Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[NH:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[CH3:11].[H][H]>[Rh].C(O)C>[CH3:1][O:2][C:3](=[O:12])[NH:4][C@H:5]1[C@@H:10]([CH3:11])[CH2:9][CH2:8][NH:7][CH2:6]1
Reactant: [H][H]
Reactant: COC(=O)Nc1cnccc1C
Agent: [Rh]
Solvent: CCO
Product: COC(=O)N[C@@H]1CNCC[C@@H]1C

Procedure:
The hydrogenation was carried out by charging 5 grams (1 equiv., 30.1 mmol) (4-methyl-pyridin-3-yl)-carbamic acid methyl ester, 50 ml ethanol (10 volumes), and 2.5 grams rhodium on alumina (0.5 wt. equivs.) to a bomb hydrogenator. The hydrogenation was performed under 100 psi hydrogen at 100° C. for 24 hours to give only cis-(4-methyl-piperidin-3-yl)-carbamic acid methyl ester and its trans isomer (5:1 ratio) in quantitative yield. 1 H NMR: δ5.6 (1 H, d, J=8.4 Hz), 3.66 (1 H, d, J=3.6 Hz), 3.65-3.57 (3 H, brs), 3.1 (2 H, d, J=9.6, minor isomer), 2.91-2.86 (2 H, m), 2.67-2.64 (1 H, m), 2.54-2.43 (1 H, m), 2.2-1.9 (1 H, m, minor isomer), 1.78-1.65 (5 H, brs, minor isomer), 1.65-1.59 (4 H, m, minor isomer), 1.36-1.25 (2 H, m), 1.24-1.13 (2 H, m), 0.92 (3 H, d, J=6.8 Hz, minor isomer), 0.83 (3 H, d, J=7.2).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[N:17]=[C:16]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[N:15]=[C:14]3[NH:27][CH3:28])=[CH:7][CH:6]=1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.Cl.Cl.O1CCOCC1>CO>[CH3:28][NH:27][C:14]1[C:13]2[C:18](=[CH:19][CH:20]=[C:11]([C:8]3[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[CH:6][CH:7]=3)[CH:12]=2)[N:17]=[C:16]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[N:15]=1
Reactant: C1COCCN1
Reactant: CNc1nc(-c2cccnc2)nc2ccc(-c3ccc(OCCCl)cc3)cc12
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CNc1nc(-c2cccnc2)nc2ccc(-c3ccc(OCCN4CCOCC4)cc3)cc12
Yield: 69.6 %

Procedure:
In a 10 mL microwave vial 6-(4-(2-chloroethoxy)phenyl)-N-methyl-2-(pyridin-3-yl)quinazolin-4-amine (70.0 mg, 0.179 mmol) and morpholine (0.155 ml, 1.791 mmol) were added in methanol (3 mL) to give a yellow suspension. The vial was irradiated at 150° C. in the microwave for 30 min. The volatiles were evaporated in vacuo. Water (10 mL) was added to the reaction mixture and extracted with ethyl acetate (2×10 mL). The organic layers were combined and washed with brine (1×20 mL), then dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography on basic silica gel (eluted with hexane/ethyl acetate 3:2 to 0:1). The product was obtained as the parent and converted to the HCl salt by addition of 4 M HCl-dioxane, then crystallized from EtOH-H2O to give 55 mg of N-methyl-6-(4-(2-morpholinoethoxy)phenyl)-2-(pyridin-3-yl)quinazolin-4-amine as a yellow powder (60% yield), LCMS m/z=442 (M+1) (Method D) (retention time=1.12 min). 1H NMR (300 MHz, DMSO) δ 11.31 (s, 1H), 10.41 (s, 1H), 9.63 (s, 1H), 9.10-8.79 (m, 3H), 8.34 (d, J=8.2 Hz, 1H), 8.28-8.12 (m, 1H), 7.92 (d, J=8.0 Hz, 2H), 7.87-7.74 (m, 1H), 7.18 (d, J=8.0 Hz, 2H), 4.60-4.46 (m, 2H), 4.06-3.91 (m, 2H), 3.91-3.74 (m, 2H), 3.67-3.41 (m, 4H), 3.38-3.09 (m, J=10.1 Hz, 5H).
Reaction SMILES: [C:1]([C:4]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([CH2:16][CH2:17][CH2:18][CH:19]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])(=[O:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([C:4]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([CH2:16][CH2:17][CH2:18][CH:19]([O:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])(=[O:3])[CH3:2]
Reactant: CCCCCC(CCCC(CCCCCCC(=O)OCC)(C(C)=O)c1ccccc1)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCC(CCCC(CCCCCCC(=O)O)(C(C)=O)c1ccccc1)OCc1ccccc1
Reaction time: 48 h

Procedure:
A mixture of ethyl 8-acetyl-8-phenyl-12-benzyloxyheptadecanoate (14 g., crude), sodium hydroxide (2.0 g., 0.05 mole) and methanol (150 ml.) is stirred for 48 hours. The methanol is removed in vacuo; and the residual oil is poured into H2O (100 ml.), acidified with 6 N HCl (100 ml.), extracted with ether, and the combined ether extracts dried over anhydrous Na2SO4. The ether is removed in vacuo, and the residual oil is chromatographed through a silica gel column (95% CHCH3 -5% MeOH) to obtain 8-acetyl-8-phenyl-12-benzyloxyheptadecanoic acid (1.43 g., slightly impure).
Reaction SMILES: [ClH:1].[C:2]1([N:8]([CH2:32][C:33]([O:35]CC)=[O:34])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>>[ClH:1].[C:2]1([N:8]([CH2:32][C:33]([OH:35])=[O:34])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH2:28])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CN(C(=O)c1ccc2c(c1)nc(CCc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cn1c(CCc2ccc(C(=N)N)cc2)nc2cc(C(=O)N(CC(=O)O)c3ccccc3)ccc21

Procedure:
Prepared analogously to Example 26 from 1-methyl-2-[2-(4-amidinophenyl)ethyl]benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(ethoxycarbonylmethyl)-amide-hydrochloride and sodium hydroxide solution.
Reaction SMILES: [NH3:1].[Cl-:2].[CH3:3][NH+:4]1[CH2:9][CH2:8][C:7]([C:10]([O:12]CC)=O)=[CH:6][CH2:5]1>O>[Cl-:2].[CH3:3][NH+:4]1[CH2:9][CH2:8][C:7]([C:10](=[O:12])[NH2:1])=[CH:6][CH2:5]1
Reactant: N
Reactant: CCOC(=O)C1=CC[NH+](C)CC1
Agent: [Cl-]
Solvent: O
Product: C[NH+]1CC=C(C(N)=O)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of ammonia in water (25%) (50 ml) was added 1-methyl-4-ethoxycarbonyl-1,2,5,6-tetrahydropyridinium chloride (Lambrecht & Mutschler, Arzneimittel Forsch. (Drug Res.) 23, 1427 (1973)) (4.5 g; 21.9 mmol) and the mixture was stirred at room temperature for 20 hours. After evaporation in vacuo, the residue was recrystallized from methanol and ether. M.P. 191°-192° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][C@@H:13]([CH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1)[C:14]([OH:16])=[O:15]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:12][C@@H:13]([CH2:17][C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][CH:19]=2)[C:14]([OH:16])=[O:15])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Product: O=C(O)[C@H](Cc1c[nH]c2ccccc12)NS(=O)(=O)c1ccc(F)cc1

Procedure:
In a manner to Example 4 (a), 4-fluoro-benzenesulfonyl chloride was condensed with (S)-2-amino-3-(1H-Indol-3-yl)-propionic acid to give the title compound, mp=57-60° C.
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[OH:14][C:15]1[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=1[C:17]([O:19][CH3:20])=[O:18].C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C.CCOC(C)=O>[CH3:20][O:19][C:17]([C:16]1[CH:21]=[CH:22][CH:23]=[CH:24][C:15]=1[O:14][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12])=[O:18]
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: COC(=O)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1ccccc1Oc1ccc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 3 h
Yield: 88.1 %

Procedure:
4-Fluoro-3-nitrobenzoic acid (5.0 g, 27.0 mmol), methyl 2-hydroxybenzoate (4.11 g, 27.0 mmol) and Cs2CO3 (18.49 g, 56.7 mmol) were dissolved in acetonitrile (100 mL) and stirred at 80° C. for 3 h. The reaction mixture was diluted with AcOEt and washed with 1M HCl and water. The organic layer was separated, dried with Na2SO4, filtered and concentrated via rotary evaporation to afford the title compound 545 (7.55 g, 88%) as a light yellow foam.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3([OH:18])[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[NH:19]1[CH2:22][CH:21]([NH:23][C:24]([CH2:26][NH:27][C:28](=[O:39])[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=2)=[O:25])[CH2:20]1>>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3([OH:18])[CH2:16][CH2:15][CH:14]([N:19]4[CH2:22][CH:21]([NH:23][C:24]([CH2:26][NH:27][C:28](=[O:39])[C:29]5[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:36])[F:37])[CH:30]=5)=[O:25])[CH2:20]4)[CH2:13][CH2:12]3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: O=C1CCC(O)(c2ccc3c(c2)OCCO3)CC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(O)(c3ccc4c(c3)OCCO4)CC2)C1

Procedure:
The title compound was prepared as a white solid by reductive amination of 4-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-4-hydroxy-cyclohexanone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in step B of Example 4) using the procedure described in Step C of Example 4.
Reaction SMILES: [N+:1]([C:4]1[CH:46]=[CH:45][C:7]([CH2:8][O:9][C:10]([NH:12][CH2:13][CH:14]([OH:44])[CH2:15][S:16][CH2:17][C@@H:18]2[CH2:22][C@@H:21]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:20][N:19]2[C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=2)=[O:32])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].N1C=CC=CC=1.[C:53](Cl)(=[O:55])[CH3:54]>ClCCl>[C:53]([O:44][CH:14]([CH2:13][NH:12][C:10]([O:9][CH2:8][C:7]1[CH:45]=[CH:46][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)=[O:11])[CH2:15][S:16][CH2:17][C@@H:18]1[CH2:22][C@@H:21]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:25])[CH3:26])[CH2:20][N:19]1[C:31]([O:33][CH2:34][C:35]1[CH:36]=[CH:37][C:38]([N+:41]([O-:43])=[O:42])=[CH:39][CH:40]=1)=[O:32])(=[O:55])[CH3:54]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](CSCC(O)CNC(=O)OCc2ccc([N+](=O)[O-])cc2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OC(CNC(=O)OCc1ccc([N+](=O)[O-])cc1)CSC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1

Procedure:
To a solution of (2S,4R)-2-[3-(4-nitrobenzyloxycarbonyl)amino-2-hydroxypropyl]thiomethyl-4-t-butyldimethylsilyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (2.24 g) in dichloromethane (40 ml) were added pyridine (0.52 ml) and acetyl chloride (0.46 ml) under ice-cooling with stirring. The mixture was stirred at the same temperature for 1 hour. The reaction mixture was washed with water, saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride, in turn, dried over anhydrous magnesium sulfate, and evaporated in vacuo to give (2S,4R)-2-[2-acetoxy-3-(4-nitrobenzyloxycarbonyl)aminopropyl]thiomethyl-4-t-butyldimethylsilyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (2.37 g).
Reaction SMILES: [CH2:1](/[C:3](=[CH:8]\[CH3:9])/[CH:4]=[CH:5]/[CH2:6][OH:7])[CH3:2].C(N(CC)CC)C.Cl.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[N:21][CH:20]=1>ClCCl>[N:21]1[CH:22]=[CH:23][CH:24]=[C:19]([C:18]([O:7][CH2:6][CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][CH3:9])=[O:25])[CH:20]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: C/C=C(/C=C/CO)CC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC=C(C=CCOC(=O)c1cccnc1)CC
Temperature: 0 °C
Reaction time: 14 h
Yield: 90 %

Procedure:
To a mixture of (E,E)-4-ethyl-2,4-hexadien-1-ol (2.0 g), triethylamine (8 ml), and dichloromethane (15 ml) at 0° C. was added nicotinic acid chloride hydrochloride (4.23 g). The solution was stirred at 0° C. for 1.5 hours and at room temperature for 14 hours. The reaction mixture was washed with water and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel (chloroform) to give 4-ethyl-2,4-hexadien-1-yl 3-pyridinecarboxylate (3.3 g) as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH2:11][C:12]([O:14]CC)=O)=[O:10])=[CH:4][CH:3]=1.[ClH:17].[NH2:18][OH:19].[Na]>CO>[ClH:17].[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH2:11][C:12]([NH:18][OH:19])=[O:14])=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)Nc1ccc(N)cc1
Reactant: NO
Agent: Cl
Agent: [Na]
Solvent: CO
Product: Nc1ccc(NC(=O)CC(=O)NO)cc1
Reaction time: 2 h
Yield: 64 %

Procedure:
A mixture of 17.8 g (0.08 mol) of ethyl 4-amino-phenylcarbamoylacetate, 7 g (0.1 mol) of hydroxylamine hydrochloride and 4.6 g (0.2 gram atom) of sodium in 250 ml of anhydrous methanol is left in contact for 2 hours at 20° C. The methanol is evaporated in vacuo, the residue is taken up in 100 ml of water and acidified with 5 N HCl and the product is filtered off. Recrystallisation from 80 ml of water gives CRL 40,472. Melting point 164°-165° C. (with decomposition). Yield: 64%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]3[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]2=3)[CH:5]=[CH:6][CH:7]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][N:25]=1.C([O-])([O-])=O.[K+].[K+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:23][C:24]1[N:25]=[CH:26][C:27]([C:2]2[CH:3]=[C:4]([N:8]3[C:16]4[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=4[C:10]4[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]3=4)[CH:5]=[CH:6][CH:7]=2)=[CH:28][CH:29]=1
Reactant: CC1(C)OB(c2ccc(F)nc2)OC1(C)C
Reactant: Cc1ccc2c(c1)c1c(n2-c2cccc(Br)c2)CCN(C)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc2c(c1)c1c(n2-c2cccc(-c3ccc(F)nc3)c2)CCN(C)C1
Temperature: 90 °C
Reaction time: 0.75 h

Procedure:
To a de-aerated solution of 5-(3-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.281 mmol), 2-fluoropyridine-5-boronic acid pinacol ester (125 mg, 0.560 mmol) and K2CO3 (120 mg, 0.845 mmol) in DME (4 mL)-water (2 mL) was added Pd(PPh3)4 (16 mg, 0.013 mmol). The reaction mixture was stirred at 90° C. for 45 min. The solvent was removed under reduced pressure, residue diluted with water (20 mL) and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to yield 5-(3-(6-fluoropyridin-3-yl)phenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (TFA salt, CD3OD) d (ppm): 8.5 (s, 1H), 8.21 (dd, 1H), 7.72 (m, 2H), 7.62 (s, 1H), 7.5 (d, 1H), 7.3 (s, 1H), 7.17 (m, 2H), 7.06 (d, 1H), 4.8 (d, 1H), 4.4 (d, 1H), 3.8 (m, 1H), 3.56 (m, 1H), 3.21 (m, 1H), 3.18 (s, 3H), 3.1 (m, 1H), 2.4 (s, 3H).
Reaction SMILES: C(O[C:4](=[O:18])[C:5](=[CH:11][NH:12][C:13]1[CH:17]=[CH:16][S:15][CH:14]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.C1(OC2C=CC=CC=2)C=CC=CC=1>C(OCC)(=O)C>[CH2:9]([O:8][C:6]([C:5]1[C:4]([OH:18])=[C:14]2[S:15][CH:16]=[CH:17][C:13]2=[N:12][CH:11]=1)=[O:7])[CH3:10]
Reactant: CCOC(=O)C(=CNc1ccsc1)C(=O)OCC
Solvent: CCOC(C)=O
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2ccsc2c1O
Temperature: 25 °C
Yield: 76 %

Procedure:
Add 2-(thiophen-3-ylaminomethylene)-malonic acid diethyl ester (7.66 g, 28.4 mmol) to refluxing phenyl ether (100 ml) over a period of 5 min under nitrogen. After the addition is complete, keep the reaction under reflux for 30 min. Cool the reaction mixture to room temperature, and then pour it into ethyl acetate (1000 ml). Collect the brown precipitate by filtration to obtain 7-hydroxy-thieno[3,2-b]pyridine-6-carboxylic acid ethyl ester (4.82 g, 76%). MS (ES+): 224 (M+H); (ES−): 222 (M−H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18].S(=O)(=O)(O)O.[CH2:25](O)[CH3:26]>>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:25][CH3:26])=[O:18]
Reactant: CCO
Reactant: O=C(O)CCCCCCCCCCCCCCCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)CCCCCCCCCCCCCCCO

Procedure:
To a solution of 5.0 g of 16-hydroxyhexadecanoic acid in 100 ml of ethanol was added 0.2 ml of sulfuric acid and the mixture was heated under reflux for one hour. The reaction solution was distilled off under reduced pressure. The residue was diluted with ethyl acetate and washed successively with water, a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and then distilled under reduced pressure to afford the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]1[C@H:12]([C:13]([CH2:15]O)=[CH2:14])[CH2:11][N:10]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:47]>ClCCl>[C:1]([O:5][C:6]([C@H:8]1[C@H:12]([C:13]([CH2:15][Br:47])=[CH2:14])[CH2:11][N:10]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: BrC(Br)(Br)Br
Reactant: C=C(CO)[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C=C(CBr)[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.4 %

Procedure:
(3S,4R)-1-Benzyloxycarbonyl-4-[1-(hydroxymethyl)vinyl]pyrrolidine-3-carboxylic acid tert-butyl ester (30.0 g, 83.0 mmol) was dissolved in dichloromethane (300 mL). Triphenylphosphine (23.2 g, 87.2 mmol) and carbon tetrabromide (29.4 g, 87.2 mmol) were added, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure. Then, the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:1→1:1) to give 26.9 g of the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]([CH:10]([CH3:12])[CH3:11])[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.[N+:15]([O-])([OH:17])=[O:16]>ClC1C=CC=CC=1Cl>[Cl:1][C:2]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:5]2[N:6]([CH:10]([CH3:12])[CH3:11])[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: CC(C)n1c(=O)[nH]c2cc(Cl)ccc21
Solvent: Clc1ccccc1Cl
Product: CC(C)n1c(=O)[nH]c2cc(Cl)c([N+](=O)[O-])cc21
Temperature: 60 °C
Reaction time: 1 h
Yield: 84.5 %

Procedure:
5-Chloro-1-isopropylbenzimidazol-2-one (4.0 g) was dissolved in o-dichlorobenzene (80 ml) and thereto was added dropwise 70% nitric acid (2.0 g). The mixture was stirred at 60° C. for 1 hour and left to stand for cooling. The precipitated crystal was separated by filtration and washed with diethyl ether and water to give 5-chloro-1-isopropyl-6-nitrobenzimidazol-2-one (4.1 g). A part of the obtained product was recrystallized from ethanol, which showed the following physical properties:
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:21])[NH:11][CH2:12][CH2:13][N:14]([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])=[N:6][CH:5]=1.[OH-].[Na+]>C1COCC1.CO>[CH:18]([N:14]([CH:15]([CH3:17])[CH3:16])[CH2:13][CH2:12][NH:11][C:10]([C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:22])=[O:2])=[CH:5][N:6]=1)=[O:21])([CH3:19])[CH3:20]
Reactant: COC(=O)c1ccc(C(=O)NCCN(C(C)C)C(C)C)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)N(CCNC(=O)c1ccc(C(=O)O)cn1)C(C)C
Yield: 88.9 %

Procedure:
To a solution of 1100 mg (3.6 mmol) 6-(2-diisopropylamino-ethylcarbamoyl)-nicotinic acid methyl ester in 10 ml THF and 3.0 ml MeOH was added 3.6 ml of an 2N aqueous NaOH solution. After 4 h at rt the solvent was evaporated. The residue was acidified with 1N HCl, filtered off and washed with water to give 936 mg (3.2 mmol) 6-(2-diisopropylamino-ethylcarbamoyl)-nicotinic acid; ; exact MW [M+H] calc'd: 294.18; MW found [M+H]: 209.15.
Reaction SMILES: [CH:1]1[C:6]([CH:7]=O)=[CH:5][C:4]2[O:9][CH2:10][O:11][C:3]=2[CH:2]=1.[N+:12]([CH3:15])([O-:14])=[O:13].[OH-].[Na+].Cl>CO.O>[CH2:10]1[O:11][C:3]2[CH:2]=[CH:1][C:6](/[CH:7]=[CH:15]/[N+:12]([O-:14])=[O:13])=[CH:5][C:4]=2[O:9]1
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=[N+]([O-])/C=C/c1ccc2c(c1)OCO2
Temperature: 12.5 °C
Reaction time: 0.5 h
Yield: 54.9 %

Procedure:
To a stirred solution of piperonal (75 g, 500 mmol) in methanol (120 mL) at 10° C. was added nitromethane (27.1 mL, 500 mmol, 1 eq)followed by the dropwise addition of sodium hydroxide (21 g, 525 mmol, 1 eq) in sufficient water to achieve a total volume of 50 mL while maintaining the temperature between 10-15° C. The reaction mixture became cloudy, turning to a thick paste. The mixture was stirred for 30 minutes upon complention of the addition, and the mixture was then diluted with ice-water (˜350 mL) maintaining the temperature below 5° C. until solution was achieved. The resultant solution was poured in a narrow stream (such that it just failed to break into drops (into a rapidly stirred solution of 36% hydrochoric acid )100 mL) in water (150 mL). A yellow solid preciptated (nitrostyrene), and this was collected by filtration, washed with water (1.5 L) until the filrate was neutral. The filter cake was air dried and then recrystallized from hot ethanol (3 L) to yield E-2-(3,4-methylenedioxy)-nitrostyrene as yellow needles (53 g, 55%). 1H NMR (300 MHz, CDCl3) δ 7.94 (1H, d, J=13.5 Hz), 7.47 (1H, d, J=13.5 Hz), 7.09 (1H, dd, J=7.5 & 2 Hz), 7.01 (1H, d, J=2 Hz), 6.87 (1H, d, J=7.5 Hz), 6.06 (2H, s). MS (DCl/NH3) m/e 194 (M+H)+, 211 (M+H+NH3)+.
Reaction SMILES: [F:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:11].[Br:12]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:12][CH2:11][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[F:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc([N+](=O)[O-])c1F
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cccc(CBr)c1F
Temperature: 25 °C
Yield: 34 %

Procedure:
A stirred solution of 2-fluoro-1-methyl-3-nitrobenzene (15.80 g, 101.94 mmol) and N-bromosuccinimide (18.14 g, 101.94 mmol) in CCl4 (400 mL) was treated with benzoyl peroxide (0.37 g, 1.52 mmol). The mixture was heated at reflux temperature overnight and then cooled to room temperature. The reaction mixture was filtered, and the filtrate was evaporated to dryness under reduced pressure. The residue was dissolved in CH2Cl2 (100 mL) and filtered again. The filtrate was evaporated to dryness under reduced pressure, and the residue was purified by MPLC on silica gel using a mixture of EtOAc and hexane as eluent to give 1-(bromomethyl)-2-fluoro-3-nitrobenzene (8.11 g, 34%) as an off-white solid. 1H NMR (400 MHz, CDCl3): δ 8.02 (m, 1H), 7.71 (m, 1H), 7.30 (td, 1H, J=8.4, 1.6 Hz), 4.55 (d, 2H, J=1.6 Hz).