Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](C)=[C:5]([C:20]([O:22]COC(=O)C(C)(C)C)=[O:21])[CH:6]([CH3:19])[C:7]=1[C:8]([O:10][CH2:11][O:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[O:9].[CH:32](OC(C)C)(C)C>O>[CH3:32][N:3]1[C:2]([CH3:1])=[C:7]([C:8]([O:10][CH2:11][O:12][C:13](=[O:18])[C:14]([CH3:16])([CH3:15])[CH3:17])=[O:9])[CH:6]([CH3:19])[C:5]([C:20]([OH:22])=[O:21])=[CH:4]1
Reactant: CC1=C(C(=O)OCOC(=O)C(C)(C)C)C(C)C(C(=O)OCOC(=O)C(C)(C)C)=C(C)N1
Reactant: CC(C)OC(C)C
Solvent: O
Product: CC1=C(C(=O)OCOC(=O)C(C)(C)C)C(C)C(C(=O)O)=CN1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
In 30 ml of isopropyl ether saturated with water was dissolved 1.32 g of the bis(pivaloyloxymethyl) 1,4-dihydro-2,4,6-trimethyl-3,5-pyridinedicarboxylate obtained in Example 18, and 300 mg of Lipase B was added thereto, followed by stirring at room temperature for 8 hours. Any insoluble matter was removed by filtration and washed with acetone. The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate/hexane =1/3) to obtain 741 mg (yield: 76%) of (+)-1,4-dihydro-1,4,6-trimethyl-5-pivaloyloxymethoxycarbonyl-3-pyridinecarboxylic acid as a pale yellow crystal.
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([O:10][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][C:3]1([CH3:20])[CH3:19].N1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27](O)=O.OO.S([O-])([O-])=O.[Na+].[Na+].S(=O)(=O)(O)O>O=C1O[C@H]([C@H](CO)O)C(O)=C1O.N1C=CC=CC=1.O.C1CCCCC1>[CH:22]1([O:1][N:2]2[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([O:10][C:11](=[O:18])[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:4][C:3]2([CH3:20])[CH3:19])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=C(O)c1ccccn1
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1O
Agent: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: O=S(=O)(O)O
Agent: O=S([O-])[O-]
Solvent: c1ccncc1
Solvent: O
Solvent: C1CCCCC1
Product: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1OC1CCCCC1
Temperature: 48 °C
Reaction time: 8 h
Yield: 330.2 %

Procedure:
To a mixture of 3.01 g (10.9 mmol) of 1-oxyl-4-benzoyloxy-2,2,6,6-tetramethylpiperidine, 20 ml of pyridine, and 12 ml of cyclohexane are added 0.153 g (0.55 mmol) of ferrous sulfate heptahydrate, 0.211 g (1.71 mmol) of picolinic acid, and 0.048 g (0.27 mmol) of ascorbic acid. Water (1 ml) is added to dissolve the metal salt. The mixture is heated to 48° C. A solution of 2.95 g (43.5 mmol) of 50% aqueous hydrogen peroxide is added dropwise over 1.25 hours to the reaction mixture while the temperature is brought to and maintained at 60-64° C. After the peroxide is added, the reaction mixture is allowed to cool slowly. After the reaction mixture is stirred overnight at room temperature, residual peroxide is decomposed by the addition of aqueous sodium sulfite solution. A mixture of 15 ml of concentrated sulfuric acid and 65 g of ice is carefully added to the reaction mixture to form a salt from the pyridine. The reaction mixture is extracted twice with ethyl acetate. The combined organic layers are washed with dilute sodium bicarbonate solution and saturated sodium chloride solution, then concentrated. Purification by flash chromatography on silica gel with 20:1 heptane-ethyl acetate affords 2.03 g (52% yield) of the title compound, a colorless syrup, GC assay 100%.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:10]=[CH:9][NH:8][N:7]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH2:23][CH2:22]1)=[O:20].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[F:33][C:30]1[CH:29]=[CH:28][C:27]([N:24]2[CH2:23][CH2:22][N:21]([C:19](=[O:20])[CH2:18][N:8]3[CH:9]=[CH:10][C:6]([C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)=[N:7]3)[CH2:26][CH2:25]2)=[CH:32][CH:31]=1
Reactant: c1csc(-c2cc[nH]n2)c1
Reactant: O=C(CCl)N1CCN(c2ccc(F)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Cn1ccc(-c2cccs2)n1)N1CCN(c2ccc(F)cc2)CC1

Procedure:
Protocol T was followed using 3-(2-thienyl)pyrazole, K2CO3, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=1/1) afforded the title compound as a white solid. 1H NMR (400 MHz, CDCl3); 7.48–7.52 (d, 1H), 7.24–7.28 (dd, 1H), 7.14–7.2 (dd, 1H), 6.98–7.2 (m, 1H), 6.88–6.96 (m, 2H), 6.78–6.84 (m, 2H), 6.46–6.52 (d, 1H), 5.0 (s, 2H), 3.64–3.8 (m, 4H), 2.94–3.1 (m, 4H). 13C NMR (400 MHz, CDCl3): 164.4, 158, 152.2, 144, 134, 132, 126, 124, 123.8, 118, 116, 115.8, 102.2, 54, 51.2, 50.8, 45.8, 42.2.
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[O:10][CH3:11].[S:12](Cl)([Cl:15])(=[O:14])=[O:13]>>[CH3:11][O:10][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([O:8][CH3:9])[C:2]=1[S:12]([Cl:15])(=[O:14])=[O:13]
Reactant: COc1cccc(OC)c1Br
Reactant: O=S(=O)(Cl)Cl
Product: COc1cccc(OC)c1S(=O)(=O)Cl

Procedure:
2,6-Dimethoxybenzenesulfonyl chloride was prepared from 2-bromo-1,3-dimethoxybenzene according to the procedure in Example 1, Step 1. The reaction gave a mixture of sulfonyl chloride and another product as a white solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6][CH2:5][CH:4]=[CH:3]1.[CH2:16]([OH:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CC([O-])(C)C.[K+].O>[CH2:16]([O:23][CH:4]1[CH2:5][CH2:6][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][C:2](=[O:1])[CH2:3]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC=CC(=O)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(OCc2ccccc2)CC(=O)C1
Temperature: 20 °C
Reaction time: 12 h
Yield: 183.5 %

Procedure:
To a mixture of tert-butyl 6-oxo-3,7-dihydro-2H-azepine-1-carboxylate (540.00 mg, 2.56 mmol, 1.00 Eq) in BnOH (2.76 g, 25.56 mmol, 10.00 Eq), was added t-BuOK (28.68 mg, 255.61 umol, 0.10 Eq) in one portion under N2. The mixture was stirred at 20° C. for 12 hours. LCMS showed the reaction was completed. The mixture was poured into water (100 mL) and stirred for 20 min. The aqueous phase was extracted with EA (40 mL*2). The combined organic phase was washed with saturated brine (20 mL*3), dried with anhydrous Na2SO4, filtered and concentrated in vacuum to afford tert-butyl 5-benzyloxy-3-oxo-azepane-1-carboxylate (1.50 g, crude) as yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[CH3:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1>O>[CH3:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[NH:19])=[CH:16][CH:15]=1
Reactant: Cc1ccc(C#N)cc1
Reactant: Nc1ccccc1
Agent: [Li]CCCC
Solvent: O
Product: Cc1ccc(C(=N)Nc2ccccc2)cc1
Reaction time: 0.5 h

Procedure:
Procedure as described for Amidine I using the following amounts: 4.60 mL of aniline (50.0 mmol); 25.0 mL of 2.0 M butyllithium (50.0 mmol), 5.86 g of 4-methylbenzonitrile (50.0 mmol). After refluxing overnight, the solution was orange. Addition of water yielded a yellow solution with suspended solid. Solution was filtered and taken to dryness. The residue was treated with 50 mL of pentane, stirred for 30 minutes, and filtered yielding 8.23 g (78%) of light yellow solid. 1H NMR (400 MHz, CDCl3): 7.76 (d, 2H), 7.36 (t, 2H), 7.25 (d, 2H), 7.06 (t, 1H), 6.98 (d, 2 H), 4.79 (s, 2H), 2.40 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[O:15][CH2:16][CH3:17])[N:5]=[C:4]([NH2:18])[N:3]=1.[NH2:19][C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1>>[NH2:18][C:4]1[N:3]=[C:2]([NH:19][C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=2)[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[O:15][CH2:16][CH3:17])[N:5]=1
Reactant: N#Cc1ccc(N)cc1
Reactant: CCOc1ccc(Cl)cc1-c1cc(Cl)nc(N)n1
Product: CCOc1ccc(Cl)cc1-c1cc(Nc2ccc(C#N)cc2)nc(N)n1
Yield: 74 %

Procedure:
Following the method described in Example 53, 4-chloro-6-(5-chloro-2-ethoxy-phenyl)-pyrimidin-2-ylamine and 4-amino-benzonitrile provided the title compound (74% yield). 1H NMR (DMSO-d6) δ 1.41 (t, 3H, J=6.9 Hz, CH3), 4.15 (q, 2H, J=7.0 Hz, CH2), 6.53 (s, 2H, NH2), 6.84 (s, 1H, Ar), 7.17 (d, 1H, J-8.9 Hz, Ar), 7.43 (dd, 1H, J=8.8, 2.9 Hz, Ar), 7.71 (d, 2H, J=8.9 Hz, Ar), 7.92 (d, 1H, J=2.9 Hz, Ar), 8.00 (d, 2H, J=8.9 Hz, Ar), 9.70 (s, 1H, NH).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:8][CH2:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=1.[CH3:20][O:21][C:22]([C:24]1[CH:43]=[CH:42][C:27]([CH2:28][CH:29]([C:36]([O:38][CH2:39][CH:40]=[CH2:41])=[O:37])[C:30]([O:32][CH2:33][CH:34]=[CH2:35])=[O:31])=[CH:26][CH:25]=1)=[O:23]>CN(C=O)C>[CH3:20][O:21][C:22]([C:24]1[CH:25]=[CH:26][C:27]([CH2:28][C:29]([CH2:8][CH2:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=2)([C:36]([O:38][CH2:39][CH:40]=[CH2:41])=[O:37])[C:30]([O:32][CH2:33][CH:34]=[CH2:35])=[O:31])=[CH:42][CH:43]=1)=[O:23]
Reactant: COC(=O)c1ccc(CCBr)cc1
Reactant: C=CCOC(=O)C(Cc1ccc(C(=O)OC)cc1)C(=O)OCC=C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C=CCOC(=O)C(CCc1ccc(C(=O)OC)cc1)(Cc1ccc(C(=O)OC)cc1)C(=O)OCC=C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At room temperature, 62.66 g (192 mmol) of cesium carbonate and 46.75 g (154 mmol) of methyl 4-(2-bromoethyl)benzoate [CAS Reg. No. 136333-97-6] are added to a solution of 42.61 g (128 mmol) of diallyl 2-(4-methoxycarbonylbenzyl)malonate in 450 ml of DMF. The mixture is then stirred at room temperature overnight. After the reaction has gone to completion, the reaction solution is evaporated to dryness, and the residue is taken up in water and extracted three times with ethyl acetate. The combined organic phases are then washed with saturated sodium chloride solution and dried over sodium sulfate. After filtration, the solvent is removed to dryness under reduced pressure. The crude product obtained is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 13:1). This gives 41.35 g (83.6 mmol, 65% of theory) of a colorless solid.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][N:8]1[CH2:20][CH2:19][C:11]2[NH:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:10]=2[CH2:9]1.[CH3:21][O:22][C:23](=[O:32])[C:24]1[CH:29]=[CH:28][C:27]([CH2:30]Br)=[CH:26][CH:25]=1>CN(C=O)C.[I-].[K+]>[CH3:21][O:22][C:23](=[O:32])[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][N:12]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:10]3[CH2:9][N:8]([CH3:7])[CH2:20][CH2:19][C:11]2=3)=[CH:26][CH:25]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: CN1CCc2[nH]c3ccccc3c2C1
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cn2c3c(c4ccccc42)CN(C)CC3)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 62.8 %

Procedure:
Potassium tert-butoxide (0.95 g, 8.5 mmol) was placed under argon and suspended in 1 mL of anhydrous DMF. To it was added 2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (17) (1.5 g, 8.1 mmol) dissolved in 3 mL of DMF upon which the reaction turned a deep orange in color. The reaction was stirred at room temperature for 15 min after which 4-bromomethyl-benzoic acid methyl ester (1.8 g, 8.1 mmol) was added in 1 mL of DMF along with approximately 5 mg of potassium iodide. The reaction then turned a light orange in color. The reaction was stirred at 80° C. for two hours after which the reaction was quenched by the addition of 15 mL of water. The pH was adjusted to approximately 12 with 2N NaOH and the organic products were extracted with ethyl acetate (3×15 mL). The combined organic layers were washed with water (15 mL), brine (15 mL), dried with anhydrous sodium sulfate, filtered, and concentrated in vacuo. Purification by column chromatography (0-80% gradient of ethyl acetate in hexane) afforded the title compound (1.7 g, 61%) as a yellow oil. 1H NMR (400 MHz, CD3OD): δ 7.83 (d, 2H, J=8.3 Hz), 7.33 (d, 1H, J=7.8 Hz), 7.23 (m, 3H), 7.07 (m, 1H), 6.97 (m, 1H), 4.59 (s, 2H), 4.01 (s, 2H), 3.82 (s, 3H), 2.90 (t, 2H, J=5.5 Hz), 2.84 (t, 2H, J=5.3 Hz), 2.48 (s, 3H). 13C NMR (100 MHz, MeOD): δ 167.1, 147.5, 134.9, 130.4, 129.2, 128.1, 128.0, 127.4, 120.4, 119.2, 177.7, 108.3, 108.1, 65.4, 51.0, 50.0, 40.2, 29.2, 20.3. ESI-MS (m/z): [M+H]+335.2 m/z.
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]([NH:7][CH:8]1[C:20](=[O:21])[N:10]2[C:11]([C:17]([OH:19])=[O:18])=[C:12]([O:15][CH3:16])[CH2:13][S:14][C@H:9]12)=[S:6])#[N:2].CO.C(OCC)(=O)CCCCC.[K].[K+:35].[Br-]>CCOCC>[K+:35].[C:1]([CH2:3][CH2:4][C:5]([NH:7][CH:8]1[C:20](=[O:21])[N:10]2[C:11]([C:17]([O-:19])=[O:18])=[C:12]([O:15][CH3:16])[CH2:13][S:14][C@H:9]12)=[S:6])#[N:2]
Reactant: COC1=C(C(=O)O)N2C(=O)C(NC(=S)CCC#N)[C@H]2SC1
Agent: [Br-]
Agent: [K+]
Agent: [K]
Solvent: CCCCCC(=O)OCC
Solvent: CCOCC
Solvent: CO
Product: COC1=C(C(=O)[O-])N2C(=O)C(NC(=S)CCC#N)[C@H]2SC1

Procedure:
7-Cyanomethylthioacetamido-3-methoxy-3-cephem-4-carboxylic acid (35 mg.) is dissolved in 1 ml. of methanol and 50 μ l of 2.5 M potassium 2-ethyl hexanoate is added. Addition of ether causes precipitation of a very hygroscopic solid. All solvent is removed in vacuo from the mixture and the residue is solidified by the addition of acetonitrile. The desired potassium salt is collected by filtration and dried yielding 19 mg; NMR (DMSO d6 δ) 3.43 (m, CH2),3.52 (s, NCCH2SCH2CO--) 3.76 (s,OCH3), 4.10 (d, J=4Hz, H6), 5.30 (q, J=4, 9.5 Hz, H7), 9.03 (d, J=9.5 Hz,NH); νmax (KBr) 3575, 3270, 2240, 1750, 1630, 1595, 1540 cm-1.
Reaction SMILES: [CH:1]([NH:3][NH:4][C:5](=[O:17])[C:6]1[CH:11]=[C:10]([CH2:12][CH3:13])[C:9]([O:14][CH3:15])=[N:8][C:7]=1[CH3:16])=O.S(Cl)(C1C=CC(C)=CC=1)(=O)=O.C(N=P1(N(CC)CC)N(C)CCCN1C)(C)(C)C>O1CCCC1>[CH2:12]([C:10]1[C:9]([O:14][CH3:15])=[N:8][C:7]([CH3:16])=[C:6]([C:5]2[O:17][CH:1]=[N:3][N:4]=2)[CH:11]=1)[CH3:13]
Reactant: CCc1cc(C(=O)NNC=O)c(C)nc1OC
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: C1CCOC1
Product: CCc1cc(-c2nnco2)c(C)nc1OC
Temperature: 145 °C
Reaction time: 0.05 h
Yield: 8.2 %

Procedure:
Into a microwave vial is added 5-ethyl-6-methoxy-2-methyl-nicotinic acid N′-formylhydrazide (132 mg), tosyl chloride (64 mg, 0.336 mmol), and 2-t-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine on polystyrene (2.2 mmol/g, 634 mg, 1.39 mmol) and anhydrous tetrahydrofuran (6 mL). The vial is flushed with nitrogen, sealed and heated in the CEM Discover microwave at 145° C. holding at that temperature for 3 min, with a maximum pressure of 6 bar. The reaction is evaporated and the residue is directly purified by flash chromatography on a 5-gram silica gel cartridge by elution with dichloromethane. Fractions containing the product are combined and the solvent evaporated, and further purified by flash chromatography on a 5-gram silica gel cartridge by elution with dichloromethane. Fractions containing the product are combined, evaporated and re-purified by flash chromatography on a 5-gram silica gel cartridge by elution with dichloromethane:methanol (1:0 increasing to 99:1). Fractions containing the product are combined, evaporated and re-purified by flash chromatography on a 5-gram silica gel cartridge by elution with dichloromethane:ethyl acetate (6:1). Fractions containing the product are combined and the solvent evaporated. The clean fraction containing the product is evaporated to give 3-ethyl-2-methoxy-6-methyl-5-[1,3,4]oxadiazol-2-yl-pyridine (10 mg, 8% yield). MS: m/e=220 (M+H); 1H NMR (CDCl3, δ, ppm): 8.45 (1H, d), 7.91 (1H, s), 4.01 (3H, s), 2.81 (3H, s), 2.61 (2H, q), 1.13 (3H, t).
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][C:8]([N:10]([C@H:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]([O:23]C)=[O:22])[CH:19]=3)[CH2:14][CH2:13]2)[CH3:11])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.O[Li].O>CO.C1COCC1.O>[CH:1]1([CH2:6][CH2:7][C:8]([N:10]([C@H:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]([OH:23])=[O:22])[CH:19]=3)[CH2:14][CH2:13]2)[CH3:11])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)c1ccc2c(c1)[C@H](N(C)C(=O)CCC1CCCC1)CC2
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CN(C(=O)CCC1CCCC1)[C@@H]1CCc2ccc(C(=O)O)cc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 83 %

Procedure:
(R)-Methyl 3-(3-cyclopentyl-N-methylpropanamido)-2,3-dihydro-1H-indene-5-carboxylate (B-80) (1.5 g, 4.56 mmol, 1.0 eq.) was dissolved in MeOH:THF:H2O (1:1:1, 24 ml); LiOH H2O (383 mg, 9.118 mmol, 2.0 eq.) was added at 0° C., and the mixture was stirred for 4 hours at RT. After monitoring by TLC, the reaction solution was concentrated under reduced pressure, and the residue was taken up in water (15 ml) and extracted with ethyl acetate (2×20 ml). The aqueous phase was adjusted to pH 1-2 with 3 M HCl solution and extracted with DCM (3×50 ml). The combined org. phases were washed with sat. NaCl solution (50 ml), dried over sodium sulfate and concentrated under reduced pressure, dried. The crude product was used in the next stage without being purified further. Yield: 83% (1.2 g, 0.415 mmol)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([CH:19]=1)[C:7]([NH:9][C:10]1[C:11]([C:16]([NH2:18])=[O:17])=[N:12][CH:13]=[CH:14][N:15]=1)=O.[OH-].[K+].CC(O)=O>O.CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C:7]2[NH:18][C:16](=[O:17])[C:11]3[C:10](=[N:15][CH:14]=[CH:13][N:12]=3)[N:9]=2)[CH:19]=1
Reactant: NC(=O)c1nccnc1NC(=O)c1cc(Br)ccc1F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: O=c1[nH]c(-c2cc(Br)ccc2F)nc2nccnc12
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 84.1 %

Procedure:
A mixture of 3-(5-bromo-2-fluorobenzoylamino)pyrazine-2-carboxamide 103 (2.3 g, 6.78 mmol) and KOH (3.81 g, 67.8 mmol) in H2O (60 mL) and DMSO (20 mL) was stirred at room temperature for 45 min. Acidification to pH 5 (pH paper control) with AcOH followed by addition of 50 mL of ice-cold water afforded a precipitate, which was filtered off, washed with H2O, acetonitrile and ether to give 1.83 g of the title product 104 as a white powder (LCMS analysis).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:27]([O:28][CH3:29])=[CH:26][C:7]2[C:8]([C:17]3[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=3)=[N:9][C@H:10]3[C@@H:15]([C:6]=2[CH:5]=1)[CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[CH3:2].[CH:30]([NH:33][C@@H:34]([CH3:45])[CH2:35][O:36][C:37](=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([CH3:32])[CH3:31]>>[CH2:1]([O:3][C:4]1[C:27]([O:28][CH3:29])=[CH:26][C:7]2[C:8]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([N:33]([CH:30]([CH3:32])[CH3:31])[C@@H:34]([CH3:45])[CH2:35][O:36][C:37](=[O:44])[C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)=[O:22])=[CH:19][CH:18]=3)=[N:9][C@H:10]3[C@@H:15]([C:6]=2[CH:5]=1)[CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[CH3:2]
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCN(C)C[C@H]21
Reactant: CC(C)N[C@@H](C)COC(=O)c1ccccc1
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N(C(C)C)[C@@H](C)COC(=O)c3ccccc3)cc1)=N[C@@H]1CCN(C)C[C@H]21

Procedure:
Prepared from 4-((4aR,10bS)-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]-naphthyridin-6-yl)benzoic acid and benzoic acid (S)-2-isopropylamino-propyl ester as described for example 1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](Cl)=[C:11]([N+:16]([O-])=O)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]1([CH:26]=[CH:25][C:23]([OH:24])=[CH:22][CH:21]=1)[OH:20]>>[NH2:16][C:11]1[CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:14]=[CH:13][C:12]=1[O:20][C:19]1[CH:26]=[CH:25][C:23]([OH:24])=[CH:22][CH:21]=1
Reactant: O=[N+]([O-])c1cc(OCc2ccccc2)ccc1Cl
Reactant: Oc1ccc(O)cc1
Product: Nc1cc(OCc2ccccc2)ccc1Oc1ccc(O)cc1

Procedure:
4-Benzyloxy-1-chloro-2-nitro-benzene (from Example 27A) was reacted with hydroquinone according to the procedure from Example 39A and reduced according to the procedure from Example 39B to provide the title product.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[N+:19]([C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25]([Cl:27])=[O:26])([O-])=O.C(O)(C)C.Cl>C1COCC1.CO.[Pd]>[ClH:27].[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:25]([C:24]2[CH:23]=[C:22]([CH:30]=[CH:29][CH:28]=2)[NH2:19])=[O:26])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCCCc1ccccc1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CC(C)O
Product: Nc1cccc(C(=O)NCCCCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 4-phenylbutylamine, 2.9 g, 0.019 moles, in 100 ml THF was added 10 ml of triethylamine. To this was added 3-nitrobenzoyl chloride, 3.0 g, 0.016 moles and the reaction was stirred at room temperature for 18 hours. The triethylamine hydrochloride was removed by filtration. To the filtrate was added 100 ml of ethyl acetate, and the organic phase was then washed with 1N hydrochloric acid, 100 ml (twice), and then with 2N sodium hydroxide, 100ml (twice). The organic phase was dried over magnesium sulfate. The solvent was evaporated to yield an oil. This oil was dissolved in 100 ml of methanol and 20 ml of isopropanol/hydrochloric acid and to this solution was added 250 mg of 10% palladium on carbon. The reaction was hydrogenated for 3 hours. The catalyst was removed by filtration and the solvent was evaporated. The residue was crystallized from hot isopropanol and ethyl acetate, and was collected by filtration to yield 3.1 g of 3-(((4-phenylbutyl)amino)carbonyl)aniline hydrochloride.
Reaction SMILES: [CH3:1][C:2]1[C:15]2[C:6](=[CH:7][N:8]=[C:9]3[C:14]=2[C:13](=O)[CH2:12][CH:11]=[CH:10]3)[CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:18].P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[Cl:18][C:7]1[N:8]=[C:9]2[C:14](=[C:15]3[C:6]=1[CH:5]=[CH:4][CH:3]=[C:2]3[CH3:1])[CH:13]=[CH:12][CH:11]=[CH:10]2
Reactant: Cc1cccc2cnc3c(c12)C(=O)CC=C3
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1cccc2c(Cl)nc3ccccc3c12
Temperature: 25 °C
Yield: 94.8 %

Procedure:
The above compound, 10-methyl-phenanthridinone (4.0 grams, 19 mmole) was added to a reaction flask containing phosphorus pentachloride (6.0 grams, 0.29 mole) and phosphoryl chloride (50 mL). The reaction mixture was refluxed for 4 hours, cooled to room temperature and diluted with toluene. The excess phosphoryl chloride and toluene were removed by a rotary evaporator. The residue was dissolved into ethyl acetate and washed with distilled water followed by brine. The solvent layer was dried over magnesium sulfate, filtered and concentrated to give 6-chloro-10-methylphenanthridine (4.1 grams, 95%) as an off-white solid. The product was confirmed by Mass Spec and NMR and not purified further but used directly in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH2:4][OH:5].Cl[C@@H:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][C@H:14]1[NH:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].C(=O)([O-])[O-].[Ba+2]>C(OCC)(=O)C>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:2]([NH:1][C@@H:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][C@H:14]2[NH:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:3]([CH2:4][OH:5])[CH:6]=1
Reactant: CCOC(=O)N[C@@H]1Cc2ccccc2[C@H]1Cl
Reactant: COc1ccc(N)c(CO)c1
Agent: O=C([O-])[O-]
Agent: [Ba+2]
Solvent: CCOC(C)=O
Product: CCOC(=O)N[C@@H]1Cc2ccccc2[C@H]1Nc1ccc(OC)cc1CO
Yield: 43.8 %

Procedure:
A solution of 2-amino-5-methoxybenzyl alcohol (5 g; 32.7 m. mol) and trans-1-chloro-2-ethoxycarbonylaminoindane (7.83 g; 32.7 m.mol) in dmethylformamide (80 ml) was treated with barium carbonate (3.37 g; 17 m.mol) in a manner similar to that in Description 3 to give the title compound (5.1 g; 44%), m.p. 142°-144° (from ethyl acetate).