Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:13]1[CH:17]=[C:16]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:15][N:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH3:25][O:26][C:27]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:29]([O:35][CH3:36])[C:28]=1[N:37]=[C:38]=[O:39].Cl.CCOCC>O1CCCC1.C([Li])CCC>[CH2:1]([C:13]1[CH:17]=[C:16]([CH:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:38]([NH:37][C:28]2[C:29]([O:35][CH3:36])=[CH:30][C:31]([O:33][CH3:34])=[CH:32][C:27]=2[O:26][CH3:25])=[O:39])[O:15][N:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: COc1cc(OC)c(N=C=O)c(OC)c1
Reactant: CCCCCCCCCCCCc1cc(Cc2ccccc2)on1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCc1cc(C(C(=O)Nc2c(OC)cc(OC)cc2OC)c2ccccc2)on1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A stirred room temperature solution of 3-dodecyl-5-(phenylmethyl)isoxazole (38.3 g, 0.117 mol) in tetrahydrofuran (600 mL) was cooled to -78° C. under nitrogen. To the resulting precipitate was added dropwise a 2.01M solution (58 mL, 0.12 mol) in n-butyl lithium in hexanes over 10 minutes. The mixture was stirred for 1.25 hours before a solution of 2,4,6-trimethoxyphenyl isocyanate (24.43 g, 0.1168 mol) in tetrahydrofuran (350 mL) was added dropwise over 30 minutes. The mixture was stirred for 45 minutes then quenched with a dropwise addition of 1M HCl (235 mL, 0.235 mol) followed by ether (500 mL). The mixture was allowed to warm to room temperature. The organic layer was washed with 0.2M HCl , water, saturated sodium bicarbonate, and saturated sodium chloride, dried (MgSO4), and rotoevaporated to a solid. The material was recrystallized twice from diisopropyl ether and chromatographed on silica gel (830 g, 230- 400 mesh) using petroleum ether-ethyl acetate (2:1, 20×900 mL) to give a white solid; yield 40.7 g (65%), mp 106°-107° C.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][C:16]1[CH:25]=[C:24]2[C:19]([C:20]([CH3:28])([CH3:27])[CH2:21][NH:22][C:23]2=[O:26])=[CH:18][CH:17]=1.[Cl:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=1.C(O)(=O)C>ClCCl>[Cl:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][NH:15][C:16]2[CH:25]=[C:24]3[C:19]([C:20]([CH3:28])([CH3:27])[CH2:21][NH:22][C:23]3=[O:26])=[CH:18][CH:17]=2)=[CH:32][CH:31]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC1(C)CNC(=O)c2cc(N)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC1(C)CNC(=O)c2cc(NCc3ccc(Cl)cc3)ccc21
Reaction time: 8 h
Yield: 38.7 %

Procedure:
Sodium triacetoxyborohydride (800 mg, 3.79 mmol) was added to a stirred solution of 7-amino-4,4-dimethyl-3,4-dihydro-2H-isoquinolin-1-one (220 mg, 1.15 mmol), 4-chlorobenzaldehyde (324 mg, 2.31 mmol) and acetic acid (69 μl, 1.15 mmol) in anhydrous dichloromethane (10 ml) at room temperature. The reaction was stirred overnight and quenched with the addition of water. The organic phase was separated, washed with brine, then dried (MgSO4) and evaporated in vacuo. The resulting residue was purified by flash column chromatography (20% ethyl acetate in dichloromethane) to afford the title compound as a light brown solid (140 mg, 39%). HPLC retention time 4.40 min. Mass spectrum (ES+) m/z 315 (M+H).
Reaction SMILES: [C:1]1(=[O:14])[C:6]2[NH:7][C:8]3[C:13]([C:5]=2[CH2:4][CH2:3][NH:2]1)=[CH:12][CH:11]=[CH:10][CH:9]=3.I[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:21]=1[CH3:22].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:22][C:21]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1[N:2]1[CH2:3][CH2:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:1]1=[O:14]
Reactant: O=C1NCCc2c1[nH]c1ccccc21
Reactant: Cc1ccncc1I
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCc2c([nH]c3ccccc23)C1=O
Yield: 1.3 %

Procedure:
2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-one (I-61e: 250 mg, 1.34 mmol) was reacted with 3-iodo-4-methylpyridine (294.3 mg, 1.34 mmol), 1,4-dioxane (10 mL), copper iodide (25.6 mg, 0.134 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (59.8 mg, 0.402 mmol) and potassium phosphate (710 mg, 3.35 mmol) at 120° C. overnight to afford the crude product. Purification by column chromatography on silica gel (40% ethyl acetate in hexane), followed by preparative HPLC afforded 5 mg of the product (2% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]=O)=[CH:7][CH:8]=1.[BH3-]C#N.[Na+].[Cl:15][C:16]1[CH:17]=[C:18]([CH2:23][C:24]([N:26]2[CH:35]3[CH:30]([CH2:31][CH2:32][CH2:33][CH:34]3[N:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)[NH:29][CH2:28][CH2:27]2)=[O:25])[CH:19]=[CH:20][C:21]=1[Cl:22].C([O-])([O-])=O.[Na+].[Na+]>CO.C(O)(=O)C>[Cl:15][C:16]1[CH:17]=[C:18]([CH2:23][C:24]([N:26]2[CH:35]3[CH:30]([CH2:31][CH2:32][CH2:33][CH:34]3[N:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)[N:29]([CH2:9][C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH2:28][CH2:27]2)=[O:25])[CH:19]=[CH:20][C:21]=1[Cl:22]
Reactant: O=C(Cc1ccc(Cl)c(Cl)c1)N1CCNC2CCCC(N3CCCC3)C21
Reactant: COc1ccc(C=O)cc1
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(CN2CCN(C(=O)Cc3ccc(Cl)c(Cl)c3)C3C(N4CCCC4)CCCC32)cc1
Reaction time: 8 h

Procedure:
Anisaldehyde (361 mg, 2.6 mmol) was dissolved in 5 ml of MeOH and NaBH3CN (170 mg, 2.6 mmol) was added. The pH was adjusted to 5 with concentrated acetic acid. 2-(3,4-Dichlorophenyl)-1-[(4aRS,8SR,8aRS)-8-(pyrrolidin-1-yl)-perhydroquinoxalin-1-yl]-ethan-1-one (105 mg, 0.26 mmol), dissolved in MeOH (15 ml), was then added to the mixture and the mixture was stirred overnight. After addition of saturated Na2CO3 solution (15 ml), the mixture was stirred at room temperature for 15 minutes. The precipitate formed was filtered off. The aqueous phase of the filtrate was washed three times with CH2Cl2 and the combined organic phases were dried over Na2SO4 and evaporated in vacuo. The residue was purified by flash chromatography (Ø 2 cm, CH2Cl2/MeOH/NH3 9.5:0.5:0.1, l=15 cm, V=5 ml). The fractions containing the product were evaporated, the residue was taken up in CH2Cl2 and the solution was extracted by shaking three times with HCl (1 N). The aqueous phase was then brought to pH 8 with NaOH (2 N) and extracted by shaking three times with CH2Cl2. The organic phases were dried over Na2SO4 and evaporated in vacuo. A yellowish resin was isolated.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:31])=[C:9]([CH2:11][O:12][C:13]2[CH:28]=[CH:27][C:16]([CH2:17][O:18][C:19]3[C:23]([CH:24]=O)=[CH:22][N:21]([CH3:26])[N:20]=3)=[CH:15][C:14]=2[O:29][CH3:30])[N:10]=1.[Cl-].[S:33]1[CH:37]=[C:36]([CH2:38][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:35]=[CH:34]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:31])=[C:9]([CH2:11][O:12][C:13]2[CH:28]=[CH:27][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:38]\[C:36]4[N:35]=[CH:34][S:33][CH:37]=4)=[CH:22][N:21]([CH3:26])[N:20]=3)=[CH:15][C:14]=2[O:29][CH3:30])[N:10]=1
Reactant: c1ccc([P+](Cc2cscn2)(c2ccccc2)c2ccccc2)cc1
Reactant: COc1cc(COc2nn(C)cc2C=O)ccc1OCc1nc(-c2ccco2)oc1C
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(COc2nn(C)cc2/C=C\c2cscn2)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 26.9 %

Procedure:
A mixture of 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-methyl-1H-pyrazole-4-carbaldehyde (0.50 g), [(1,3-thiazol-4-yl)methyl]triphenylphosphonium chloride (0.95 g), potassium carbonate (0.33 g) and N,N-dimethylformamide (20 mL) was stirred at room temperature for 15 hrs, and further stirred at 50° C. for 3 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:1 to 3:1, v/v) to give 2-(2-furyl)-4-({2-methoxy-4-[({1-methyl-4-[(Z)-2-(1,3-thiazol-4-yl)ethenyl]-1H-pyrazol-3-yl}oxy)methyl]phenoxy}methyl)-5-methyl-1,3-oxazole as colorless crystals (0.16 g, yield 26%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 97-98° C.
Reaction SMILES: [P:1]([Cl:5])(Cl)([Cl:3])=[O:2].[CH2:6]([CH:8]([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:9]O)[CH3:7].Cl>O>[CH2:6]([CH:8]([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:9][P:1]([Cl:5])([Cl:3])=[O:2])[CH3:7]
Reactant: CCCCC(CC)CO
Reactant: O=P(Cl)(Cl)Cl
Agent: Cl
Solvent: O
Product: CCCCC(CC)CP(=O)(Cl)Cl
Temperature: 50 °C
Reaction time: 5 h
Yield: 108.2 %

Procedure:
The synthesis of mono-2-ethylhexyldiphenyl phosphate: To 460 g of phosphorus oxychloride put into a 2 liter four-necked flask with cooling by iced water, while stirring, were added dropwise spending the period of an hour and ten minutes 402 g (3.09 M) of 2-ethylhexanol at the temperature of 10° C. And the mixture, with continued stirring, was heated slowly up to 50° C. spending 5 hours and a half, and was then kept at the same temperature for two hours, during which the inside of the flask was slowly decompressed, and finally decompressed down to 200 mmHg to remove the hydrochloric acid gas produced thereinside. When the hydrochloric acid gas was no longer produced, 750 g of mono-2-ethylhexylphosphoryldichloride were obtained (yield: 99.7%).
Reaction SMILES: [CH2:1]([N:4]([CH2:15][CH2:16][CH3:17])[CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:14])[CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].C(N(CC)CC)C.[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1.C([O-])([O-])=O.[Na+].[Na+]>ClCCl>[CH2:15]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:14][S:31]([C:28]3[CH:29]=[CH:30][C:25]([CH3:35])=[CH:26][CH:27]=3)(=[O:33])=[O:32])[CH:11]=2)[CH2:6]1)[CH2:16][CH3:17]
Reactant: CCCN(CCC)C1Cc2ccc(O)cc2C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCN(CCC)C1Cc2ccc(OS(=O)(=O)c3ccc(C)cc3)cc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.1 %

Procedure:
2-Dipropylamino-indan-5-ol (Preparation 9, 140 mg, 0.47 mmol) was dissolved in dichloromethane (25 mL) and cooled to 0 C. Thereafter was added triethylamine (99 mg, 0.98 mmol) and toluene-4-sulfonyl chloride (101 mg, 0.54 mmol). The reaction mixture was allowed to reach room temperature and was then stirred at ambient temperature for 2 h. Aqueous Na2CO3 solution (25 mL, 10%) was added and the mixture was stirred for an additional 5 min. The layers were separated and the organic layer was washed, dried (Na2SO4) and the solvent evaporated. The crude product was chromatograped using dichloromethane-methanol (19:1) as eluant. The pure fractions were pooled, and the solvent removed in vacuo yielding 135 mg (78%) of toluene-4-sulfonic acid 2-dipropylamino-indan-5-yl ester as an oil. The amine was converted to its hydrochloride salt (hydroscopic).; 1H NMR (300 MHz, CDCl3) δ 0.85 (t, 6H), 1.45 (m, 4H), 2.4-2.5 (m, 7H), 2.75-2.85 (m, 2H), 2.90-3.00 (m, 2H), 3.60-3.70 (m, 1H), 6.65 (dd, J=2.5, 8.3 Hz, 1H), 6.85 (d, J=2.5 Hz, 1H), 7.05 (d, J=8.0 Hz, 1H), 7.30 (d, J=8.5 Hz, 2H), 7.70 (d, J=8.7 Hz, 2H); 13C NMR (75.4 MHz, CDCl3) δ 11.99, 20.24, 21.73, 36.11, 36.70, 53.37, 63.44, 118.57, 120.14, 125.03, 128.51, 129.67, 132.60, 140.96, 143.74, 145.16, 148.27; MS m/e 387 (3, M+), 358 (100), 232 (49), 91 (15), 155 (13).
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH:20]=[CH:19][C:18]([O:21][CH:22]3[CH2:27][CH2:26][N:25]([C:28]4[N:33]=[CH:32][C:31]([CH2:34][CH2:35][CH3:36])=[CH:30][N:29]=4)[CH2:24][CH2:23]3)=[CH:17][C:16]2=[O:37])=[CH:11][CH:10]=1)(=[O:8])=[O:7])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[O:37]=[C:16]1[CH:17]=[C:18]([O:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[N:33]=[CH:32][C:31]([CH2:34][CH2:35][CH3:36])=[CH:30][N:29]=3)[CH2:24][CH2:23]2)[CH:19]=[CH:20][N:15]1[C:12]1[CH:11]=[CH:10][C:9]([S:6]([NH2:5])(=[O:7])=[O:8])=[CH:14][CH:13]=1
Reactant: CCCc1cnc(N2CCC(Oc3ccn(-c4ccc(S(=O)(=O)NC(C)(C)C)cc4)c(=O)c3)CC2)nc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCc1cnc(N2CCC(Oc3ccn(-c4ccc(S(N)(=O)=O)cc4)c(=O)c3)CC2)nc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 53.2 %

Procedure:
To a stirring solution of N-tert-butyl-4-(2-oxo-4-(1-(5-propylpyrimidin-2-yl)piperidin-4-yloxy)pyridin-1(2H)-yl)benzenesulfonamide (23 mg, 0.044 mmol) in CH2Cl2 (1 mL) was added trifluoroacetic acid (0.4 mL, 5 mmol, Aldrich). The reaction was stirred at room temperature for 2 days and then concentrated in vacuo to a yellow oil. The oil was purified by flash chromatography (SiO2, 0 to 5% MeOH in CH2Cl2) to yield 11 mg of the desired product as an off-white solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.18 (s, 2 H), 8.03 (d, J=8.53 Hz, 2 H), 7.54 (d, J=8.28 Hz, 2 H), 7.23 (d, J=7.78 Hz, 1 H), 6.07 (dd, J=7.65, 2.63 Hz, 1 H), 6.03 (d, J=2.51 Hz, 1 H), 4.56-4.65 (m, 1 H), 4.16-4.25 (m, 2 H), 3.60-3.71 (m, 2 H), 2.42 (t, J=7.53 Hz, 2 H), 2.04-2.14 (m, 2 H), 1.80-1.90 (m, 2 H), 1.53-1.64 (m, 2 H), 0.95 (t, J=7.28 Hz, 3 H). MS (ESI) 470 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C:12]2=[O:22])[CH:4]=1.[CH3:23]OC(=O)C(OC)=O.C[O-].[Na+]>C1COCC1.CO>[CH3:1][O:2][C:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][C:11](=[CH2:23])[C:12]2=[O:22])[CH:4]=1
Reactant: COC(=O)C(=O)OC
Reactant: COC1=CC2=CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@@]2(C)CC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: C=C1C[C@H]2[C@@H]3CC=C4C=C(OC)CC[C@]4(C)[C@H]3CC[C@]2(C)C1=O

Procedure:
3-Methoxyandrosta-3,5-dien-17-one (I, 50.0 g) was dissolved in THF containing TEA (1 ml). Dimethyloxalate (55.5 ml) was added and the mixture cooled to 2°. Sodium methoxide (25%) in methanol (45.7 ml) was added slowly over 10 minutes. The ice bath was removed and the reaction warmed to 24° over five minutes with stirring. The mixture was stirred at 20°-25° for 55 minutes, then cooled to 5° over 10 minutes. Acetic acid (2.4 ml) was added, immediately followed by TEA (17.4 ml), then paraformaldehyde (7.49 g), followed by methanol (63 ml). The ice bath was removed and the mixture warmed to 20°-25° over 5 minutes. The mixture was stirred at 28° for 5 hrs and stored in a freezer (-20°) overnight. The mixture was then warmed to 20°-25° and stirred at 25° for 4 hrs for a total time of approximately 9.0 hrs at 20°-28°. Water (300 ml) and ethyl acetate (300 ml) were added, the mixture stirred and the layers separated. The organic layer was washed with saline (2×100 ml). The aqueous portion is backextracted with ethyl acetate (2×100 ml, washing each with 50 ml of saline). The organic phases are combined, concentrated under reduced pressure to an oil, taken up in methylene chloride (450 ml) and ethyl acetate (200 ml). This mixture was dried over sodium sulfate, filtered and concentrated under reduced pressure to a solid. Trituration of the solid with boiling methanol (100 ml) containing 1% TEA gives the title compound in crystalline form.
Reaction SMILES: [OH:1][C:2]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]#[N:16])=[C:10]([C:17]([F:20])([F:19])[F:18])[CH:9]=2)([CH3:5])[CH2:3][OH:4].[H-].[Na+].F[C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=1>CN(C=O)C>[C:28]([C:27]1[CH:30]=[CH:31][C:24]([O:4][CH2:3][C:2]([C:6]2[NH:7][C:8]3[C:13]([CH:14]=2)=[CH:12][C:11]([C:15]#[N:16])=[C:10]([C:17]([F:20])([F:18])[F:19])[CH:9]=3)([OH:1])[CH3:5])=[CH:25][CH:26]=1)#[N:29]
Reactant: N#Cc1ccc(F)cc1
Reactant: CC(O)(CO)c1cc2cc(C#N)c(C(F)(F)F)cc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(O)(COc1ccc(C#N)cc1)c1cc2cc(C#N)c(C(F)(F)F)cc2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(1,2-dihydroxy-1-methyl-ethyl)-6-trifluoromethyl-1-H-indole-5-carbonitrile (209.6 mg, 0.7374 mmol) in dry DMF (4 ml) was added NaH (60 mg, 1.4749 mmol, 60% in mineral oil). After the reaction mixture was stirred at room temperature for 30 min., 4-fluorobenzonitrile (98.15 mg, 0.8115 mmol) was added, and the reaction mixture stirred at room temperature. After HPLC indicated the consumption of starting material, the reaction mixture was poured onto water and extracted with ethyl acetate. The organic layer was washed with 10% LiCl, brine and dried over MgSO4. Column chromatography (EtOAc/Hexanes 50%-100%) yielded the title product as a light yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].CS(O[CH2:21][CH2:22][O:23][CH:24]1[CH2:33][CH2:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25]1)(=O)=O>CN(C)C=O.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:21][CH2:22][O:23][CH:24]2[CH2:33][CH2:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:25]2)=[CH:7][CH:6]=1
Reactant: CS(=O)(=O)OCCOC1CCc2ccccc2C1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COC(=O)C(=O)c1ccc(OCCOC2CCc3ccccc3C2)cc1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (0.724 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.175 g), stirred for 15 minutes and treated with rac.-2-(1,2,3,4-tetrahydro-2-naphthalenyloxy)ethyl methanesulfonate (1.08 g). The mixture was heated under argon at 60° C. overnight. The cooled mixture was treated with glacial acetic acid (2 drops) and the volatiles were removed under vacuum. The residue was mixed with water and extracted with dichloromethane. The organic layers were dried (Na2SO4), filtered and evaporated to give crude product. The material was purified by HPLC (dichloromethane-hexane; 1:1 plus 2% ethyl acetate) to provide, after crystallization from diethyl ether-hexane, 0.79 g of rac.-alpha-oxo-4-[[2-(1,2,3,4-tetrahydro-2-naphthalenyloxy)ethyl]oxy]benzeneacetic acid methyl ester as a colorless solid, mp 86°-87° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([NH:12][S:13]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]([NH2:26])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:8][CH2:7]1)=[O:5])[CH3:2].COC1C=CC(N)=CC=1.C(=O)(O)[O-].[Na+].[CH3:41][C:42]1[N:50]=[CH:49][CH:48]=[CH:47][C:43]=1[C:44](Cl)=[O:45]>C(Cl)Cl>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][CH:9]([NH:12][S:13]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]([NH:26][C:44]([C:43]3[C:42]([CH3:41])=[N:50][CH:49]=[CH:48][CH:47]=3)=[O:45])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC(NS(=O)(=O)c2ccc(N)c3ccccc23)CC1
Reactant: Cc1ncccc1C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COc1ccc(N)cc1
Solvent: ClCCl
Product: CCOC(=O)N1CCC(NS(=O)(=O)c2ccc(NC(=O)c3cccnc3C)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 4-(4-Amino-naphthalene-1-sulfonylamino)-piperidine-1-carboxylic acid ethyl ester (0.26 g, 0.71 mmol) (prepared following the general procedure in Scheme 3, substituting 4-amino-piperidine-1-carboxylic acid ethyl ester for p-anisidine) in CH2Cl2 (10 mL) and aqueous saturated sodium bicarbonate solution (4 mL) was added 2-methyl nicotinic chloride (0.16 g, 1.07 mmol) and the resulting mixture was stirred at room temperature overnight. The organic layer was separated, dried over sodium sulfate and concentrated. Purification of the residue by column chromatography (2-5% MeOH/CH2Cl2) provided the B-24 (0.09 g, 26%). 1H NMR (300 MHz, CDCl3) δ 8.61-8.66 (m, 2H), 8.34 (s, 1H), 8.19-8.28 (m, 1H), 7.94 (d, 2H), 7.60-7.70 (m, 2H), 7.28-7.31 (m, 1H), 4.91 (d, 1H), 4.03 (q, 2H), 3.85 (d, 2H), 3.20-3.32 (m, 1H), 2.80 (s, 2H), 2.63-2.74 (m, 2H), 1.67 (br s, 4H), 1.16-1.21 (m, 5H). LC/MS m/z 497 (M+H)+.
Reaction SMILES: [CH3:1][S:2][CH2:3][N:4]1[C:9](=[O:10])[N:8]2[CH:11]=[N:12][C:13]([C:14](N)=[O:15])=[C:7]2[N:6]=[N:5]1.N([O-])=[O:18].[Na+]>C(O)(C(F)(F)F)=O.O>[CH3:1][S:2][CH2:3][N:4]1[C:9](=[O:10])[N:8]2[CH:11]=[N:12][C:13]([C:14]([OH:15])=[O:18])=[C:7]2[N:6]=[N:5]1
Reactant: O=N[O-]
Reactant: CSCn1nnc2c(C(N)=O)ncn2c1=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CSCn1nnc2c(C(=O)O)ncn2c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 61 %

Procedure:
To a solution of 3-(methylthiomethyl)-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxamide (12.43 mmol, 3 g, 1 eq.) in TFA (12 mL) was added sodium nitrite (43.5 mmol, 3 g, 3.5 eq.) dissolved in water (6 mL) portion-wise keeping exothermic effervescence under control and the mixture was stirred at room temperature for over 3 hours. The reaction mixture was poured into ice and it was gently stirred until the ice melted. The resulted suspension was filtered, washed with water and ether and dried under vacuum to give the title compound. Yield=61%. δH (DMSO-d6) 8.85 (1H, s), 5.44 (2H, s), 2.25 (3H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][CH2:11][CH2:12][CH3:13])=[C:7]([C:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH:24]([OH:35])[CH2:25][N:26]([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:27][CH2:28][CH2:29][CH3:30])=[CH:18][CH:17]=3)=[O:15])[C:6]=2[CH:36]=1.N1C=CC=CC=1.[CH3:43][S:44](Cl)(=[O:46])=[O:45]>ClCCl>[CH2:10]([C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([NH:1][S:44]([CH3:43])(=[O:46])=[O:45])=[CH:36][C:6]=2[C:7]=1[C:14](=[O:15])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH:24]([OH:35])[CH2:25][N:26]([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:31][CH2:32][CH2:33][CH3:34])=[CH:18][CH:17]=1)[CH2:11][CH2:12][CH3:13]
Reactant: CCCCc1oc2ccc(N)cc2c1C(=O)c1ccc(OCC(O)CN(CCCC)CCCC)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCc1oc2ccc(NS(C)(=O)=O)cc2c1C(=O)c1ccc(OCC(O)CN(CCCC)CCCC)cc1
Temperature: 32.5 °C
Reaction time: 2 h

Procedure:
0.3 g of (5-amino-2-butyl-1-benzofuran-3-yl) {4-[3-(dibutylamino)-2-hydroxy-propoxy]-phenyl}methanone (III) was dissolved in 10 ml of dichloromethane. The solution was warmed to 30-35° C. and 0.06 g of pyridine was added at this temperature. After this 0.093 g of methanesulfonyl chloride was added and the mixture was stirred at 30-35° C. for 2 hours. The mixture was cooled to 20-25° C., washed with 2×15 ml of water, 2×15 ml of sodium hydrogencarbonate solution of 5%, 1×15 ml of water. The phases were sepatated and the dichloromethane phase was evaporated.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[CH:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[NH:10][C:7]2=[N:8][CH:9]=1)([O-])=O.[H][H]>[Pd].CO>[NH2:1][C:4]1[CH:5]=[C:6]2[CH:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[NH:10][C:7]2=[N:8][CH:9]=1
Reactant: COC(=O)c1cc2cc([N+](=O)[O-])cnc2[nH]1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc2cc(N)cnc2[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.9 %

Procedure:
An autoclave is charged with 2.9 g (13.12 mmol) of methyl 5-nitro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (Azasynth), 290 mg of palladium on charcoal 10% and 200 mL of methanol. The reaction mixture is placed under 20 bar of hydrogen, and stirred for 18 h at room temperature. The solution is then filtered on Celite, and the Celite is rinsed with 3×100 mL of hot methanol. The filtrate is evaporated under reduced pressure. 2.38 g of a yellow solid is obtained at a yield of 95%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].[Br:10]Br.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Br:10][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([CH3:1])=[CH:3][C:4]=1[OH:9]
Reactant: Cc1ccc(O)cc1C
Reactant: BrBr
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(O)c(Br)cc1C
Reaction time: 1 h
Yield: 60.8 %

Procedure:
A mixture of 3,4-dimethylphenol (2 g, 16.37 mmol) in DCM (10 mL) at −78° C. was added bromine (0.843 mL, 16.37 mmol) dropwise and the reaction was stirred for 1 h at this temperature. Sat. sodium sulfite solution was added and it was then stirred 5 min at rt and then extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated to obtain 2 g oil. It was then purified with 5% EtOAc/hexane to isolate 800 mg (24%) of the desired product as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.22 (s, 1H), 6.84 (s, 1H), 5.33-5.23 (m, 1H), 2.20 (s, 3H), 2.19 (s, 3H).