Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:12](=[O:13])[C:11]2[NH:10][C:9](/[CH:14]=[CH:15]/[C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:18][CH:17]=3)=[N:8][C:7]=2[N:6]([CH2:28][CH3:29])[C:4]1=[O:5])[CH3:2].[OH-].[Na+].S(OC)(O[CH3:36])(=O)=O>O.CO>[CH2:1]([N:3]1[C:12](=[O:13])[C:11]2[N:10]([CH3:36])[C:9](/[CH:14]=[CH:15]/[C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:18][CH:17]=3)=[N:8][C:7]=2[N:6]([CH2:28][CH3:29])[C:4]1=[O:5])[CH3:2]
Reactant: COS(=O)(=O)OC
Reactant: CCn1c(=O)c2[nH]c(/C=C/c3ccc(-c4ccccc4)cc3)nc2n(CC)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCn1c(=O)c2c(nc(/C=C/c3ccc(-c4ccccc4)cc3)n2C)n(CC)c1=O
Yield: 30.8 %

Procedure:
Compound 170 (1.50 g, 3.89 mmol) obtained in Reference Example 167 was suspended in a mixed solvent of 13 ml of water, 3.9 ml of a 2N aqueous solution of sodium hydroxide, and 7 ml of methanol. To the suspension was dropwise added 0.55 ml (5.83 mmol) of dimethyl sulfate, and the resultant mixture was stirred at 60° C. for 4 hours. Water (10 ml) was added thereto, and the deposited crystals were collected by filtration and dried. The obtained crude crystals were purified by silica gel column chromatography, followed by recrystallization from ethyl acetate to give 480 mg (yield 28%) of Compound 171 as yellow columns.
Reaction SMILES: CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.[C:18]([C:21]1[C:22]([C:29]([OH:31])=O)=[C:23]([CH3:28])[N:24]([CH3:27])[C:25]=1[CH3:26])(=[O:20])[CH3:19].C(Cl)CCl.[CH3:36][O:37][C:38](=[O:58])[C@H:39]([CH2:41][C:42]1[CH:47]=[CH:46][C:45]([O:48][CH2:49][C:50]2[C:55]([Cl:56])=[CH:54][CH:53]=[CH:52][C:51]=2[Cl:57])=[CH:44][CH:43]=1)[NH2:40]>CN(C=O)C>[CH3:36][O:37][C:38](=[O:58])[C@H:39]([CH2:41][C:42]1[CH:43]=[CH:44][C:45]([O:48][CH2:49][C:50]2[C:55]([Cl:56])=[CH:54][CH:53]=[CH:52][C:51]=2[Cl:57])=[CH:46][CH:47]=1)[NH:40][C:29]([C:22]1[C:21]([C:18](=[O:20])[CH3:19])=[C:25]([CH3:26])[N:24]([CH3:27])[C:23]=1[CH3:28])=[O:31]
Reactant: CC(=O)c1c(C(=O)O)c(C)n(C)c1C
Reactant: COC(=O)[C@@H](N)Cc1ccc(OCc2c(Cl)cccc2Cl)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(OCc2c(Cl)cccc2Cl)cc1)NC(=O)c1c(C(C)=O)c(C)n(C)c1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.1 %

Procedure:
NMM (155 mg, 169 μl, 1.54 mmol), HOBT (227 mg, 1.68 mmol), 4-acetyl-1,2,5-trimethylpyrrole-3-carboxylic acid (300 mg, 1.54 mmol) and EDC (295 mg, 1.54 mmol) were added sequentially to a stirred solution of O-(2,6-dichlorobenzyl)-L-tyrosine methyl ester hydrochloric (546 mg, 1.40 mmol) in dry DMF (15 ml). The reaction was stirred at room temperature under N2 for 18 h. The solvent was removed in vacuo and the residue partitioned between EtOAc (50 ml), and 10%aqueous Na2CO3 (40 ml). The phases were separated and the queous phase extracted with EtOac (2×25 ml). The combined organic extracts were washed consecutively with 5% aqueous hydrochloric acid (20 ml), 10% aqueous Na2SO3 (20 ml) and brine (10 ml), dried (Na2SO4) and evaporated in vacuo. The obtained orange foam (0.6 g) was chromatographed (silica; 50% EtOAc/Hexane→100% EtOAc) affording the title compound as a white foam (380 mg, 51%); 'Hnmr (d6DMSO) 8.53 (1H, d, J 8Hz, NH), 7.57-7.43 (3H, m's, aryl-H), 7.22 (2H, d, J 8.5Hz), aryl-H), 6.95 (2H, d, J 8.5 Hz, aryl-H), 5.18 (2H, br s, CH2-O), 4.67 (1H, m, α-tyr-H), 3.66 (3H, s, Me-O), 3.34 (3H, s, Me-N), 3.12 (1H, dd, J 4.1, 13.8Hz, CHABBAr), 2.90 (1H, dd, J 11.3 13.8Hz, CH2HBAr), 2.32 (3H, s, MeCO), 2.0 (3H, s, pyrrole-Me) and 1.94 (3H, s, pyrrole-Me). m/z (ES+60V) 531 (MH+, 100 ), 533 (MH+, 75) 553( MNz+, 15%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([O:20][CH3:21])[CH:18]=[CH:19][C:14]=3[S:13][CH2:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[O:23]=[C:24]1[CH2:29][O:28][C:27]2[CH:30]=[CH:31][C:32]([CH:34]=O)=[N:33][C:26]=2[NH:25]1.C([BH3-])#N.[Na+]>>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]2[S:13][CH2:12][C:11](=[O:22])[N:10]([CH2:9][CH2:8][N:5]3[CH2:4][CH2:3][CH:2]([NH:1][CH2:34][C:32]4[CH:31]=[CH:30][C:27]5[O:28][CH2:29][C:24](=[O:23])[NH:25][C:26]=5[N:33]=4)[CH2:7][CH2:6]3)[C:15]=2[CH:16]=1
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Reactant: COc1ccc2c(c1)N(CCN1CCC(N)CC1)C(=O)CS2
Agent: [BH3-]C#N
Agent: [Na+]
Product: COc1ccc2c(c1)N(CCN1CCC(NCc3ccc4c(n3)NC(=O)CO4)CC1)C(=O)CS2
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
4-[2-(4-Aminopiperidin-1-yl)ethyl]-6-methoxy-2H-1,4-benzothiazin-3(4H)-one (Intermediate 50) (0.9 mmol), 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) (190 mg, 1.1 mmol) and sodium cyanoborohydride (110 mg, 1.77 mmol) were reacted as described under Example 21, with stirring for 2.5 hours at room temperature after sodium cyanoborohydride addition. The title compound was obtained as a solid, 52 mg (12%).
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10](=[O:23])[CH2:11][C@H:12]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH2:13][CH2:14]O)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Br)(Br)[Br:25].Br>C(OCC)C>[C:1]1([C@@H:7]([NH:9][C:10](=[O:23])[CH2:11][C@H:12]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH2:13][CH2:14][Br:25])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@H](NC(=O)C[C@@H](CCO)c1ccc(F)cc1)c1ccccc1
Reactant: BrP(Br)Br
Agent: Br
Solvent: CCOCC
Product: C[C@H](NC(=O)C[C@@H](CCBr)c1ccc(F)cc1)c1ccccc1
Temperature: 0 °C
Reaction time: 72 h
Yield: 72 %

Procedure:
To a solution of 4.5 g of alcohol 8 250 mL of dry ethyl ether in an ice bath was added dropwise of 1.7 mL of phosphorous tribromide. After stirring for 3 days in an ice bath, 0.5 mL of conc. hydrobromic acid was added to this mixture. The resulting solution was stirred continuously at room temperature overnight, and 100 mL of ice was added to quench the reaction. The white solid was collected, dissolved in ethyl acetate, washed with saturated sodium hydrocarbonate solution and saturated brine. The organic layer was filtered through a silica gel pad. After the solvent evaporated, the crude solid was recrystallized from ethyl acetate and hexanes to form 3.8 g of the title compound as a white solid (72% yield, >95% de): mp 156.5-157.5 ° C.; [α]25D=−38.2 (c 1.0, CH3OH); 1H NMR (200 MHz, CDCl3) δ 7.40-7.10 (m, 7 H), 6.99 (m, 2 H), 5.52 (br d, J=7.6 Hz, 1 H), 4.98 (m, 1 H), 3.35-3.20 (m, 2 H), 3.05 (m, 1 H), 2.51 (dd, J=6.3, 14.0 Hz, 1 H), 2.37 (dd, J=8.7, 14.0 Hz, 1 H), 2.25-2.05 (m, 2 H), 1.25 (d, J=6.9 Hz, 3 H); 13C NMR (125 MHz, CDCl3) δ 169.7, 161.8, 142.8, 137.7, 129.1, 128.6, 127.4, 126.1, 115.7, 48.6, 44.0, 40.6, 38.7, 30.9, 21.3. Anal. Calcd for C19H21BrFNO: C, 60.33; H, 5.60; N, 3.70. Found: C, 60.57; H, 5.54; N, 3.82.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[CH2:5][CH2:6][C@H:7]([NH2:10])[CH2:8][F:9].C(N(CC)CC)C.C1C=CC=CC=1.[Cl:25][C:26]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:27]=1[CH:28]=O>C(OCC)(=O)C>[Cl:25][C:26]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:27]=1[CH:28]=[N:10][C@H:7]([CH2:8][F:9])[CH2:6][CH2:5][C:4]([O:3][CH3:2])=[O:11]
Reactant: O=Cc1c(Cl)cccc1Cl
Reactant: COC(=O)CC[C@H](N)CF
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: COC(=O)CC[C@@H](CF)N=Cc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.36 g of 4 and 0.27 ml of triethylamine were mixed with 20 ml of benzene containing 0.5 g of 3A molecular sieve. 0.33 g of 2,6-dichlorobenzaldehyde was added and the mixture was stirred at room temperature overnight. 20 ml of ethyl acetate was added to the mixture, then it was filtered and the solvent was evaporated from the filtrate. The residue was dissolved in ethyl acetate, the solution was washed with saturated aqueous sodium bicarbonate solution, dried (Na2SO4) and the solvent was evaporated from the filtrate. The residue was thin layer chromatographed, using a 4:16:80 v:v:v mixture of tetrahydrofuran, ethyl acetate and hexane as eluent. Workup gave 20, as a yellow oil.
Reaction SMILES: [CH3:1][O-:2].[Na+].[NH2:4][C:5]1[N:10]=[C:9](F)[N:8]=[C:7]([O:12][C:13]([F:16])([F:15])[F:14])[N:6]=1>CO>[NH2:4][C:5]1[N:10]=[C:9]([O:2][CH3:1])[N:8]=[C:7]([O:12][C:13]([F:16])([F:15])[F:14])[N:6]=1
Reactant: C[O-]
Reactant: Nc1nc(F)nc(OC(F)(F)F)n1
Agent: [Na+]
Solvent: CO
Product: COc1nc(N)nc(OC(F)(F)F)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
9.1 g (0.0505 mol) of 30% strength sodium methylate were added over the course of 15 minutes to a stirred mixture of 10 g (0.0505 mol ) of 2-amino-4-fluoro-6-trifluoromethoxy-1,3,5-triazine and 100 ml of methanol at 0° C. The mixture was stirred at 0° C. for one hour and then concentrated under reduced pressure, taken up in methylene chloride and extracted with water. Drying and concentration yielded 10.5 g (99% of theory) of the title compound of melting point 96°-101° C.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[C@@H:12]([CH3:27])[C:13]([N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][C@H:16]1[C:24]([OH:26])=[O:25])=[O:14].C1(NC2CCCCC2)CCCCC1.S(=O)(=O)(O)[O-].[K+].NN>CO>[NH2:3][C@@H:12]([CH3:27])[C:13]([N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][C@H:16]1[C:24]([OH:26])=[O:25])=[O:14]
Reactant: C[C@@H](C(=O)N1c2ccccc2C[C@H]1C(=O)O)N1C(=O)c2ccccc2C1=O
Agent: C1CCC(NC2CCCCC2)CC1
Agent: NN
Agent: O=S(=O)([O-])O
Solvent: CO
Product: C[C@H](N)C(=O)N1c2ccccc2C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
(S)-2,3-Dihydro-1-[(S)-2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-oxopropyl]-1H-indole-2-carboxylic acid, dicyclohexylamine (20.4 g.) was treated with 5% aqueous potassium bisulfate solution (300 ml.), and the free acid that formed was extracted three times with methylene chloride (combined extracts 450 ml.). The combined extracts were washed with saline twice, then dried over anhydrous sodium sulfate. Evaporation of the methylene chloride on a rotary evaporator under reduced pressure, then in high vacuum gave an amorphous solid which was dissolved in methanol (200 ml.). Hydrazine (95%, 1.43 g.) was added to the methanol solution. The resulting mixture was stirred under nitrogen atmosphere at room temperature for 24 hr., then chilled in an ice-salt mixture for 3 hr. A precipitate (phthalhydrazide, 4.06 g.) was collected on a filter, and washed with methanol. The combined filtrate and washings were evaporated on a rotary evaporator under reduced pressure, then in vacuo to give a solid residue. The residue was triturated with methylene chloride (ca. 250 ml.) and filtered. The filter residue was washed with methylene chloride several times and dried in vacuo. The crude product was dissolved in water (ca. 50 ml.) at room temperature, and filtered. The filter residue was washed with water. The combined filtrate and washings were evaporated carefully on a rotary evaporator under reduced pressure to give a solid residue which was dried over phosphorous pentoxide in vacuo to give the title product (6.31 g.), [α]D25 =-140.85 (c=1.44%, water). The analytical sample which was obtained by recrystallizations from methanol melted at 171°-172° (when the melting point was determined with rapid heating, the compound melted at 206.5°-209°), [α]D25 =-161.17° (c=1.065%, EtOH).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH3:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([C:16]2[N:20]=[C:19]([C:21]3[CH:22]=[CH:23][C:24]([OH:27])=[N:25][CH:26]=3)[O:18][N:17]=2)[N:3]=1.I[CH2:29][C:30]#[N:31].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH3:15])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:5]=[C:4]([C:16]2[N:20]=[C:19]([C:21]3[CH:22]=[CH:23][C:24]([O:27][CH2:29][C:30]#[N:31])=[N:25][CH:26]=3)[O:18][N:17]=2)[N:3]=1
Reactant: N#CCI
Reactant: CN(c1ccccc1)c1nc(N)nc(-c2noc(-c3ccc(O)nc3)n2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(c1ccccc1)c1nc(N)nc(-c2noc(-c3ccc(OCC#N)nc3)n2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 1.8 %

Procedure:
A mixture of 5-(3-{4-amino-6-[methyl(phenyl)amino]-1,3,5-triazin-2-yl}-1,2,4-oxadiazol-5-yl)pyridin-2-ol (Intermediate 136, 0.150 g, 0.414 mmol), 2-iodoacetonitrile (0.036 mL, 0.497 mmol), cesium carbonate (0.270 g, 0.827 mmol) in DMF (2 mL) was stirred at 90 C in a pressure tube for 18 h. A further 0.6 equivalent of 2-iodoacetonitrile was added and the mixture was stirred overnight at 90 C. The reaction mixture was cooled to room temperature, diluted with water, the precipitate was collected by filtration, washed with water and dried under vacuum. The resulting solid was purified by preparative HPLC to afford the title compound (3 mg, 2%).
Reaction SMILES: [CH:1]([C:3]1[CH2:4][CH2:5][CH2:6][O:7][CH:8]=1)=[CH2:2].[CH:9]([CH:11]=[CH2:12])=[O:10].O>C(Cl)Cl>[O:7]1[C@H:8]2[C:3](=[CH:1][CH2:2][CH2:12][C@H:11]2[CH:9]=[O:10])[CH2:4][CH2:5][CH2:6]1
Reactant: C=CC1=COCCC1
Reactant: C=CC=O
Solvent: O
Solvent: ClCCl
Product: O=C[C@@H]1CCC=C2CCCO[C@@H]21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2.613 g 5-ethenyl-3,4-dihydro-2H-pyran and 8.9 mL acrolein (90% pure) was dissolved in 39 mL CH2Cl2 and stirred overnight at RT. The reaction was added to water and extracted with CH2Cl2. The crude extract was filtered, concentrated using a rotovap, then purified on silica gel to provide the title compound. 1H NMR (500 MHz, CDCl3) δ=1.64-1.98 (m, 5H), 2.04-2.16 (m, 1H), 2.23-2.29 (m, 1H), 2.34-2.38 (m, 1H), 2.60-2.64 (m, 1H), 3.55-3.61 in, 1H), 3.99-4.04 (m, 1H), 4.21 (d, J=5.6 Hz, 1H), 5.55 (s, 1H), 9.88 (s, 1H) ppm.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Cl:24])(Cl)(Cl)Cl.[CH2:25]([O:32][C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[C:40]([F:43])[CH:41]=2)[CH:36]=[C:35](CO)[C:34]=1[CH3:46])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCCC1>[CH2:25]([O:32][C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[C:40]([F:43])[CH:41]=2)[CH:36]=[C:35]([CH2:20][Cl:24])[C:34]=1[CH3:46])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: Cc1c(CO)cc2ccc(F)cc2c1OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1c(CCl)cc2ccc(F)cc2c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 77.7 %

Procedure:
A three-neck round-bottom flask was charged with triphenylphosphine (23.33 g, 88.34 mmol), tetrahydrofuran (70 mL), and carbon tetrachloride (35 mL, 0.36 mol) under an argon atmosphere. The resulting mixture was stirred at room temperature for 20 minutes. A solution of (4-benzyloxy-6-fluoro-3-methyl-naphthalen-2-yl)-methanol (13.09 g, 44.17 mmol) in tetrahydrofuran (50 mL) was added rapidly to the reaction mixture via an addition funnel. The reaction mixture was heated at reflux for 1 hour. The reaction mixture was cooled to room temperature, and the solvents were removed in vacuo. The residue was diluted with water, and the resulting mixture was extracted twice with ethyl acetate. The organic phases were washed twice with water, and the resulting aqueous layers were extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated. The crude product was purified using flash chromatography (Analogix SuperFlash™ column, 10-25% dichloromethane in hexane), affording 10.8 g (77%) 1-benzyloxy-3-chloromethyl-7-fluoro-2-methyl-naphthalene as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.02 (dd, J=8.9, 5.9 Hz, 1 H), 7.89 (s, 1 H), 7.53-7.65 (m, 3 H), 7.35-7.50 (m, 4 H), 4.97 (s, 4 H), 2.47 (s, 3 H).
Reaction SMILES: [ClH:1].O1CCOCC1.[CH3:8][C:9]1[C:14]([N:15](C(OC(C)(C)C)=O)[NH:16]C(OC(C)(C)C)=O)=[CH:13][CH:12]=[CH:11][N:10]=1>CC(O)C.C(OCC)C>[ClH:1].[NH:15]([C:14]1[C:9]([CH3:8])=[N:10][CH:11]=[CH:12][CH:13]=1)[NH2:16]
Reactant: Cc1ncccc1N(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: CC(C)O
Product: Cc1ncccc1NN
Yield: 100 %

Procedure:
is Hydrogen chloride in dioxane (5.67 mL, 22.67 mmol) was added to a solution of di-tert-butyl 1-(2-methylpyridin-3-yl)hydrazine-1,2-dicarboxylate (Intermediate V1) (733 mg, 2.27 mmol) in IPA (10 mL). The reaction mixture was heated at reflux for 20 mins. The reaction mixture was allowed to cool and then diluted with diethyl ether (30 mL). The resultant precipitate was collected by filtration and dried in vacuo to afford 3-hydrazinyl-2-methylpyridine hydrochloride (362 mg, 100%). 1H NMR (400 MHz, DMSO) δ 2.66 (3H, s), 7.80-7.83 (1H, m), 7.95-7.97 (1H, m), 8.23-8.25 (1H, m), 9.15 (1H, s), 11.30 (1H, s); no ion in LCMS (1NH missing).
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]([C:6]([N:8]([O:10][CH3:11])[CH3:9])=[O:7])=[CH:4][CH:3]=1.[I:14]I>[OH-].[NH4+].O>[OH:1][C:2]1[CH:13]=[CH:12][C:5]([C:6]([N:8]([O:10][CH3:11])[CH3:9])=[O:7])=[CH:4][C:3]=1[I:14]
Reactant: II
Reactant: CON(C)C(=O)c1ccc(O)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: CON(C)C(=O)c1ccc(O)c(I)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.5 %

Procedure:
The product from Example 71C (10.3 g, 56.84 mmol) in concentrated ammonium hydroxide (400 mL) was stirred at 25° C. for 15 minutes and then treated with KI (45.96 g, 276.83 mmol) and I2 (14.43 g, 56.84 mmol) in water (65 mL). After stirring at room temperature for 16 hours, the solvent was removed under reduced pressure and the residue was redissolved in DCM (500 mL) and washed with water (350 mL×2). The organic phase was dried, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using 90% CH2Cl2, 10% MeOH, to provide the title compound as a white solid (11.6 g, 67% yield). 1HNMR (300 MHz, CD3OD) δ 3.32 (s, 3H), 3.59 (s, 3H), 6.83 (d, 1H, J=8.9 Hz). 7.58 (d, 1H, J=8.9 Hz), 8.06 (s, 1H); MS (DCI) m/z 308 (M+H)+, 325 (M+NH4)+.
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:20]([N+:21]([O-:23])=[O:22])=[C:19]([NH:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][CH2:30][C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)[C:18]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=2[N:12]=1>COCCOCCOC>[N+:21]([C:20]1[C:11]([O:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[N:12][C:13]2[CH2:14][CH2:15][CH2:16][CH2:17][C:18]=2[C:19]=1[NH:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][CH2:30][C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1)([O-:23])=[O:22]
Reactant: Oc1ccccc1
Reactant: O=[N+]([O-])c1c(Cl)nc2c(c1NCCOCCCc1cccnc1)CCCC2
Agent: [H-]
Agent: [Na+]
Solvent: COCCOCCOC
Product: O=[N+]([O-])c1c(Oc2ccccc2)nc2c(c1NCCOCCCc1cccnc1)CCCC2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 66.9 %

Procedure:
A 200 mL round bottom flask was charged with 60% sodium hydride (2.5 g, 0.06 mol, 1.7 equivalents) and washed with hexane (50 mL). A solution of phenol (5.7 g, 0.06 mol, 1.6 equivalents) in diglyme (25 mL) was then slowly added to the sodium hydride. The reaction was maintained with stirring at room temperature for 1.5 hours. To the phenol anion solution was slowly added a solution of 2-chloro-3-nitro-N-[2-(3-pyridin-3-ylpropoxy)ethyl]-5,6,7,8-tetrahydroquinolin-4-amine (14.8 g, 0.04 mol) in diglyme (25 mL). The stirred reaction mixture was heated to 60° C. and maintained overnight. The reaction was quenched by pouring onto ice (1000 mL). The product oiled out of solution. The mixture was extracted with dichloromethane (4×100 mL). The combined extracts were concentrated to dryness. The residue was taken up in 1:1 hexane/ethyl acetate (250 mL) and washed with water (2×50 mL). The organic layer was concentrated to dryness. The residue was found to contain excess phenol. The phenol was removed by taking the residue up in diethyl ether (500 mL) and stirring over 10% sodium hydroxide (250 mL) overnight. The layers were separated. The ether layer was concentrated to provide 3-nitro-2-phenoxy-N-[2-(3-pyridin-3-ylpropoxy)ethyl]-5,6,7,8-tetrahydroquinolin-4-amine as a pale orange syrup (12.0 g, 71%). TLC=(10% MeOH/CH2Cl2, Rf=0.58).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12](Cl)=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.[F:24][C:25]1[C:30]([F:31])=[CH:29][C:28]([F:32])=[C:27]([F:33])[C:26]=1[OH:34]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12]([O:34][C:26]3[C:27]([F:33])=[C:28]([F:32])[CH:29]=[C:30]([F:31])[C:25]=3[F:24])=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cc(Cl)nnc2-c2ccc(OC)cc2)cc1
Reactant: Oc1c(F)c(F)cc(F)c1F
Product: COc1ccc(-c2cc(Oc3c(F)c(F)cc(F)c3F)nnc2-c2ccc(OC)cc2)cc1

Procedure:
In a similar manner as in Example 2, 3,4-bis(4-methoxyphenyl)-6-chloropyridazine (200 mg, 0.613 mmol) and 2,3,5,6-tetrafluorophenol were reacted as starting materials at 150° C. for 12 hours and post-treatment was then conducted, whereby the title compound was obtained as a colorless crystalline powder (105.7 mg, 37.8%). Melting point: 172.5-174.5° C. (hexane).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O>[OH:2][CH2:3][CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:7]=1
Reactant: COC(=O)CCc1cn(C(=O)OC(C)(C)C)c2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Product: CC(C)(C)OC(=O)n1cc(CCCO)c2ccccc21
Reaction time: 1 h
Yield: 99.2 %

Procedure:
To a stirring solution of tert-butyl 3-(3-methoxy-3-oxopropyl)-1H-indole-1-carboxylate (50 mg) was added lithium aluminum hydride (6 mg) at 0° C. After 1 hour, to the mixture was added water, and the resulting mixture was extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography (n-hexane:EtOAc=5:1) to give tert-butyl 3-(3-hydroxypropyl)-1H-indole-1-carboxylate (45 mg).
Reaction SMILES: [K].[CH2:2]([O:4][C:5](=[O:18])/[C:6](/[O-:17])=[CH:7]/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15])[CH3:3].[K+].[C:20]([O:23][C@@H:24]1[C@@H:30]([O:31][C:32](=[O:34])[CH3:33])[C@H:29]([O:35][C:36](=[O:38])[CH3:37])[C@@H:28]([CH2:39][O:40][C:41](=[O:43])[CH3:42])[O:27][C@@H:25]1O)(=[O:22])[CH3:21]>CN(C=O)C>[C:36]([O:35][C@@H:29]1[C@@H:30]([O:31][C:32](=[O:34])[CH3:33])[C@H:24]([O:23][C:20](=[O:22])[CH3:21])[C@@H:25]([O:17]/[C:6](/[C:5]([O:4][CH2:2][CH3:3])=[O:18])=[CH:7]\[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])[O:27][C@H:28]1[CH2:39][O:40][C:41](=[O:43])[CH3:42])(=[O:38])[CH3:37]
Reactant: CCOC(=O)/C([O-])=C/c1ccccc1[N+](=O)[O-]
Reactant: CC(=O)OC[C@H]1O[C@H](O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [K+]
Agent: [K]
Solvent: CN(C)C=O
Product: CCOC(=O)/C(=C/c1ccccc1[N+](=O)[O-])O[C@H]1O[C@@H](COC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 40 %

Procedure:
A solution of the potassium salt of 2-nitrophenylpyruvate B2 (100 mg, 0.36 mmol) in dry DMF (3 mL) was added dropwise over a period of 15 min, to a pre-cooled stirred solution of 2,3,4,6-tetra-O-acetyl-α-D-glucose (149 mg, 0.36 mmol) in dry DMF (2 mL) at 0° C. under nitrogen atmosphere. The temperature was gradually raised to room temperature. Reaction mixture was allowed to stir for 15 h, and the reaction was quenched with chilled, saturated aq. NaCl (25 mL). Extraction with ethyl acetate (3×30 mL), drying (MgSO4), concentration under reduced pressure, and purification by flash chromatography (SiO2, hexane-benzene-acetone-methanol, 5:4:5:1) to isolate the pure resultant compound C2 in 40% yield.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([C:13](OCC)=O)=[C:5]([CH3:12])[C:6]=1[C:7](OCC)=O.I.C=O>C(O)(=O)C>[CH3:1][C:2]1[NH:3][C:4]([CH3:13])=[C:5]([CH3:12])[C:6]=1[CH3:7]
Reactant: CCOC(=O)c1[nH]c(C)c(C(=O)OCC)c1C
Agent: C=O
Agent: I
Solvent: CC(=O)O
Product: Cc1[nH]c(C)c(C)c1C

Procedure:
2,4-Dimethyl-3,5-dicarbethoxy-pyrrole (2.4 g), acetic acid (35 ml), aq. hydriodic acid (35 ml) and paraformaldehyde (1.2 g) were heated at 100° C. for 4 hours under a stream of nitrogen. The crude product was obtained as in Example 5 then distilled (15 mm, 65° C.) to yield 0.44 g (36%), m.p. 107°-109°.