Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:5]([N:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:16]=2)=[C:6]([N:8]2CCOCC2)[N:7]=1.[Cl:23][CH:24]([CH:28]1[O:32][CH2:31][CH2:30][O:29]1)[CH2:25][CH2:26][CH3:27].N(CC)(C(C)C)C(C)C.Cl>C1(C)C=CC=CC=1.CN(C=O)C.C(Cl)Cl.CCOC(C)=O>[ClH:23].[O:29]1[CH2:30][CH2:31][O:32][CH:28]1[CH2:24][CH2:25][CH2:26][CH2:27][N:14]1[C:5]2[C:6]([NH2:8])=[N:7][C:2]([CH3:1])=[N:3][C:4]=2[CH:16]=[C:15]1[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCCC(Cl)C1OCCO1
Reactant: Cc1nc(N2CCOCC2)c2nc(-c3ccccc3)cc-2[nH]1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nc(N)c2c(cc(-c3ccccc3)n2CCCCC2OCCO2)n1
Temperature: 25 °C
Yield: 21.3 %

Procedure:
A solution of 2-methyl-4-amino-6-phenylpyrrolo[3,2-d]pyrimidine (Example 22) (0.079 g, 0.35 mmol), 2-(1-chlorobutyl)-1,3-dioxolane (Fluka Chemika) (0.14 g, 0.85 mmol), and iso-Pr2NEt (0.3 mL, 1.7 mmol) in toluene/DMF (2.5:1.0 mL) was heated at reflux for 6 days. The mixture was allowed to cool to room temperature and purified by flash chromatography on silica gel with 5% NH3 (2N in MeOH) 5% MeOH in CH2Cl2 to afford the product. The product was dissolved in CH2Cl2/EtOAc (1:1) and the solution was treated with a 2 M ethereal HCl (2 mL). The resulting slurry was filtered, and the solid was washed with hot EtOAc (3×) to give a yellow solid (29 mg, 23%). 1H NMR (DMSO-d6; 400 MHz): d 1.53 (m, 2), 1.64 (m, 2), 1.84 (m, 2), 2.68 (s, 3), 3.86 (m, 2), 4.32 (br t, 2), 4.80 (t, 1), 7.34 (s, 1), 7.48-7.58 (m, 3), 8.11 (d, 2), 8.89 (s, 1), 9.17 (s, 1), 13.90 (s, 1). MS m/z: 353 (M+1). Anal. Calcd for C20H24N4O2.2HCl: C, 56.47; H, 6.16; N, 13.18. Found: C, 56.36; H, 6.08; N, 13.21.
Reaction SMILES: [NH2:1][C@:2]1([C:21]([O:23][CH3:24])=[O:22])[CH2:6][CH2:5][C@@H:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[C:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:9][CH:8]=2)[CH2:3]1.[C:25]([OH:34])(=[O:33])[C@@H:26]([C@H:28]([C:30]([OH:32])=[O:31])[OH:29])[OH:27]>CO.[OH-].[OH-].[Pd+2]>[NH2:1][C@:2]1([C:21]([O:23][CH3:24])=[O:22])[CH2:6][CH2:5][C@@H:4]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:9][CH:8]=2)[CH2:3]1.[C:25]([OH:34])(=[O:33])[C@@H:26]([C@H:28]([C:30]([OH:32])=[O:31])[OH:29])[OH:27]
Reactant: COCCCCC#Cc1ccc([C@@H]2CC[C@](N)(C(=O)OC)C2)cc1
Agent: [Pd+2]
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: [OH-]
Solvent: CO
Product: COCCCCCCc1ccc([C@@H]2CC[C@](N)(C(=O)OC)C2)cc1

Procedure:
To a slurry of palladium hydroxide on carbon (1.867 g, 2.66 mmol) in MeOH (250 mL) was added a solution of (1R,3R)-methyl 1-amino-3-(4-(6-methoxyhex-1-ynyl)phenyl)cyclopentanecarboxylate, L-tartaric Acid 2 (25.5 g, 53.2 mmol) in MeOH (50 mL). The reaction mixture was purged with hydrogen and an atmosphere of hydrogen was maintained via balloon. After about 15 hours the reaction mixture was filtered through Celite® and concentrated in vacuo to provide (1R,3R)-methyl 1-amino-3-(4-(6-methoxyhexyl)phenyl)cyclopentanecarboxylate, L-tartaric acid 2 (25.6 g, 52.9 mmol, 100% yield) as a colorless solid.
Reaction SMILES: Cl.Cl.[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N:9]([CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])[C:10]([C:12]2[CH:32]=[CH:31][C:15]3[N:16]([CH3:30])[C:17]([CH2:19][NH:20][C:21]4[CH:26]=[CH:25][C:24]([C:27](=[NH:29])[NH2:28])=[CH:23][CH:22]=4)=[N:18][C:14]=3[CH:13]=2)=[O:11])[CH:4]=1.[OH-].[Na+]>>[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N:9]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])[C:10]([C:12]2[CH:32]=[CH:31][C:15]3[N:16]([CH3:30])[C:17]([CH2:19][NH:20][C:21]4[CH:22]=[CH:23][C:24]([C:27](=[NH:28])[NH2:29])=[CH:25][CH:26]=4)=[N:18][C:14]=3[CH:13]=2)=[O:11])[CH:4]=1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1cccnc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cn1c(CNc2ccc(C(=N)N)cc2)nc2cc(C(=O)N(CCC(=O)O)c3cccnc3)ccc21
Yield: 85 %

Procedure:
Prepared analogously to Example 26 from 1-methyl-2-[N-(4-amidinophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-(3-pyridyl)-N-(2-ethoxycarbonylethyl)amide dihydrochloride and sodium hydroxide solution. Yield: 85% of theory, C25H25N7O3 (471.5); EKA mass spectrum: (M+H)+=472; (M+2H)++=236.6; (M+2Na)++=258.6.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][C:8]1[CH:13]=[C:12]([Br:14])[CH:11]=[C:10]([CH3:15])[C:9]=1[OH:16].[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CN(C=O)C>[CH2:17]([O:16][C:9]1[C:8]([CH3:7])=[CH:13][C:12]([Br:14])=[CH:11][C:10]=1[CH3:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1cc(Br)cc(C)c1O
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Br)cc(C)c1OCc1ccccc1
Reaction time: 0.33 h

Procedure:
39.9 g (286 mmol) K2CO3 were added to a solution of 50.0 g (249 mmol) 2,6-dimethyl-4-bromophenol in 500 mL DMF and stirred for 20 min. Then 34.0 mL (286 mmol) benzylchloride were slowly added dropwise and the reaction mixture was stirred for 3 h at 100° C. bath temperature. After the reaction had ended the mixture was poured onto 500 mL water and exhaustively extracted with EtOAc. The organic phases were combined, dried over Na2SO4 and evaporated down i. vac.
Reaction SMILES: C([O:4][C@H:5]1[C@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@H:8]([C:19]2[CH:24]=[C:23]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH3:34])=[CH:28][CH:27]=3)[C:22]([Cl:35])=[CH:21][C:20]=2[CH2:36][O:37][CH2:38][C:39]#[CH:40])[O:7][C@@H:6]1[CH2:41][O:42][C:43](=[O:45])[CH3:44])(=O)C.O[Li].O>C1COCC1.CO.O>[C:43]([O:42][CH2:41][C@@H:6]1[C@@H:5]([OH:4])[C@H:10]([OH:11])[C@@H:9]([OH:15])[C@H:8]([C:19]2[CH:24]=[C:23]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH3:34])=[CH:28][CH:27]=3)[C:22]([Cl:35])=[CH:21][C:20]=2[CH2:36][O:37][CH2:38][C:39]#[CH:40])[O:7]1)(=[O:45])[CH3:44]
Reactant: C#CCOCc1cc(Cl)c(Cc2ccc(OCC)cc2)cc1[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: C#CCOCc1cc(Cl)c(Cc2ccc(OCC)cc2)cc1[C@@H]1O[C@H](COC(C)=O)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 5 h
Yield: 79.2 %

Procedure:
To a stirred solution of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-5-(4-ethoxybenzyl)-2-((prop-2-ynyloxy)methyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (prepared using methods analogous to those in Example 1 and Example 5 above, 251 mg, 0.39 mmol) in THF:MeOH:H2O (2:3:1, 6.0 mL) at 15° C., was added LiOH.H2O (16.4 mg, 0.39 mmol). After stirring for 5 h at room temperature, the reaction was complete, as indicated by HPLC. The reaction mixture was concentrated and the residue was dissolved in 20 mL of ethyl acetate. The organic layer was washed with brine (20 mL), 5% KHSO4 in brine (20 mL), dried over anhydrous sodium sulfate, evaporated, and the residue was purified by preparative TLC (PE:EtOAc:MeOH=8:80:1, Rf=0.45) to afford 160 mg of title compound as a white solid (yield 79.2%; purity 99.1%, as determined by HPLC). 1H-NMR (CD3OD, 400 MHz) δ 7.48 (s, 1H), 7.40 (s, 1H), 7.12 (s, 4H), 4.85 (d, J=12.0 Hz, 1H), 4.62 (d, J=12.0 Hz, 1H), 4.51 (d, J=9.2 Hz, 1H), 4.23 (s, 2H), 4.10 (d, J=14.8 Hz, 1H), 4.05 (d, J=14.8 Hz, 1H), 3.96 (q, J=6.8 Hz, 2H), 3.88 (d, J=12.4 Hz, 1H), 3.71-3.67 (m, TH), 3.52-3.41 (m, 4H), 2.94 (s, 1H), 2.15 (s, 3H), 1.34 (t, J=6.8 Hz, 3H); LC-MS (m/z) 519 [(M+1)+], 563 [(M+45)−].
Reaction SMILES: [OH:1][C:2]1[CH:11]=[N:10][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1.N12CCCN=C1CCCCC2.Br[CH2:24][CH2:25][CH2:26][CH2:27][Cl:28].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:28][CH2:27][CH2:26][CH2:25][CH2:24][O:1][C:2]1[CH:11]=[N:10][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: ClCCCCBr
Reactant: Oc1cnc2c(n1)CCCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: ClCCCCOc1cnc2c(n1)CCCC2
Temperature: 60 °C
Yield: 54.6 %

Procedure:
300 mg (2 mmol) of 2-hydroxy-5,6,7,8-tetrahydroquinoxaline was dissolved in 5 ml of DMF, and 360 μl (2.4 mmol) of 1,8-diazabicyclo[5.4.0]undeca-7-ene (DBU) and 277 μl (2.4 mmol) of 1-bromo-4-chlorobutane were added thereto. The resultant mixture was stirred with heating at 60° C. for 22 hours to effect a reaction. The DMF in the resultant reaction mixture was distilled off in vacuo to thereby obtain a residue. An aqueous solution of potassium carbonate was added to the obtained residue, followed by extraction with chloroform to obtain an extract. The extract was dried over sodium sulfate anhydride, and subjected to filtration to thereby obtain a filtrate. The solvent of the filtrate was distilled off to thereby obtain a residue. The obtained residue was purified by silica gel column chromatography. That is, the residue was charged in a column of 20 g of silica gel (Art7734, manufactured and sold by E. Merck, Darmstadt) and eluted with chloroform, to thereby obtain 263 mg of 2-(4-chlorobutoxy)-5,6,7,8-tetrahydroquinoxaline (yield: 54.7%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:20]=[C:19]([C:21](O)=[O:22])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].Cl.[OH:25][C:26]1[C:35]([CH3:36])=[CH:34][CH:33]=[C:32]2[C:27]=1[CH2:28][CH2:29][NH:30][CH2:31]2>>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:20]=[C:19]([C:21]([N:30]3[CH2:29][CH2:28][C:27]4[C:32](=[CH:33][CH:34]=[C:35]([CH3:36])[C:26]=4[OH:25])[CH2:31]3)=[O:22])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: Cc1ccc2c(c1O)CCNC2
Reactant: CC(=O)Nc1ccc(-c2nc(C(=O)O)c3ccccc3n2)cc1
Agent: Cl
Product: CC(=O)Nc1ccc(-c2nc(C(=O)N3CCc4c(ccc(C)c4O)C3)c3ccccc3n2)cc1
Yield: 8 %

Procedure:
Reaction of 2-(4-acetamidophenyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 64 (8% yield) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 2.09-2.17 (m, 6H), 2.66 and 2.92 (2t, 2H), 3.49 and 4.06 (2t, 2H), 4.40 and 4.93 (2s, 2H), 6.30 and 6.74 (2d, 1H), 6.79 and 7.00 (2d, 1H), 7.64-7.95 (m, 4H), 8.02-8.13 (m, 2H), 8.39-8.50 (m, 3H), 10.22-10.24 (m, 1H); MS (ESI) m/z 453 ([M+H]+).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH2:21][C:22]([OH:24])=O)=[O:19])[CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([Cl:25])=[CH:7][CH:8]=2)[N:3]=1.[CH3:26][NH:27][CH3:28].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[NH2:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH2:21][C:22]([N:27]([CH3:28])[CH3:26])=[O:24])=[O:19])[CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([Cl:25])=[CH:7][CH:8]=2)[N:3]=1
Reactant: CNC
Reactant: Nc1cc(N2CCN(C(=O)NCC(=O)O)CC2)c2ccc(Cl)cc2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)CNC(=O)N1CCN(c2cc(N)nc3cc(Cl)ccc23)CC1

Procedure:
As described for example 171, [[[4-(2-amino-7-chloro-4-quinolinyl)-1-piperazinyl]carbonyl]amino]-acetic acid, di-methylamine, iPr2NEt, and HATU are reacted to afford the product. LC-MS: 390 (M++1). 1H NMR (CDCl3): δ 3.05 (s, 6H), 3.1–3.2 (m, 4H), 3.6–3.8 (m, 4H), 4.05–4.15 (d, 2H), 4.9–5.0 (s, H), 5.8 (m, 1H), 6.1–6.2 (s, 1H), 7.1–7.2 (m, 1H), 7.6 (m, 1H), 7.7–7.8 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:7][C:8]2[C:13]([OH:14])=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:5][N:6]=1.ClCCl.CN(C)C=[O:21].ClC1C=CC=C(C(OO)=O)C=1>C(Cl)(Cl)Cl>[NH2:1][C:2]1[S:3][C:4]([S:7]([C:8]2[C:13]([OH:14])=[CH:12][CH:11]=[CH:10][N:9]=2)=[O:21])=[CH:5][N:6]=1
Reactant: Nc1ncc(Sc2ncccc2O)s1
Reactant: CN(C)C=O
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Nc1ncc(S(=O)c2ncccc2O)s1
Yield: 12.2 %

Procedure:
To a mixture of 2-amino-5-(3-hydroxypyridin-2-ylthio)thiazole (4.6 g) in a mixture of chloroform (100 ml), dichloromethane (200 ml) and N,N-dimethylformamide (50 ml) was added dropwise the solution of 3-chloroperbenzoic acid (4.3 g) in chloroform (50 ml) at 5° C. with stirring. The mixture was stirred at room temperature for 5 hours. The reaction mixture was extracted with aqueous diluted hydrochloric acid and the aqueous layer was washed with ethyl acetate. The aqueous layer was adjusted to pH 5.7 using sodium bicarbonate and extracted with a mixture of tetrahydrofuran and ethyl acetate (1:1). The organic layer was washed with aqueous saturated sodium chloride and dried over magnesium sulfate. The solvent was concentrated under reduced pressure to give solid. The solid was subjected to column chromatography on silica gel (silica gel 60, 70-230 mesh; Merck: 250 g) and eluted with a mixture of chloroform and methanol (10:1). The fractions containing the objective compound were combined and concentrated under reduced pressure to give 2-amino-5-(3-hydroxypyridin-2-ylsulfinyl)thiazole (0.65 g, yield: 12.2%). mp: 155-158° C. (dec.) IR (Nujol): 3300, 3150, 1620, 1565, 1515, 1300 cm-1
Reaction SMILES: [NH3:1].[S:2]([O-:6])([O-:5])(=[O:4])=[O:3].[Zn+2:7].[S:8](=[O:12])(=[O:11])([OH:10])[OH:9]>>[S:2]([O-:6])([O-:5])(=[O:4])=[O:3].[Zn+2:7].[S:8]([O-:12])([O-:11])(=[O:10])=[O:9].[NH4+:1].[NH4+:1]
Reactant: N
Reactant: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Zn+2]
Product: [NH4+]

Procedure:
A more preferred process for the direct reduction of ammonia from a waste stream includes reacting an aqueous ammonia stream with a zinc sulfate and sulfuric acid solution to produce a spent regeneration solution of zinc sulfate and ammonium sulfate and treating such solution to cause crystallization of zinc ammonium sulfate hydrate. Preferably, the crystallization is caused by concentrating the stream by removing water. Typically this is accomplished by evaporation by conventional heating, vacuum or a combination of the two. The crystallization may also be caused by reducing the temperature of the zinc sulfate/ammonium sulfate solution or by a combination of concentration and cooling.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[F:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][C:18]=1[CH3:19])[NH2:15].Cl.O>C(OCCO)C>[F:11][C:12]1[CH:13]=[C:14]([NH:15][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:16]=[CH:17][C:18]=1[CH3:19]
Reactant: Cc1ccc(N)cc1F
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: Cl
Solvent: CCOCCO
Solvent: O
Product: Cc1ccc(Nc2ncccc2[N+](=O)[O-])cc1F
Temperature: 25 °C
Yield: 82342.5 %

Procedure:
45 g (0.28 mmol) of 2-chloro-3-nitropyridine was dissolved in 2-ethoxyethanol (300 ml), and 36 g (0.28 mmol) of 3-fluoro-4-methylaniline, 12N-hydrochloric acid and water (300 ml) were added thereto. Mixed solution was heated to reflux for 24 hours while stirring. The reaction solution was cooled to room temperature, and the solvent was distilled off under reduced pressure. The solution was extracted with ethyl acetate, and washed with saturated brine, and then the obtained organic layer was dried over anhydrous magnesium sulfate. The mixture was concentrated under reduced pressure, and the residue thus obtained was washed with diisopropyl ether to obtain 57 g (yield: 82%) of N-(3-fluoro-4-methylphenyl)-3-nitro-2-pyridylamine.
Reaction SMILES: Br[C:2]1[C:5](=[O:6])[C:4]2([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[C:3]=1[NH:12][C@@H:13]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:34])[C:26]2[C:31]([Cl:32])=[CH:30][N:29]=[CH:28][C:27]=2[Cl:33])=[CH:20][CH:19]=1)[C:14]([OH:16])=[O:15].O.Cl.[C:37](OCC)(=[O:39])[CH3:38]>C(N(CC)CC)C>[O:6]=[C:5]1[C:4]2([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[C:3]([NH:12][C@@H:13]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:34])[C:26]3[C:31]([Cl:32])=[CH:30][N:29]=[CH:28][C:27]=3[Cl:33])=[CH:20][CH:19]=2)[C:14]([O:16][CH2:38][CH2:37][OH:39])=[O:15])=[CH:2]1
Reactant: CCOC(C)=O
Reactant: O=C(Nc1ccc(C[C@H](NC2=C(Br)C(=O)C23CCCCC3)C(=O)O)cc1)c1c(Cl)cncc1Cl
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(C[C@H](NC2=CC(=O)C23CCCCC3)C(=O)OCCO)cc1)c1c(Cl)cncc1Cl
Reaction time: 1.5 h
Yield: 95.6 %

Procedure:
Intermediate 2 (31.0 g) was introduced dropwise to a well-stirred solution of Intermediate 16 (50.0 g) in ethyl acetate (500 mL) and triethylamine (25 mL). The reaction temperature was kept below 25° C. throughout by external cooling. Acylation of the starting material was complete after a 1.5 hour stir-out. Water (150 mL) was charged at the end of this period, followed by sufficient 2M hydrochloric acid to lower the pH to 1-1.5. Following separation, the organic phase was washed with water (2×150 mL), 5% sodium carbonate solution (150 mL) and 10% brine (2×150 mL) then dried (MgSO4), filtered and evaporated in vacuo to afford the title compound as a yellow-brown foam (71.1 g, 95.6% yield). 1H NMR D6-DMSO: δ1.1-1.73 (10H, b,m); 2.98 (1H, dd); 3.20 (1H, dd); 3.64 (2H, m); 4.13 (2H, t); 4.24 (1H, m); 4.39 (1H, s); 4.87 (1H, t); 7.28 (2H, d); 7.59 (2H, d); 8.37 (1H, d); 8.81 (2H, s); 10.88 (1H, s) ppm. Mass Spectrum: ESI+ m/z 532/534
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[C:5](=[CH:7][CH:8]=1)[OH:6].[CH2:10]([CH:12]1[O:14][CH2:13]1)Cl.[OH-].[Na+]>O>[OH:14][CH2:13][CH:12]1[O:6][C:5]2[CH:7]=[CH:8][C:2]([CH3:1])=[CH:3][C:4]=2[O:9][CH2:10]1
Reactant: Cc1ccc(O)c(O)c1
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc2c(c1)OCC(CO)O2
Yield: 38.8 %

Procedure:
In a reactor fitted with a stirring device 149 g 4-methyl pyrocatechol and 144 g epichlorhydrin are mixed together and heated at 70°, then a solution of 53 g sodium hydroxide in 440 ml water is slowly added. The reaction mixture is further heated at 70° for 2.30 hours then poured in water and extracted with ethyl acetate. The resulting raw product is separated after evaporation of the solvent and purified by fractional distillation under reduced pressure. 84 g of the title compound are obtained, boiling at 136°-140°/2 mm Hg.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]2[CH:10]=[C:11]([O:16]C)[C:12]([O:14]C)=[CH:13][C:7]=2[C:6]=1[Cl:18])=[O:4].B(Br)(Br)Br>ClCCl>[Cl:18][C:6]1[C:7]2[CH:13]=[C:12]([OH:14])[C:11]([OH:16])=[CH:10][C:8]=2[S:9][C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1sc2cc(OC)c(OC)cc2c1Cl
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(O)c1sc2cc(O)c(O)cc2c1Cl
Temperature: -20 °C
Reaction time: 8 h

Procedure:
3-Chloro-5,6-dimethoxy-benzo[b]thiophene-2-carboxylic acid methyl ester (0.2 g) was suspended in dichloromethane (10 ml) under nitrogen, cooled to −20° C. and boron tribromide (0.4 ml) was added. The resultant mixture was stirred at −20° C. for 30 min and then in cool overnight. The mixture was poured into ice-cold water, extracted into ethyl acetate and evaporated to dryness. The product was used for the next step without any purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7](=O)[CH:8]2[CH2:13][C:14]([O:16]CC)=O.[NH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4]2[CH2:5][CH2:6][C@H:7]3[C@H:8]([CH2:13][C:14](=[O:16])[N:20]3[CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: NCCN1CCOCC1
Reactant: CCOC(=O)CC1C(=O)CCc2c(OC)cccc21
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cccc2c1CC[C@H]1[C@@H]2CC(=O)N1CCN1CCOCC1
Yield: 85.7 %

Procedure:
A solution of 6.30 g (0.024 mol) of ethyl rac-1,2,3,4-tetrahydro-5-methoxy-2-oxo-1-napthylacetate in 100 ml of toluene was treated with 3.1 ml (0.024 mol) of 4-(2-aminoethyl)morpholine, whereupon the mixture was boiled on a water separator for 20 hours. After concentration the residue was hydrogenated with 1 g of Raney-nickel in 100 ml of ethanol at 120° and 180 bar. The product was chromatographed over silica gel with methylene chloride/methanol (9:1). There were obtained 6.80 g (86%) of oily rac-cis-1,3,3a, 4,5,9b-hexahydro-6-methoxy-3-(2-morpholinoethyl)-2H-benzo[e]indol-2-one.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10](O)=[CH:9][C:8](=[O:12])[N:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:6]=1)=[O:4].P(Cl)(Cl)([Cl:21])=O>>[CH3:1][O:2][C:3]([C:5]1[C:10]([Cl:21])=[CH:9][C:8](=[O:12])[N:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:6]=1)=[O:4]
Reactant: COC(=O)c1nn(-c2ccccc2)c(=O)cc1O
Reactant: O=P(Cl)(Cl)Cl
Product: COC(=O)c1nn(-c2ccccc2)c(=O)cc1Cl
Temperature: 85 °C
Reaction time: 20 h
Yield: 84 %

Procedure:
A mixture of 4-hydroxy-6-oxo-1-phenyl-1,6-dihydropyridazine-3-carboxylic acid methyl ester (3.83 g, 15.6 mmol) and phosphorous oxychloride (50 mL) was heated to 85° C. After 20 hours, the reaction mixture was concentrated under reduced pressure. The resulting residue was quenched with water. The precipitate was filtered and dissolved in EtOAc, dried (MgSO4) and concentrated under reduced pressure to yield 3.44 g (84%) of desired product.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][N:7]=[C:6]1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-])=O)[CH:11]=1>CO.[Pd]>[CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][N:7]=[C:6]1[C:10]1[CH:11]=[C:12]([NH2:16])[CH:13]=[CH:14][CH:15]=1
Reactant: CN(C)CCn1ccnc1-c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: CN(C)CCn1ccnc1-c1cccc(N)c1

Procedure:
Dimethyl-{2-[2-(3-nitrophenyl)imidazol-1-yl]ethyl}amine (88 mg, 0.34 mmol) in methanol (5 mL) was hydrogenated in the presence of 10% Pd/C (80 mg) for 16 h. The reaction mixture was filtered through a Celite pad. The filtrate was concentrated in vacuo to afford the title compound, which was used directly in the next step without purification. 1H-NMR (CDCl3, 400 MHz): δ=2.23 (s, 6H), 2.63 (t, J=7.2 Hz, 2H), 4.13 (d, J=7.2 Hz, 2H), 6.72-6.75 (m, 1H), 6.90-6.92 (m, 1H), 6.96 (t, J=2.0 Hz, 1H), 7.08 (d, J=1.2 Hz, 1H), 7.11 (d, J=1.2 Hz, 1H), 7.22 (t, J=7.6 Hz, 1H). MS (ES+): m/z 231.22 [MH+]. HPLC: tR=0.33 min (ZQ2000, polar—5 min).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:5]=[CH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].CO[CH:18]1[CH2:22][CH2:21][CH:20](OC)O1>C(O)(=O)C>[N:1]1([C:2]2[N:6]([C:7]([CH3:8])([CH3:9])[CH3:10])[N:5]=[CH:4][C:3]=2[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:18]=[CH:22][CH:21]=[CH:20]1
Reactant: CCOC(=O)c1cnn(C(C)(C)C)c1N
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Product: CCOC(=O)c1cnn(C(C)(C)C)c1-n1cccc1
Yield: 85.6 %

Procedure:
8.45 g of ethyl 5-amino-1-t-butyl-1H-pyrazole-4-carboxylate was dissolved in 60 ml of acetic acid, and 7.93 g of 2,5-dimethoxytetrahydrofuran was then added. The mixture was heated to reflux for 2 hours. The reaction mixture was concentrated under reduced pressure. After water was added, the residue was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 8.95 g of ethyl 5-(1H-pyrrol-1-yl)-1-t-butyl-1H-pyrazole-4-carboxylate.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:9]=[C:10]([I:14])[C:11]=1[O:12][CH3:13])[NH2:8])([CH3:4])([CH3:3])[CH3:2].Cl[C:16]([O:18][CH2:19][CH2:20][Cl:21])=[O:17].C(N(CC)CC)C>ClCCl>[Cl:21][CH2:20][CH2:19][O:18][C:16](=[O:17])[NH:8][C:7]1[CH:9]=[C:10]([I:14])[C:11]([O:12][CH3:13])=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=1
Reactant: COc1c(I)cc(N)cc1C(C)(C)C
Reactant: O=C(Cl)OCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(I)cc(NC(=O)OCCCl)cc1C(C)(C)C
Reaction time: 3 h

Procedure:
To a solution of 3-tert-butyl-5-iodo-4-methoxyaniline (0.305 g, 1.0 mmol) in dichloromethane (5.00 mL) was added 2-chloroethyl chloroformate (0.143 g, 1.000 mmol) and triethylamine (0.279 mL, 2.0 mmol) to give a solution. The mixture was stirred for 3 hours and concentrated to give the title compound that was used without purification.