Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].C([S:6][CH:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][O:10][C:9]2[CH:18]=[CH:19][C:20]([O:22][CH2:23][C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][C:28]([Cl:34])=[CH:29][CH:30]=4)[N:25]=3)=[CH:21][C:8]1=2)(=O)C.O.Cl>C(O)C>[Cl:34][C:28]1[CH:27]=[C:26]2[C:31]([CH:32]=[CH:33][C:24]([CH2:23][O:22][C:20]3[CH:19]=[CH:18][C:9]4[O:10][CH2:11][C:12]5[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=5[CH:7]([SH:6])[C:8]=4[CH:21]=3)=[N:25]2)=[CH:30][CH:29]=1
Reactant: CC(=O)SC1c2ccccc2COc2ccc(OCc3ccc4ccc(Cl)cc4n3)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: SC1c2ccccc2COc2ccc(OCc3ccc4ccc(Cl)cc4n3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.5 %

Procedure:
19 ml of a 1N-sodium hydroxide aqueous solution was added to 3.49 g of 11-acetylthio-2-(7-chloroquinolin-2-yl)methoxy-6,11-dihydrodibenz[b,e]oxepine obtained in Reference example 71 dissolved in 66 ml of ethanol and the mixture was stirred at room temperature for 1 hour. 250 ml of water was added to the reaction mixture and the mixture was adjusted to about pH 4 with 1N-hydrochloric acid. Crystals precipitated were dissolved in 300 ml of methylene chloride and the organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was removed to obtain 3.03 g of the title compound as a crude product.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:12].Cl[CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][CH3:31])[CH2:19][CH2:18]1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[CH3:31][O:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[CH2:23][N:20]1[CH2:19][CH2:18][N:17]([CH2:16][CH2:15][CH2:14][O:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH2:4][CH2:5][CH2:6][C:7]3=[O:12])[CH2:22][CH2:21]1
Reactant: O=C1CCCc2c(O)cccc21
Reactant: COc1ccccc1CN1CCN(CCCCl)CC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: COc1ccccc1CN1CCN(CCCOc2cccc3c2CCCC3=O)CC1
Yield: 57.1 %

Procedure:
from 5-hydroxy-1-oxotetraline and 1-(3-chloropropyl)-4-(2-methoxybenzyl)-piperazine; yield 57.1% of theory; m.p. of the dihydrochloride (recrystallized from 1N hydrochloric acid) 241°-243°C;
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[C:6]([C:8](=O)[CH3:9])[CH:7]=1.Cl.[NH2:18][OH:19].N1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[C:6]([C:8](=[N:18][OH:19])[CH3:9])[CH:7]=1
Reactant: NO
Reactant: CC(=O)c1cc(Br)ccc1OC1CCCC1
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(=NO)c1cc(Br)ccc1OC1CCCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 87.4 %

Procedure:
1-(5-Bromo-2-cyclopentyloxyphenyl)ethanone (5.0 g, 17.65 mmol) was dissolved in a mixed solvent of chloroform (18 ml) and methanol (70 ml). Hydroxylamine hydrochloride (1.88 g, 27.0 mmol) and pyridine (4.36 ml, 54.1 mmol) were added to the resulting solution, and the mixture was stirred for 6 hours while heating under reflux. The reaction mixture was cooled to room temperature, and then concentrated under reduced pressure. 2N Hydrochloric acid (13.9 ml) was added to the residue, and the resulting mixture was extracted with dichloromethane. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over magnesium sulfate, and concentrated to dryness under reduced pressure. The residue was washed with n-hexane and dried to thereby obtain 4.6 g of powdery white 1-(5-bromo-2-cyclopentyloxyphenyl)ethanone oxime (yield: 87%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([NH:7][C:8](=[O:12])[CH2:9][NH:10][CH3:11])=[O:6].[N:13]([O-])=[O:14].[Na+].CO>C(O)=O>[Cl:1][CH2:2][CH2:3][N:4]([N:13]=[O:14])[C:5]([NH:7][C:8](=[O:12])[CH2:9][NH:10][CH3:11])=[O:6]
Reactant: CNCC(=O)NC(=O)NCCCl
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CO
Solvent: O=CO
Product: CNCC(=O)NC(=O)N(CCCl)N=O
Reaction time: 0.5 h
Yield: 53.9 %

Procedure:
N-[N'-(2-Chloroethyl)carbamoyl]sarcosine amide (100 mg, 0.516 mmol.) was dissolved in a 99% formic acid (0.7 ml) under ice-cooling, to which sodium nitrite (53.4 mg, 1.5 moles per mole of the starting compound) was slowly added and the mixture was held under stirring for further 30 minutes to complete the reaction. Then, Amberlite IR-120 (H+ form), a strongly acidic cation exchange resin made and sold by Rohm & Haas Company, (1 ml) and methanol (1 ml) were added to the resulting reaction solution and the mixture was stirred for 10 minutes. After the resin was removed by filtration, the reaction solution was concentrated in vacuo to leave an oily residue. The residue was purified by column chromatography on silica gel (Wako-gel C-300) with a developer system of toluene-ethanol (3:1 by volume), where the eluate was collected in fractions and the fractions containing the main product were collected together and concentrated in vacuo to afford N-[N'-(2-chloroethyl)-N'-nitrosocarbamoyl]sarcosine amide (62 mg) as a white crystalline residue.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:37][O:38][C:39]([C:41]1[CH:46]=[CH:45][C:44](B(O)O)=[CH:43][CH:42]=1)=[O:40].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.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>[CH3:37][O:38][C:39](=[O:40])[C:41]1[CH:46]=[CH:45][C:44]([C:19]([C:11]2[N:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:8])=[O:9])[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=2)=[CH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:43][CH:42]=1
Reactant: Cc1ccc(S(=O)(=O)OC(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(C(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Yield: 71.7 %

Procedure:
To a mixture of toluene-4-sulfonic acid-1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl ester (prepared as in Example 43, 1.0 g, 1.92 mmol), 4-methoxycarbonylphenylboronic acid (0.86 g, 4.8 mmol) and dichlorobis(triphenylphosphine)palladium (II) (134 mg, 0.02 mmol) in dioxane (16 mL) was added an aqueous sodium carbonate solution (2 M, 2.4 mL). The resulting mixture was subjected to microwave irradiation for 2 h at 100° C. The mixture was diluted with ethyl acetate (100 mL), washed with a saturated aqueous sodium bicarbonate solution (2×30 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 25% ethyl acetate/hexanes) afforded 4-[1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl]-benzoic acid methyl ester (0.67 g, 72%) as a white solid: LC/MS m/e calcd for C28H26N2O4S [M+H]+ 487.59, observed 487.0.
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.C(O[CH2:17][CH3:18])(=O)CC([O-])=O.S([CH2:29][N+:30]#[C-])(C1C=CC(C)=CC=1)(=O)=O>>[I:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]2[CH:18]=[CH:17][NH:30][CH:29]=2)=[CH:4][CH:3]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: O=Cc1ccc(I)cc1
Product: Ic1ccc(-c2cc[nH]c2)cc1
Yield: 91 %

Procedure:
The synthesis of the β-substituted EH begins in the same manner as the prior synthesis of β-substituted dipyrromethanes (Balasubramanian, T.; Lindsey, J. S. Tetrahedron 1999, 55, 6771-6784) but employs a number of significant improvements (FIG. 54). The iodophenyl substituted pyrrole (3) is readily prepared from 4-iodobenzaldehyde, monoethyl malonate, and tosylmethylisocyanide. The ethoxycarbonyl group was removed by treatment with NaOH in ethylene glycol at 160° C. to give the 3-(4-iodophenyl)pyrrole (4) in 91% yield as pale brown crystals. It is noteworthy that this single-step decarboxylation is superior to the two-step transformation on similar pyrrole compounds (Pavri, N. R.; Trudell, M. L. J. Org. Chem. 1997, 62, 2649-2651). Vilsmeier-Haack formylation of 4 yielded a mixture of two regioisomers (˜6:1 ratio) which were readily distinguished by 1H NMR spectroscopy (See Experimental Section). The major isomer was the desired compound (5) and was obtained in pure form by recrystallization in 62% yield. Protection of the pyrrolic nitrogen with the BOC group (Tietze, L. F.; Kettschau, G.; Heitmann, K. Synthesis 1996, 851-857) gave pyrrole 6 in quantitative yield. Reduction to alcohol 7 was achieved by treatment with LiBH4 at low temperature (longer reaction time or higher temperature led to the over-reduced and deprotected compound 2-methyl-3-(4-iodophenyl)pyrrole). Treatment of 7 with excess pyrrole under acidic conditions furnished the β-substituted, mono-protected dipyrromethane 8 in 68% yield. Excess pyrrole is necessary to minimize the formation of the tripyrromethane, while protection of the pyrrolic nitrogen is necessary to facilitate the reaction, avoid self condensation and allow the subsequent selective monoacylation. This methodology afforded the β-substituted dipyrromethane as a single regioisomer, in contrast to earlier methodology which gave a mixture of two regioisomers (Balasubramanian, T.; Lindsey, J. S. Tetrahedron 1999, 55, 6771-6784).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C@H:4]([CH2:13][SH:14])[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].CCN(C(C)C)C(C)C.[Na+].[I-].[CH2:27](Br)[C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:29].Cl>CC#N.O>[CH3:1][O:2][C:3](=[O:15])[C@H:4]([CH2:13][S:14][CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:29])[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7]
Reactant: COC(=O)[C@H](CS)NC(=O)OC(C)(C)C
Reactant: O=C(CBr)c1ccccc1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CSCC(=O)c1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 19 h
Yield: 124.5 %

Procedure:
To a solution of the N-Boc cysteine methyl ester (2.05 ml, 9.93 mmol) in MeCN (20 ml) at 0° C. were added DIPEA (3.55 ml, 20.1 mmol), NaI (0.48 g, 3.20 mmol), and then a solution of phenacyl bromide (2.41 g, 12.1 mmol) in MeCN (4 ml). The mixture was stirred at room temperature for 19 h. Water (100 ml) and 1N aqueous HCl. (30 ml) was added, and the product was extracted (3×AcOEt). The combined extracts were washed with brine, dried (MgSO4), and concentrated under reduced pressure to yield 4.37 g of an oil. Crystallization from AcOEt (approx 10 ml) and heptane (approx 40 ml) at −20° C. overnight yielded 3.49 g (99%) of the title methyl ester as a brown solid.
Reaction SMILES: CO.[N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]3[CH:45]=[CH:44][C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[N:37]=3)=[CH:30][CH:29]=2)([CH3:27])[CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:17][CH:16]=1.[OH-].[Na+:47]>O1CCOCC1>[Na+:47].[N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]3[CH:45]=[CH:44][C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[N:37]=3)=[CH:30][CH:29]=2)([CH3:27])[CH2:22][CH2:23][C:24]([O-:26])=[O:25])=[CH:17][CH:16]=1
Reactant: CC(CCC(=O)O)(c1ccc(OCc2ccc3ccccc3n2)cc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: CC(CCC(=O)[O-])(c1ccc(OCc2ccc3ccccc3n2)cc1)c1ccc(OCc2ccc3ccccc3n2)cc1

Procedure:
To a solution in dioxane (10 mL) and methanol (10 mL) of 4,4-bis(4-(2-quinolylmethoxy)phenyl)pentanoic acid (320 mg, 0.56 mmol), prepared as in step 1, was added aqueous 1N sodium hydroxide (0.55 ml, 0.55 mmol). The mixture was then concentrated in vacuo. The product was crystallized by dissolving in CH2Cl2 and precipitation by dropwise addition of a mixture of ethyl acetate-ethyl ether (1:2): 1 H NMR (300 MHz, DMSO-d6) d 1.47 (s, 3H), 1.63 (m, 2H), 2.18 (m, 2H), 5.31 (s, 4H), 6.95 (d, 4H, J=9 Hz), 7.08 (d, 4H, J=9 Hz), 7.64 (m, 4H), 7.78 (m, 2H), 8.00 (m, 4H), 8.40 (d, 2H, J=8 Hz); MS (FAB+) m/e 591 (M+H)+ ; (FAB-) 589 (M-H)-. Anal. Calc'd. for C37 H31N2O4Na.0.25 H2O:C, 74.67; H, 5.34; N, 4.71; Found: C, 74.57; H, 5.32; N, 4.52.
Reaction SMILES: Cl.[O:2]1[C@@H:14]2[C@@:15]34[CH2:17][CH2:18][N:19]([CH2:20][CH3:21])[C@@H:9]([C@:10]3([O:23][CH2:24][CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:11][CH2:12][C:13]2=[O:22])[CH2:8][C:7]2=[C:16]4[C:3]1=[C:4]([OH:33])[CH:5]=[CH:6]2.[CH3:34][I:35]>C(#N)C>[I-:35].[O:2]1[C@@H:14]2[C@@:15]34[CH2:17][CH2:18][N@@+:19]([CH2:20][CH3:21])([CH3:34])[C@@H:9]([C@:10]3([O:23][CH2:24][CH2:25][CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:11][CH2:12][C:13]2=[O:22])[CH2:8][C:7]2=[C:16]4[C:3]1=[C:4]([OH:33])[CH:5]=[CH:6]2
Reactant: CI
Reactant: CCN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)CC[C@@]3(OCCCc2ccccc2)[C@H]1C5
Agent: Cl
Solvent: CC#N
Product: CC[N@@+]1(C)CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)CC[C@@]3(OCCCc2ccccc2)[C@H]1C5
Product: [I-]

Procedure:
A solution of compound 20 (see Example 20) (250 mg, 0.58 mmol) and methyl iodide (0.36 ml, 5.80 mmol) in acetonitrile (10 ml) was stirred for 6 days at 50° C. (bath temperature) under N2. The solution was evaporated down and the evaporation residue (320 mg of bright beige foamy resin) was purified using column chromatography (silica gel; CH2Cl2/MeOH: each 1 l: (95/5), (92.5/7.5)). Evaporation residue (240 mg, 72%) of amorphous compound 39. Fp. 171-176° C.; IR (KBr): 1723 (C═O) cm−1; 1H-NMR (DMSO-d6): δ 9.55 (s, C3-OH), 7.31-7.16 (m, 5 arom. H), 6.68 (s, 2 arom. H, C1—H, C2—H), 4.87 (s, C5—H), 3.44 (3H, N+CH3, axial), 1.34 (t, 3H, +NCH2CH3, J=7 Hz); MS (CI): m/z 448 (M+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=3)[CH:14]=[N:13]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[N+:24]([O-])([OH:26])=[O:25]>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:3]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([N+:24]([O-:26])=[O:25])=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=3)[CH:14]=[N:13]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: O=[N+]([O-])c1ccc2cnn(-c3ncc(C(F)(F)F)cc3Cl)c2c1
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc2cnn(-c3ncc(C(F)(F)F)cc3Cl)c2cc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 70.7 %

Procedure:
To a solution of 1-(3-chloro-5-trifluoromethylpyridin-2-yl)-6-nitroindazole [Compound No. 3] (10 g) in conc. sulfuric acid (100 g), fuming nitric acid (3.2 g) was added dropwise while cooling with ice, and the resultant mixture was stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was poured into ice water, and precipitated crystals were collected by filtration, washed and dried. The crystals were purified by silica gel column chromatography with hexane-ethyl acetate (4:1) to give 1-(3-chloro-5-trifluoromethylpyridin-2-yl)-5,6-dinitroindazole (8.0 g).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([O:13][C:14](=[O:29])[CH2:15][CH:16]([NH:20][C:21]([CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)=[O:22])[C:17](=O)[CH3:18])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O>CN(C=O)C>[CH2:6]([O:13][C:14](=[O:29])[CH2:15][C:16]1[N:20]=[C:21]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[O:22][C:17]=1[CH3:18])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(=O)C(CC(=O)OCc1ccccc1)NC(=O)C1CCCCC1
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: Cc1oc(C2CCCCC2)nc1CC(=O)OCc1ccccc1
Temperature: 90 °C

Procedure:
Phosphorous oxychloride (22 mL, 0.235 moles, 3.0 eq) was added dropwise to a solution of 3-(cyclohexanecarbonyl-amino)-4-oxo-pentanoic acid benzyl ester (26.0 g, 0.078 moles) in DMF (330 mL). The mixture was heated to 90° C. for 30 min, and then cooled to ambient temperature before diluting by slowly adding DI water (600 mL, Caution, exothermic). The mixture was cooled to ambient temperature and extracted with MTBE (3×150 mL). The combined organic phases were washed with DI water, brine (150 mL), dried over MgSO4 and concentrated to obtain 21.1 g as a brown oil. Further purification was not necessary.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:7][CH:6]([N:8]2[C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=[CH:9]2)[C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=2[O:3]1.C(N1C=CN=C1)(N1[CH:27]=[CH:26]N=C1)=O.C(=O)=O.[O-]CC.[Na+]>CN(C)C=O.C(O)C>[CH3:1][C:2]1([CH3:20])[CH2:7][CH:6]([N:8]2[C:12]([C:13]([O:15][CH2:26][CH3:27])=[O:14])=[CH:11][N:10]=[CH:9]2)[C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=2[O:3]1
Reactant: CC1(C)CC(n2cncc2C(=O)O)c2ccccc2O1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CC[O-]
Agent: O=C=O
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CCOC(=O)c1cncn1C1CC(C)(C)Oc2ccccc21
Yield: 63.5 %

Procedure:
A solution of 3.3 parts of 1-(2,3-dihydro-2,2-dimethyl-4H-1-benzopyran-4-yl)-1H-imidazole-5-carboxylic acid in 45 parts in warm N,N-dimethylformamide was cooled to room temperature and then 2 parts of 1,1'-carbonylbis[1H-imidazole] were added. The whole was stirred at room temperature till CO2 evolution had ceased (±30 minutes). The mixture was heated to ±70° C. and 2.4 parts of ethanol and 0.1 parts of sodium ethoxide were added. Stirring was continued over weekend at ±70° C. After evaporation, the residue was taken up in water and trichloromethane. The organic layer was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using trichloromethane as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from hexane. The product was filtered off and dried, yielding 2.36 parts (63.5%) of ethyl 1-(2,3-dihydro-2,2-dimethyl-4H-1-benzopyran-4-yl)-1H-imidazole-5-carboxylate; mp. 80.9° C. (compound 1.138).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[N:17]=[C:16]2[C:11]([CH:12]=[CH:13][C:14]([N:18]3[CH:26]([O:27]C(OC4C=CC=CC=4)=O)[C:25]4[C:20](=[N:21][CH:22]=[CH:23][N:24]=4)[C:19]3=[O:37])=[N:15]2)=[CH:10][CH:9]=1.[CH:38]([O:41]C(C)C)(C)C>CN(C)C=O>[Cl:7][C:8]1[N:17]=[C:16]2[C:11]([CH:12]=[CH:13][C:14]([N:18]3[CH:26]([O:27][C:38]([N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)=[O:41])[C:25]4[C:20](=[N:21][CH:22]=[CH:23][N:24]=4)[C:19]3=[O:37])=[N:15]2)=[CH:10][CH:9]=1
Reactant: CC(C)OC(C)C
Reactant: O=C(Oc1ccccc1)OC1c2nccnc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Reactant: C1CCNCC1
Solvent: CN(C)C=O
Product: O=C(OC1c2nccnc2C(=O)N1c1ccc2ccc(Cl)nc2n1)N1CCCCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of piperidine (3.06 g.) in anhydrous dimethylformamide (5 cc.) is added to a suspension of 6-(7-chloro-1,8-naphthyridin-2-yl)-7-oxo-5-phenoxycarbonyloxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine (5.2 g.) in anhydrous dimethylformamide (21 cc.). The reaction mixture is stirred for 15 minutes at a temperature of about 25° C., after which diisopropyl ether (75 cc.) is added. The insoluble product is filtered off, washed with diisopropyl ether (4 × 10 cc.) and then treated with methylene chloride (100 cc.). A slight amount of insoluble matter is filtered off, and the organic solution obtained is then washed by twice successively decanting it with 1N sodium hydroxide solution (25 cc.) and water (25 cc.), dried over anhydrous sodium sulphate and evaporated to dryness under reduced pressure. After recrystallising the residue obtained from acetonitrile (130 cc.), 6-(7-chloro-1,8-naphthyridin-2-yl)-7-oxo-5-piperidinocarbonyloxy-6,7-dihydro-5H-pyrrolo[3,4-b]-pyrazine (2.25 g.), melting at 249° C., is obtained.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.N12CCN(CC1)C[CH2:17]2.[C:24]1(C)[C:25]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:27]=[CH:28][CH:29]=1>COC(C)(C)C.CCOCC>[CH3:17][C:28]1[CH:29]=[CH:24][C:25]([S:30]([O:1][CH2:2][CH:3]2[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]2)(=[O:31])=[O:32])=[CH:26][CH:27]=1
Reactant: C1CN2CCN1CC2
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Solvent: COC(C)(C)C
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 62906.5 %

Procedure:
To a solution of 4-hydroxymethyl-1-tert-butyloxycarbonylpiperidine (52.5 g, 0.244 mol) in tert-butyl methyl ether (525 ml) was added 1,4-diazabicyclo[2.2.2]octane (42.4 g, 0.378 mol). After stirring for 15 minutes at ambient temperature, the mixture was cooled to 5° C. and a solution of toluene sulphonyl chloride (62.8 g, 0.33 mmol) in tert-butyl methyl ether (525 ml) was added dropwise over 2 hours while maintaining the temperature at 0° C. After stirring for 1 hour at ambient temperature, petroleum ether (11) was added. The precipitate was removed by filtration. The filtrate was evaporated to give a solid. The solid was dissolved in ether and washed successively with 0.5M aqueous hydrochloric acid (2×500 ml), water, saturated sodium hydrogen carbonate and brine, dried (MgSO4) and evaporated to give 4-(4-methylphenylsulphonyloxymethyl)-1-tert-butyloxycarbonylpiperidine (76.7 g, 85%).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].Br[CH2:33][C:34]#[C:35][Si:36]([CH3:39])([CH3:38])[CH3:37].O>C1COCC1>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:33][C:34]#[C:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3)cc1
Reactant: C[Si](C)(C)C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3CC#C[Si](C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In THF (27.4 ml) was dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-2,3-dihydro-1-benzazepine-4-carboxylate (1.37 g). To the solution was added 60% sodium hydride (0.27 g) at 0° C., and the mixture was stirred at room temperature for 1 hour. To the mixture was added 3-bromo-1-(trimethylsilyl)-1-propyne (1.48 ml), and the mixture was stirred at 65° C. for 90 hours. After cooled to room temperature, the reaction solution was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried with magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified with silica gel column chromatography (hexane/ethyl acetate=3/1) to give methyl 7-[4-(2-butoxyethoxy)phenyl]-1-(3-trimethylsilyl-2-propynyl)-2,3-dihydro-1-benzazepine-4-carboxylate (0.78 g).