOCC1
Solvent: CC#N
Product: CC(C)(C)c1cc2cc(Br)c(Cl)c(C=O)c2n1C(=O)O
Temperature: 50 °C
Reaction time: 7 h
Yield: 47.6 %

Procedure:
To a mixture of tert-butyl 5-bromo-7-(bromomethyl)-6-chloro-1H-indole-1-carboxylic acid (7.2 g) and acetonitrile (50 mL) was added 4-methyl morpholine-4-oxide (2.7 g) at room temperature. The reaction mixture was stirred at 50° C. for 7 hours and then at 70° C. overnight. The reaction mixture was concentrated under reduced pressure, ethyl acetate and water were added thereto, and a liquid-separation operation was carried out. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0-90:10) to obtain tert-butyl 5-bromo-6-chloro-7-formyl 1H-indole-1-carboxylic acid (2.9 g).
Reaction SMILES: [N:1]1([C:8]([NH:10][C@@H:11]([CH:15]([CH3:18])[CH2:16][CH3:17])[C:12]([OH:14])=O)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:19]([O:23][C:24](=[O:42])[C@@H:25]([NH2:41])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:29][CH:28]=1)([CH3:22])([CH3:21])[CH3:20]>>[C:19]([O:23][C:24](=[O:42])[C@@H:25]([NH:41][C:12](=[O:14])[C@@H:11]([NH:10][C:8]([N:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1)=[O:9])[CH:15]([CH3:18])[CH2:16][CH3:17])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:29][CH:28]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CCC(C)[C@H](NC(=O)N1CCCCCC1)C(=O)O
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(OCc2ccccc2)cc1
Product: CCC(C)[C@H](NC(=O)N1CCCCCC1)C(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)OC(C)(C)C

Procedure:
A solution of the product from Example AB ((S)-2-[(azepane-1-carbonyl)-amino]-3-methyl-pentanoic acid) (0.50 g, 1.95 mmol) and the product from Example A ((S)-2-amino-3-(4-benzyloxy-phenyl)-propionic acid tert-butyl ester) (0.63 g, 1.95 mmol) were coupled according to the procedure described in Example AH. The crude reaction product was purified by chromatography (silica gel, 1:1 EtOAc/heptane) to give the title compound as a white foam, mp=53-57° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:30](=O)[CH3:31])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:29])[C:15]2[CH:20]=[C:19]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:18]=[CH:17][C:16]=2[O:25][CH:26]([CH3:28])[CH3:27])[CH2:10][CH2:9]1.Cl.[NH2:34][OH:35].C([O-])(=O)C.[Na+]>C(O)C.O>[F:1][C:2]1[CH:3]=[C:4]([C:30](=[N:34][OH:35])[CH3:31])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:29])[C:15]2[CH:20]=[C:19]([S:21]([CH3:24])(=[O:22])=[O:23])[CH:18]=[CH:17][C:16]=2[O:25][CH:26]([CH3:27])[CH3:28])[CH2:10][CH2:9]1
Reactant: NO
Reactant: CC(=O)c1ccc(N2CCN(C(=O)c3cc(S(C)(=O)=O)ccc3OC(C)C)CC2)c(F)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(=NO)c1ccc(N2CCN(C(=O)c3cc(S(C)(=O)=O)ccc3OC(C)C)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.12 mmol of 1-{3-Fluoro-4-[4-(2-isopropoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-phenyl}-ethanone was dissolved in 1 ml of a 1:1 mixture of ethanol and water. 0.8 mmol of hydroxylamine hydrochloride was added, followed by 8.4 mmol of sodium acetate. The resulting mixture was stirred overnight at room temperature, diluted with water, filtered, washed and dried to yield the title compound as a colorless solid.
Reaction SMILES: C([O:8][C:9]1[CH:21]=[CH:20][C:12]([O:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C1COCC1>[Pd].CCO>[N:17]1[CH:16]=[CH:15][C:14]([O:13][C:12]2[CH:20]=[CH:21][C:9]([OH:8])=[CH:10][CH:11]=2)=[CH:19][CH:18]=1
Reactant: c1ccc(COc2ccc(Oc3ccncc3)cc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Oc1ccc(Oc2ccncc2)cc1
Yield: 94.4 %

Procedure:
The same procedure from Example 143, step 2 was followed using the product from step 1 (306 mg, 0.905 mmol), THF (3 ml), EtOH (9 ml), 10% Pd/C (300 mg, 0.0905 mmol) to give the title compound (160 mg, 95%).
Reaction SMILES: [CH2:1]([CH:3]([CH2:16][CH3:17])[C:4]([C:6]1[S:7][C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[C:10]=1[CH3:11])=O)[CH3:2].[NH2:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=1.C(=O)([O-])O.[Na+].C([BH3-])#N.[Na+]>C(Cl)Cl.O1CCCC1.[Ti](Cl)(Cl)(Cl)Cl.C(O)(=O)C.C(N(CC)CC)C>[CH2:1]([CH:3]([CH2:16][CH3:17])[CH:4]([NH:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:27][CH:28]=1)[C:6]1[S:7][C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[C:10]=1[CH3:11])[CH3:2]
Reactant: COC(=O)c1ccc(N)cc1
Reactant: CCC(CC)C(=O)c1sc2ccccc2c1C
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCC(CC)C(Nc1ccc(C(=O)OC)cc1)c1sc2ccccc2c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.7 %

Procedure:
To a mixture of 2-ethyl-1-(3-methyl-1-benzothiophen-2-yl)butan-1-one (1.65 g) synthesized above, methyl 4-aminobenzoate (1.15 g), triethylamine (7.47 mL) and methylene chloride (15 mL) was added a 1.0M solution (8.04 mL) of titanium (IV) chloride in methylene chloride, and the mixture was stirred under argon atmosphere overnight at room temperature. Saturated aqueous sodium hydrogen carbonate solution was added to quench the reaction, methylene chloride was evaporated in an evaporator, and the residue was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a dark brown oil. To a mixture of the obtained oil, methyl 4-aminobenzoate (506 mg), triethylamine (7.47 mL) and methylene chloride (30 mL) was added titanium (IV) chloride (882 μL), and the mixture was stirred under argon atmosphere overnight at room temperature. Saturated aqueous sodium hydrogen carbonate solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a dark brown oil. To a solution (30 mL) of the obtained oil in tetrahydrofuran were added acetic acid (797 μL) and sodium cyanoborohydride (842 mg) and the mixture was stirred at room temperature stirred for 1.5 hr. Saturated aqueous sodium hydrogen carbonate solution was added to quench the reaction, the organic solvent was evaporated in an evaporator, and the residue was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10-40% ethyl acetate/hexane) to give the title object compound (580 mg, 23%) as a pale-brown solid.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH:17]=O)[N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[N:3]=1.[NH:25]1[CH2:30][CH2:29][CH:28]([C:31]([OH:34])([CH3:33])[CH3:32])[CH2:27][CH2:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(=O)(O)[O-].[Na+]>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:17][N:25]3[CH2:30][CH2:29][CH:28]([C:31]([OH:34])([CH3:33])[CH3:32])[CH2:27][CH2:26]3)[N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[N:3]=1
Reactant: O=Cc1nc2c(N3CCOCC3)nc(Cl)nc2n1C1CCCCO1
Reactant: CC(C)(O)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(O)C1CCN(Cc2nc3c(N4CCOCC4)nc(Cl)nc3n2C2CCCCO2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.4 %

Procedure:
A mixture of 2-chloro-6-morpholino-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-8-carbaldehyde (245 mg, 0.696 mmol), 2-(4-piperidyl)-2-propanol (110 mg, 0.77 mmol) and sodium triacetoxyborohydride (162 mg, 0.77 mmol) in 1,2-dichloroethane (10 mL) was stirred at room temperature for 30 minutes. The reaction mixture was then diluted with saturated aqueous sodium bicarbonate. The aqueous layer was then extracted with DCM. The combined organic extracts were then washed with water, dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography (0-100% gradient EtOAc-heptane) to give the title compound (328 mg, 98%). LCMS: M+H+=480.2.
Reaction SMILES: [BH4-].[Na+].[N:3]1([CH:8]2[C:13](=[O:14])[C:12]3[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=3[O:10][CH2:9]2)[CH:7]=[CH:6][N:5]=[CH:4]1.O>CO>[N:3]1([CH:8]2[CH:13]([OH:14])[C:12]3[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=3[O:10][CH2:9]2)[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: O=C1c2cc(Cl)ccc2OCC1n1ccnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OC1c2cc(Cl)ccc2OCC1n1ccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.2 %

Procedure:
NaBH4 (1 g) was added portionwise to a solution of 3-(1-imidazolyl)-2,3-dihydro-6-chloro-4H-1-benzopyran-4-one (2.7 g) in MeOH (70 ml) at 5°-10° C. The mixture, stirred at room temperature for 2 hours, added with water (300 ml), extracted with CHCl3, dried and evaporated to dryness gave (2.7 g) 3-(1-imidazolyl)-2,3-dihydro-6-chloro-4H-1-benzopyran-4-ol.
Reaction SMILES: Br[C:2]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[C:5]2[N:6]([CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.[Cu][C:28]#[N:29].C(=O)(O)[O-].[Na+]>CN(C)C=O>[O:9]=[C:7]1[N:6]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[C:5]2[C:21]([C:23]([F:26])([F:25])[F:24])=[CH:22][C:2]([C:28]#[N:29])=[CH:3][C:4]=2[NH:8]1
Reactant: N#C[Cu]
Reactant: O=c1[nH]c2cc(Br)cc(C(F)(F)F)c2n1Cc1cccc(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cc(C(F)(F)F)c2c(c1)[nH]c(=O)n2Cc1cccc(C(F)(F)F)c1
Yield: 92.5 %

Procedure:
To a solution of 5-bromo-7-(trifluoromethyl)-1-[3-(trifluoromethyl)benzyl]-1,3-dihydro-2H-benzimidazol-2-one (171.9 mg) and copper(I) cyanide (76.3 mg) in N,N-dimethylformamide (10 ml) was heated at reflux for 11 hours. Copper(I) cyanide (51.0 mg) was further added, and the mixture was heated at reflux for 13 hours. To the reaction mixture was added saturated aqueous sodium bicarbonate solution, and the mixture was extracted 5 times with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and concentrated in vacuo to give the title compound (139.5 mg, 93%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][S:6]([NH:9][CH2:10][CH:11]([O:35][CH3:36])[CH2:12][O:13][C:14](=[O:34])[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])(=[O:8])=[O:7].[I-:37].[Na+]>C(C(C)=O)C>[I:37][CH2:2][CH2:3][CH2:4][CH2:5][S:6]([NH:9][CH2:10][CH:11]([O:35][CH3:36])[CH2:12][O:13][C:14](=[O:34])[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])(=[O:8])=[O:7]
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CNS(=O)(=O)CCCCCl)OC
Reactant: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CNS(=O)(=O)CCCCI)OC
Yield: 81 %

Procedure:
To a solution of 1.23 g (2.22 mM) of 3-(4-chlorobutylsulfonylamino)-2-methoxy-1-octadecylcarbamoyloxypropane IIIa5 in 20 ml of methyl ethyl ketone is added 0.67 g (4.44 mM) of sodium iodide and the mixture is heated for 3 hours with stirring. After the solvent is evaporated, the residue is purified by the column chromatography on silica gel with a n-hexane-ethyl acetate (1:1) mixture as an eluent. The product is recrystallized from chloroform-n-hexane to give 1.16 g (1.79 mM) of 3-(4-iodobutylsulfonylamino)-2-methoxy-1-octadecylcarbamoyloxypropane IIa5 in 81% yield.
Reaction SMILES: [CH:1]1[N:5]2[C:6]3[CH2:17][C:16]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=4[C:7]=3[NH:8][C:9](=[O:10])[C:4]2=[N:3][CH:2]=1.CS(C)=O.O.[C:23]([OH:27])(=[O:26])[CH:24]=[O:25].[H-].[Na+]>O.C(O)(=O)C>[O:10]=[C:9]1[NH:8][C:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[CH:17]([CH:24]([OH:25])[C:23]([OH:27])=[O:26])[C:6]=2[N:5]2[CH:1]=[CH:2][N:3]=[C:4]12
Reactant: O=c1[nH]c2c(n3ccnc13)Cc1ccccc1-2
Reactant: O=CC(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)C(O)C1c2ccccc2-c2[nH]c(=O)c3nccn3c21
Temperature: 20 °C
Reaction time: 18 h
Yield: 63.9 %

Procedure:
To a stirred mixture of 6.7 g of 5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one, 140 ml of dimethyl sulphoxide and 4.15 g of glyoxylic acid monohydrate, under an argon atmosphere, are added portionwise 4.95 g of 80% sodium hydride while maintaining the temperature at about 20° C. The stirring is continued for 18 hours, and the reaction medium is acidified using acetic acid (11 ml) and is heated at a temperature in the region of 80° C. for 2 hours. The reaction mixture is filtered and the solid is washed with acetone (3×75 ml), with methanol (75 ml), again with acetone (2×75 ml) and dried under vacuum (1 mmHg; 0.13 kPa). The light-beige-coloured solid obtained (10.1 g) is dissolved in 500 ml of distilled water and the aqueous solution is washed with ethyl acetate (2×100 ml), then treated with 0.5 g of animal black and filtered. The filtrate is acidified with 45 ml of 1N hydrochloric acid and the precipitate formed is filtered off, washed with distilled water (50 ml) and with acetone (3×75 ml), and dried at 70° C. under vacuum (1 mmHg; 0.13 kPa). 5.7 g of (4,5-dihydro-4-oxo-10H-imidazo(1,2-a]indeno[1,2-e]pyrazin-10-yl)glycolic acid are obtained in the form of a pale yellow solid melting above 260° C. (1H NMR spectrum (200 MHz, (CD3)2 SO-d6, δ in ppm): 4.60 (d, J=3 Hz, 1H: H 10); 5.09 (d, J=3 Hz, 1H: CHO); 5.60 (broad mult., 1H: OH); from 7.25 to 7.50 (mt, 2H: H 7 and H 8); 7.45 and 7.85 (2 broad d, J=7.5 Hz, 1H each: H 6 and H 8); 7.57 and 8.23 (2 broad s, 1H each: H of the imidazole); 12.35 (broad s, 1H: NH 5)).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[S:5][CH:6]=1.CN(C=O)C.[CH:17]#[C:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C(N(CC)CC)C>[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OC)(C)(C)C>[C:17]([C:2]1[CH:3]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[S:5][CH:6]=1)#[C:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: C#CCCCCC
Reactant: CCOC(=O)c1cc(Br)cs1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCCC#Cc1csc(C(=O)OCC)c1
Temperature: 65 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
A reaction mixture of compound 1015 (5.64 g, 24.0 mmol), DMF (50 mL), copper (I) iodide (1.37 g, 7.2 mmol), 1-heptyne (9.42 mL, 72.0 mmol), triethylamine (6.70 mL, 48.0 mmol) and tetrakis(triphenylphosphine)palladium(0) (2.77 g, 2.4 mmol) was stirred at 65° C. for 2 hours and then cooled to room temperature. Methyl tert-butyl ether (300 mL) was added to the reaction mixture and the precipitation was removed by filtration. The clear organic solution was washed with saturated sodium chloride, dried over magnesium sulfate and concentrated under vacuum. The crude brown oil was purified with flash silica gel chromatogram (with 0%→5% EtOAc in hexane) to afford ethyl 4-(hept-1-ynyl)thiophene-2-carboxylate (1016, 5.89 g) as a brown oil. 1H NMR (300 MHz, δ, CDCl3) 0.89 (t, 3H). 1.28-1.45 (m, 7H), 1.52-1.62 (m, 2H), 2.36 (t, 12.4 Hz, 2H), 4.33 (q, 2H), 7.48 (s, 1H), 7.72 (s, 1H).