Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([BH3-])#N.[Na+].[N+:5]([C:8]1[CH:19]=[CH:18][C:17]2[CH2:16][CH:15]3[C:20](=[N:21][OH:22])[CH:12]([CH2:13][CH2:14]3)[CH2:11][C:10]=2[CH:9]=1)([O-:7])=[O:6].Cl.CN(C1C=CC(N=NC2C=CC(S(O)(=O)=O)=CC=2)=CC=1)C>CO.[OH-].[Na+]>[N+:5]([C:8]1[CH:19]=[CH:18][C:17]2[CH2:16][CH:15]3[CH:20]([NH:21][OH:22])[CH:12]([CH2:13][CH2:14]3)[CH2:11][C:10]=2[CH:9]=1)([O-:7])=[O:6]
Reactant: O=[N+]([O-])c1ccc2c(c1)CC1CCC(C2)C1=NO
Agent: CN(C)c1ccc(N=Nc2ccc(S(=O)(=O)O)cc2)cc1
Agent: Cl
Agent: [BH3-]C#N
Solvent: CO
Product: O=[N+]([O-])c1ccc2c(c1)CC1CCC(C2)C1NO
Yield: 94.6 %

Procedure:
Sodium cyanoborohydride (255 mg) was added in a single portion to a solution of the oxime of Step 1 (500 mg) in dry methanol (20 mL) at −20° C. 2N HCl was then added until the solution was at pH 3 (Methyl Orange). After 3 hours the reaction was diluted with 4N NaOH (50 mL) and reduced to 1/3 volume. The residue was extracted with DCM (4×50 mL), the organic layers combined and dried over MgSO4, filtered and the solvent removed under reduced pressure to afford the title compound as a white foam (477 mg). m/z 249 (M+H+). Step 3: Tricyclo[8.2.1.03,8]trideca-3(8),4,6-triene-5,13-diamine
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[CH2:6][CH2:7][N:8]([CH2:10][CH2:11]O)[CH3:9].S(Cl)([Cl:20])=O>C(Cl)Cl>[Cl:20][CH2:11][CH2:10][N:8]([CH2:7][CH2:6][C:5]1[CH:13]=[CH:14][C:15]([O:16][CH3:17])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:9]
Reactant: COc1ccc(CCN(C)CCO)cc1OC
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(CCN(C)CCCl)cc1OC
Reaction time: 24 h

Procedure:
The 2-[N-(3,4-dimethoxyphenethyl)-N-methylamino]ethanol as produced in Example 4-(1) in an amount of 2 g (8.36 mmol) was added to methylene chloride (20 ml) and thionyl chloride (0.91 ml, 12.54 mmol) was slowly added dropwise at room temperature, followed by stirring for 24 h. Thereafter, the reaction mixture was subjected to extraction with methylene chloride and washed with a saturated solution of sodium bicarbonate, followed by drying with anhydrous magnesium sulfate and evaporation of the solvent to yield the end compound 1-chloro-2-[N-(3,4-dimethoxyphenethyl)-N-methylamino]ethane (2.15 g)
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:22][CH2:23][O:24][CH3:25]>CN(C=O)C.O>[CH3:25][O:24][CH2:23][CH2:22][N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reaction time: 1 h
Yield: 116.1 %

Procedure:
A solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.8 g, 4.1 mmol), cesium carbonate (2.0 g, 6.2 mmol), and 1-bromo-2-methoxyethane (0.41 mL, 4.3 mmol) in DMF (14 mL) was heated in a microwave at 90° C. for 1 hr. After the initial heating, additional 1-bromo-2-methoxyethane (0.41 mL) was added to the reaction. Heating was repeated for an additional 1 hr. The crude reaction mixtures were then diluted with water (250 mL) and extracted with ethyl acetate (3×50 mL). Product was purified by silica gel column using DCM/EtOAc/MeOH (8/1.5/0.5) as eluent to give 1-(2-methoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.2 g) as a light yellow oil. ESI-MS:m/z 253.2 (M+H)+.
Reaction SMILES: S([O:11][CH2:12][C@@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])(C1C=CC(C)=CC=1)(=O)=O.C1(O)C=CC=CC=1.[OH:32][C@@H:33]([C:44]1[CH:49]=[CH:48][CH:47]=[C:46](O)[CH:45]=1)[CH2:34][CH2:35][NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40].C([O-])(C)(C)C.[K+]>CN(C=O)C>[C:39]([O:38][C:37]([NH:36][CH2:35][CH2:34][C@H:33]([C:44]1[CH:49]=[C:48]([CH:47]=[CH:46][CH:45]=1)[O:11][CH2:12][C@@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[OH:32])=[O:43])([CH3:42])([CH3:40])[CH3:41]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Reactant: CC(C)(C)OC(=O)NCC[C@@H](O)c1cccc(O)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Oc1ccccc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC[C@@H](O)c1cccc(OC[C@@H]2CCCN2C(=O)OC(C)(C)C)c1

Procedure:
A mixture of (S)-tert-butyl 2-((tosyloxy)methyl)pyrrolidine-1-carboxylate (1.6 g, 5.4 mmol), phenol (7, Intermediate I) (0.8 g, 2.9 mmol), t-BuO−K+ (0.5 g, 4.5 mmol) in anhydrous DMF (5 mL) was heated at +45° C. for 16 hrs. The reaction mixture was concentrated under reduced pressure, partitioned between EtOAc and 5% NaOH, organic layer was dried over anhydrous Na2SO4, concentrated under reduced pressure. Purification by column chromatography gave (S)-tert-butyl 2-((3-((R)-3-((tert-butoxycarbonyl)amino)-1-hydroxypropyl)phenoxy)methyl)pyrrolidine-1-carboxylate as a light yellow oil. Yield (0.8 g, 59%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([O:24][CH3:25])[CH:18]=2)[N:5]=1)[CH3:2].Cl.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33]Cl)[CH:28]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:33][C:29]3[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=3)=[C:19]([O:24][CH3:25])[CH:18]=2)[N:5]=1)[CH3:2]
Reactant: ClCc1cccnc1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)c(OC)c2)nc1OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3cccnc3)c(OC)c2)nc1OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.4 %

Procedure:
A mixture of ethyl 3-[3-ethoxy-1-(4-hydroxy-3-methoxybenzyl)-1H-pyrazol-4-yl]propionate (505 mg), 3-picolyl chloride hydrochloride (476 mg), potassium carbonate (601 mg), and N,N-dimethylformamide (10 ml) was stirred at room temperature overnight. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water, then, with saturated aqueous sodium chloride solution, and dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[3-ethoxy-1-[3-methoxy-4-(3-pyridylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (531 mg, yield: 83%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:18])[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][CH:16]=[O:17])[N:10]=1)=O)C.Cl.[O:20]([NH2:23])[CH2:21][CH3:22]>C(O)C>[CH:16]([NH:15][C:11]1[N:10]=[C:9]([C:7](=[N:23][O:20][CH2:21][CH3:22])[C:6]([OH:5])=[O:18])[CH:14]=[CH:13][CH:12]=1)=[O:17]
Reactant: CCON
Reactant: CCOC(=O)C(=O)c1cccc(NC=O)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCON=C(C(=O)O)c1cccc(NC=O)n1
Reaction time: 0.5 h
Yield: 45.4 %

Procedure:
1N Sodium hydroxide solution (8.5 ml.) was added to a stirred solution of ethyl-2-(6-formamidopyridin- 2-yl)-glyoxylate (1.9 g.) in ethanol (30 ml.) at room temperature and stirred at the same temperature for 30 minutes. After adding ethoxylamine hydrochloride (912 mg.) to the solution, the solution was stirred at room temperature for 4 hours. The resultant solution was concentrated under reduced pressure, and ethyl acetate and an aqueous solution of sodium bicarbonate were added to the residue. The aqueous layer was separated and ethyl acetate was added to the solution. The solution was adjusted to pH 1 with 10% hydrochloric acid. The ethyl acetate layer was separated, dried over magnesium sulfate and concentrated under reduced pressure. The residue was triturated with a mixture of diethyl ether and petroleum ether to give 2-(6-formamidopyridin-2-yl)-2-ethoxyiminoacetic acid (920 mg.), mp. 155° to 156° C. (dec.).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].[Cl-].[Mg+2].[Cl-].[P:13]([Cl:17])(Cl)(Cl)=[O:14]>O>[C:3]1([O:9][P:13]([Cl:17])(=[O:14])[O:9][C:3]2[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cccc(C)c1O
Agent: [Cl-]
Agent: [Mg+2]
Solvent: O
Product: Cc1cccc(C)c1OP(=O)(Cl)Oc1c(C)cccc1C
Temperature: 120 °C

Procedure:
A 1,000-ml four-necked flask provided with a stirring machine, a temperature gauge, a dropping funnel, and a nitrogen-introducing pipe was mounted with a condenser to which a water scrubber had been connected, and then 2.0 mol (244 g) of 2,6-dimethylphenol, and 0.016 mol (1.5 g) of magnesium chloride were loaded into the resultant reactor. The atmosphere in the reactor was replaced with nitrogen and then its temperature was increased to 120° C. 1.0 Mole (153 g) of phosphorus oxychloride was dropped to the reactor at the temperature over 2 hours. After the completion of the dropping, the temperature was increased to 180° C. over 2 hours. Thus, di(2,6-xylyl)phosphorochloridate was obtained. The temperature in the flask was cooled to 20° C., and then 0.5 mol (55 g) of 1,3-benzenediol and 0.016 mol (1.5 g) of magnesium chloride were loaded into the flask. The temperature was increased to 180° C. over 2 hours and then the mixture was aged for 2 hours. After that, the catalyst was removed by an ordinary method and then the remainder was dried at 140° C. under reduced pressure. Thus, B-3 represented by general formula (24) was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][C@:13]([CH3:19])([C:16](O)=[O:17])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(OC(OC(OC(C)(C)C)=O)=O)(C)C.[N:35]1C=CC=CC=1.[NH4+].[OH-].O>C(OCC)(=O)C.O>[C:16]([C@@:13]1([CH3:19])[CH2:14][CH2:15][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:12]1)(=[O:17])[NH2:35]
Reactant: c1ccncc1
Reactant: C[C@]1(C(=O)O)CCN(C(=O)OCc2ccccc2)C1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@]1(C(N)=O)CCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.6 %

Procedure:
To a mixture of (S)-1-(benzyloxycarbonyl)-3-methylpyrrolidine-3-carboxylic acid (32.87 g, 124.8 mmol), Boc2O (29.97 g, 137.3 mmol) in ethyl acetate (200 mL) was added pyridine (12.62 mL, 156.1 mmol) and the reaction mixture was stirred at ambient temperature for 3 hours. A solution of 28-30% w/w NH4OH/water (21.79 mL, 162.3 mmol) was added. The reaction was stirred at ambient temperature for 5 hours. Water (50 mL) was added. The organic layer was separated, washed with 1N HCl (50 mL) and brine, dried and concentrated under reduced pressure to give (S)-benzyl 3-carbamoyl-3-methylpyrrolidine-1-carboxylate (31.30 g, 119.3 mmol, 95.6% yield) as an oil.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7](=[O:15])[C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[N:20]1([CH2:26][CH2:27][CH2:28][CH:29]2[CH2:34][CH2:33][CH2:32][NH:31][CH2:30]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C(#N)C>[N:20]1([CH2:26][CH2:27][CH2:28][CH:29]2[CH2:34][CH2:33][CH2:32][N:31]([C:2]([N:4]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[NH:8][C:7](=[O:15])[C:6]4[CH:16]=[CH:17][CH:18]=[N:19][C:5]3=4)=[O:3])[CH2:30]2)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: C1CCN(CCCC2CCCNC2)CC1
Reactant: O=C1Nc2ccccc2N(C(=O)Cl)c2ncccc21
Solvent: CC#N
Product: O=C1Nc2ccccc2N(C(=O)N2CCCC(CCCN3CCCCC3)C2)c2ncccc21
Yield: 58 %

Procedure:
Prepared analogously to Example 4 from 11-(chlorocarbonyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one and 3-[3-(1-piperidinyl)propyl]piperidine in a yield of 58% of theory. Colourless crystals, m.p. 165.5°-167.0° C. (acetonitrile).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH:16]([CH3:18])[CH3:17])[CH3:15])[C:11]([Cl:19])=[CH:10][C:9]=1[NH2:20])(C)(C)C.C(O[C:27](=[O:50])[CH2:28][C:29](=O)[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[O:37][CH:38]=[C:39]([CH2:41][O:42]C3CCCCO3)[N:40]=2)[CH:31]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:19][C:11]1[C:12]([N:14]([CH:16]([CH3:18])[CH3:17])[CH3:15])=[CH:13][C:8]2[N:7]=[C:29]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]4[O:37][CH:38]=[C:39]([CH2:41][OH:42])[N:40]=4)[CH:31]=3)[CH2:28][C:27](=[O:50])[NH:20][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2nc(COC3CCCCO3)co2)c1
Reactant: CC(C)N(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)N(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3nc(CO)co3)c1)=N2

Procedure:
The title compound was prepared from [2-amino-4-chloro-5-(isopropyl-methyl-amino)-phenyl]-carbamic acid tert-butyl ester (0.17 g) (Example J26) and 3-oxo-3-[3-[4-(tetrahydro-pyran-2-yloxymethyl)-oxazol-2-yl]-phenyl]-propionic acid tert-butyl ester (0.22 g) (Example K11) according to the general procedure M. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (0.05 g).
Reaction SMILES: [OH:1][C:2]1([CH2:21][NH:22]C(OC(C)(C)C)=O)[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:4][CH2:3]1.[ClH:30].C(O)(C)C>C(O)(C)C>[ClH:30].[ClH:30].[NH2:22][CH2:21][C:2]1([OH:1])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13](=[O:20])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)NCC1(O)CCN(CCCCCC(=O)c2ccccc2)CC1
Agent: Cl
Solvent: CC(C)O
Product: NCC1(O)CCN(CCCCCC(=O)c2ccccc2)CC1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
1H-NMR (CDCl3,ppm) δ: 1.36-1.82(20 H,m), 2.36-2.88(4 H,m), 2.60-2.67(2 H,m), 2.97(2 H,t,J=7.3 Hz), 3.14(2 H,d,J=6.6 Hz), 5.01(1 H,br), 7.42-7.59(3 H,m), 7.93-7.97(2 H,m) (2) 4-Hydroxy-1-(6-oxo-6-phenylhexyl)-4-tert-butoxycarbonylaminomethylpiperidine (3.6 g) was dissolved in isopropyl alcohol (30 ml) and 15% hydrochloric acid-isopropyl alcohol (10 ml) was added under ice-cooling, which was followed by stirring at 60° C. for 3 hr. The solvent was evaporated under reduced pressure to give 2.92 g of 4-aminomethyl-4-hydroxy-1-(6-oxo-6-phenylhexyl)piperidine dihydrochloride.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][NH:12][CH2:13][CH2:14][CH:15]2[CH2:20][CH2:19][N:18]([C:21]3[S:22][C:23]4[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:24]=4[N:25]=3)[CH2:17][CH2:16]2)[CH:6]=1.[OH-].[Na+].O1CCCC1.Cl>CO>[Cl:30][C:28]1[CH:27]=[CH:26][C:24]2[N:25]=[C:21]([N:18]3[CH2:19][CH2:20][CH:15]([CH2:14][CH2:13][NH:12][CH2:11][C:7]4[CH:6]=[C:5]([CH2:4][C:3]([OH:31])=[O:2])[CH:10]=[CH:9][CH:8]=4)[CH2:16][CH2:17]3)[S:22][C:23]=2[CH:29]=1
Reactant: COC(=O)Cc1cccc(CNCCC2CCN(c3nc4ccc(Cl)cc4s3)CC2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)Cc1cccc(CNCCC2CCN(c3nc4ccc(Cl)cc4s3)CC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.2 %

Procedure:
A mixture of [3-[[[1-(6-chlorobenzothiazole-2-yl)piperidine-4-yl]ethylamino]methyl]phenyl]acetic acid methyl ester (65 mg), 2N sodium hydroxide (0.36 mL), tetrahydrofuran (1 mL) and methanol (1 mL) was stirred at room temperature for 1 hour. The solution was neutralized with 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over sodium sulphate. The solvent was evaporated under reduced pressure and the obtained residue was washed with the mixed solvent of ethyl acetate and n-hexane to give the title compound (19 mg). Yield: 30%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1Cl)[N:8]([CH2:13][CH3:14])[CH:7]=[C:6]([C:15]([OH:17])=[O:16])[C:5]2=[O:18].[NH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)[N:8]([CH2:13][CH3:14])[CH:7]=[C:6]([C:15]([OH:17])=[O:16])[C:5]2=[O:18]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(Cl)c(Cl)cc21
Reactant: C1CCNC1
Solvent: CS(C)=O
Product: CCn1cc(C(=O)O)c(=O)c2cc(Cl)c(N3CCCC3)cc21
Temperature: 110 °C

Procedure:
A mixture of 6,7-dichloro-1-ethyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (4.3 g), pyrrolidine (10 cm3) and DMSO (45 cm3) was heated for 2 hours at 110° C. Part of the reaction product precipitated during the reaction. After cooling, it was filtered off and recrystallised from DMF (50 cm3). 3 g of 6-chloro-1-ethyl-4-oxo-7-pyrrolidino-1,4-dihydro-quinoline-3-carboxylic acid, m.p. 325° C., were obtained.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=O)[CH2:10]2)(=[O:3])[CH3:2].[ClH:16].[CH2:17]([NH2:23])[C:18]1[O:22][CH:21]=[CH:20][CH:19]=1>>[ClH:16].[C:1]([NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][CH:9]([NH:23][CH2:17][C:18]1[O:22][CH:21]=[CH:20][CH:19]=1)[CH2:10]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc2c1CCC(=O)C2
Reactant: NCc1ccco1
Agent: Cl
Product: CC(=O)Nc1cccc2c1CCC(NCc1ccco1)C2

Procedure:
Starting from 2.03 g (0.01 mol) of 5-acetylamino-2-tetralone and 4.0 g (0.03 mol) of furfurylaminehydrochloride the title compound is obtained analogously to Example 4.1.11 in a yield of 2.1 g (65.4% of theory) and with a melting point of 296° C., which does not change after recrystallisation from methanol/ether.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1.C(N(CC)CC)C>C(Cl)Cl>[C:11]([O:10][C:8]([N:5]1[CH2:4][CH2:3][CH:2]([NH:1][CH2:20][C:19]2[CH:22]=[CH:23][C:16]([Cl:15])=[CH:17][CH:18]=2)[CH2:7][CH2:6]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Clc1ccc(CBr)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(NCc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 27.7 %

Procedure:
4-Amino-1-N-Boc piperidine (1.80 g, 8.9 mmol) was dissolved in CH2Cl2 and 4-chlorobenzylbromide (1.84g, 8.9 mmol) and triethylamine (1.25 mL, 8.9 mmol) were added. The solution was allowed to stir for 14 h at room temperature and evaporated in vacuo and partitioned between ether/1N NaOH. The aqueous layer was removed and the ether was washed with brine and dried over MgSO4, filtered and evaporated in vacuo, then purified by Biotage flash chromatography (5% methanol/95% methylene chloride) to yield the title compound (0.800 g, 27%). 1H-NMR (CDCl3): δ 1.26 (m, 1H), 1.44 (s, 9H), 1.83 (d, 2H), 2.63 (t, 1H), 2.78 (t, 2H), 3.46 (s, 2H), 3.78 (s, 2H), 4.00 (bs, 2H), 7.26 (bs, 4H). ESI-MS m/z: 325.1 (M+1), retention time 1.86.
Reaction SMILES: C([O:3][C:4](=[O:19])[C:5]([CH3:18])([CH3:17])[C:6]([NH:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)=[O:7])C.[OH-].[K+].C(O)C>O>[CH3:17][C:5]([CH3:18])([C:6]([NH:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)=[O:7])[C:4]([OH:19])=[O:3]
Reactant: CCOC(=O)C(C)(C)C(=O)NCCN1CCOCC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C(=O)O)C(=O)NCCN1CCOCC1

Procedure:
34.1 g 2,2-Dimethyl-N-(2-morpholin-4-yl-ethyl)-malonamic acid ethyl ester, 8.4 g potassium hydroxide, 200 ml ethanol and 4.5 ml H2O were stirred at 80° C. for 6 hours. Then most of the solvent was removed and the pH was adjusted to pH 3-4 with about 100 ml 2N HCl. The solvent was evaporated and toluol was added and then removed. To the final residue methanol was added and the suspension was filtered to remove salts. The solvent was removed and the residue was dissolved in H2O and lyophilized. The product was characterized by 1H-NMR.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[C:21]([F:22])=[CH:20][C:19]([F:23])=[C:18]([NH2:24])[C:14]=3[C:15](=[O:17])[CH:16]=2)=[CH:7][C:6]=1[F:25])(=[O:3])[CH3:2].[Br:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]Br.[H-].[Na+].O>CN(C)C=O>[C:1]([N:4]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[C:21]([F:22])=[CH:20][C:19]([F:23])=[C:18]([NH2:24])[C:14]=3[C:15](=[O:17])[CH:16]=2)=[CH:7][C:6]=1[F:25])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][Br:26])(=[O:3])[CH3:2]
Reactant: BrCCCCCCBr
Reactant: CC(=O)Nc1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)N(CCCCCCBr)c1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
5.00 g (14.4 mmol) of Compound 27 obtained in Example 27 was dissolved in 150 ml of dimethylformamide under argon atmosphere, 10.9 ml of 1,6-dibromohexane and 575 mg of sodium hydride (60% oil dispersion) were added under ice-cooling and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed once with water and once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:acetone=20:1) to give 6.11 g (83%) of 2-[4-[N-acetyl-N-(6-bromohexyl)amino]-3-fluorophenyl]-5-amino-6,8-difluoro-4H-1-benzopyran-4-one.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:12]=[CH:11][C:10]([S:13]([N:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH3:23])[CH2:18][CH2:17]2)(=[O:15])=[O:14])=[CH:9][C:5]=1[C:6]([OH:8])=O)[CH3:2].[NH2:24][C:25]1[C:26]([C:36]([NH2:38])=[O:37])=[N:27][N:28]([CH2:32][CH2:33][O:34][CH3:35])[C:29]=1[CH2:30][CH3:31]>C(OCC)(=O)C>[C:36]([C:26]1[C:25]([NH:24][C:6](=[O:8])[C:5]2[CH:9]=[C:10]([S:13]([N:16]3[CH2:17][CH2:18][N:19]([CH2:22][CH3:23])[CH2:20][CH2:21]3)(=[O:14])=[O:15])[CH:11]=[N:12][C:4]=2[O:3][CH2:1][CH3:2])=[C:29]([CH2:30][CH3:31])[N:28]([CH2:32][CH2:33][O:34][CH3:35])[N:27]=1)(=[O:37])[NH2:38]
Reactant: CCc1c(N)c(C(N)=O)nn1CCOC
Reactant: CCOc1ncc(S(=O)(=O)N2CCN(CC)CC2)cc1C(=O)O
Solvent: CCOC(C)=O
Product: CCOc1ncc(S(=O)(=O)N2CCN(CC)CC2)cc1C(=O)Nc1c(C(N)=O)nn(CCOC)c1CC
Temperature: 45 °C
Reaction time: 0.67 h

Procedure:
2-ethoxy-5-(4-ethyl-1-piperazinylsulfonyl)nicotinic acid (2.31 kg, 6.73 Mol) was suspended in ethyl acetate (16.2 L) and 1,1-carbonyldimidazole (1.09 kg, 6.73 Mol) was added at room temperature. The reaction mixture was heated at 45° C. for 40 minutes and then the reaction was stirred for a further 40 minutes at reflux. After cooling to ambient temperature 4-amino-5-ethyl-1-(2-methoxyethyl)-1H-pyrazole-3-carboxamide (1.5 kg, 7.06 Mol) was added to the cooled mixture, and the reaction stirred for a further 15 hours under reflux. The mixture was cooled filtered and the filter cake was washed with 90% water/10% ethyl acetate, (2 mL/g) to afford N-[3-carbamoyl-5-ethyl-1-(2-methoxyethyl)-1H-pyrazol-4-yl}-2-ethoxy-5-(4-ethyl-1-piperazinyl sulfonyl)nicotinamide as an off white crystalline solid, 3.16 kg, 88%. m.p.=156° C. Found: C, 51.33; H, 6.56; N, 18.36. C23H35N7O6S requires C, 51.40; H, 6.53; N, 18.25%.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:12][O-:13].[Na+]>CN(C=O)C>[CH3:12][O:13][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: C[O-]
Reactant: Brc1cnc2ccccc2c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cnc2ccccc2c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 6.2 %

Procedure:
A solution of 3-bromoquinoline (22.54 g, 108 mmol) in anhydrous DMF (110 mL) was treated with sodium methoxide (11.70 g, 217 mmol) and stirred at 80° C. for 16 hours. The reaction mixture was then concentrated and the residue taken up in ethyl acetate (300 mL) and water (60 mL). The organic phase was separated, washed with brine (2×60 mL), dried (MgSO4), filtered, concentrated and purified by column chromatography on silica gel (ethyl acetate/hexane; 1:3) to give 3-methoxyquinoline (1.06 g, 6%). 1H NMR (CDCl3) δ3.95 (s, 3H), 7.38 (d, 1H, J=1.5 Hz), 7.54 (m, 2H), 7.72 (d, 1H, J=7.5 Hz), 8.04 (d, 1H, J=7.5 Hz), 8.67 (d, 1H, J=1.5 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH:11]([CH2:16][CH2:17][CH2:18]C)[CH2:12][C:13]([OH:15])=[O:14].[CH2:20]([Mg]Br)C(C)C>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH:11]([CH2:16][CH:17]([CH3:18])[CH3:20])[CH2:12][C:13]([OH:15])=[O:14]
Reactant: CCCCC(CC(=O)O)c1ccc(OC)cc1OC
Reactant: CC(C)C[Mg]Br
Product: COc1ccc(C(CC(=O)O)CC(C)C)c(OC)c1

Procedure:
Following a similar procedure to that described in Preparation 42a, but using isobutylmagnesium bromide instead of butylmagnesium bromide, the title compound was obtained as an oily substance.