Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:8](=[O:42])[CH:9]([C:19]1[CH:41]=[CH:40][C:22]([C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:24])=[CH:21][CH:20]=1)[C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:43]C(C)([O-])C.[K+].CI>C1COCC1.C(OCC)(=O)C>[NH:1]([C:8](=[O:42])[C:9]([C:19]1[CH:41]=[CH:40][C:22]([C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[NH:32][C:33](=[O:39])[O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:24])=[CH:21][CH:20]=1)([C:10]([NH:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:11])[CH3:43])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C(C(=O)Nc2ccccc2)C(=O)Nc2ccccc2)cc1
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C(C)(C(=O)Nc2ccccc2)C(=O)Nc2ccccc2)cc1
Reaction time: 0.5 h
Yield: 33.1 %

Procedure:
To a solution of tert-butyl [2-({-4-[2-anilino-1-(anilinocarbonyl)-2-oxoethyl]benzoyl}amino)phenyl]carbamate (41 mg, 0.073 mmol) in THF (1 mL) at room temperature was added potassium tert-butoxide (85 μL, 1 M in THF, 0.085 mmol). The solution was stirred for 30 min and methyl iodide (6 μL, 0.096 mmol) was added. The reaction mixture was stirred at room temperature for 4 h, diluted with ethyl acetate, washed with water (1×), brine (1×), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (20% to 65% ethyl acetate in hexanes) gave tert-butyl [2-({4-[2-anilino-1-(anilinocarbonyl)-1-methyl-2-oxoethyl]benzoyl}amino)phenyl]carbamate (14 mg, 33%) as a white solid: 1H NMR (600 MHz, CDCl3) δ 9.29 (s br, 1H), 8.93 (s br, 2H), 7.98 (d, J=8.2 Hz, 2H), 7.75 (d, J=7.6 Hz, 1H), 7.52-7.50 (m, 6H), 7.34 (t, J=8.2 Hz, 4H), 7.27 (d, J=7.0 Hz, 1H), 7.21 (td, J=7.9, 1.5 Hz, 1H), 7.17-7.14 (m, 3H), 6.92 (s br, 1H), 2.07 (s, 3H), 1.49 (s, 913); ESIMS calcd 579.3 (M++H), found 579.2 (M++H).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([OH:5])[CH3:4].[C:6]([N:10]=[C:11]=[S:12])([CH3:9])([CH3:8])[CH3:7]>C(O)C.C(OCC)C>[OH:5][C@@H:3]([CH3:4])[CH2:2][NH:1][C:11]([NH:10][C:6]([CH3:9])([CH3:8])[CH3:7])=[S:12]
Reactant: C[C@H](O)CN
Reactant: CC(C)(C)N=C=S
Solvent: CCOCC
Solvent: CCO
Product: C[C@H](O)CNC(=S)NC(C)(C)C
Temperature: 20 °C
Reaction time: 5 h
Yield: 93.6 %

Procedure:
The process is performed as in Example 1, starting with 5 g of (+)-(S)-1-amino-2-propanol and 8.43 g of tert-butyl isothiocyanate in 60 cm3 of ethanol. After stirring the reaction medium for 5 hours at a temperature in the region of 20° C. and then concentration under reduced pressure (5 kPa) at a temperature in the region of 50° C., the white solid obtained is taken up in diethyl ether. The suspension is again concentrated under the same conditions as above. 11.86 g of N-[(2S)-2-hydroxypropyl]-N′-tert-butylthiourea are obtained in the form of a white solid melting at 106° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].[CH3:7][S:8](Cl)(=[O:10])=[O:9]>[OH-].[Na+]>[CH3:7][S:8]([NH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5])(=[O:10])=[O:9]
Reactant: NCCC(=O)O
Reactant: CS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Product: CS(=O)(=O)NCCC(=O)O
Reaction time: 3 h

Procedure:
22.3 g of β--alanine are dissolved in 125 ml of 2N NaOH. 20 ml of methanesulfonyl chloride and 145 ml of 2N NaOH are simultaneously added dropwise at 0°-5° C., with vibromixing, and the mixture is vibrated at room temperature for 3 hours. The solution is extracted with ether and the extract is diluted to 400 ml and stirred with a strongly acid ion exchanger (Lewatit® S 100) until the pH reaches about 2. The solution is then evaporated to dryness in vacuo. The residue is taken up in ethyl acetate, the mixture is dried over sodium sulfate and DCA is added until an alkaline reaction is obtained. The precipitate which separates out is filtered off, washed with ethyl acetate and ether, dried and recrystallized from tetrahydrofuran.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[CH:15]=[C:14]([CH3:16])[N:13]=[C:12]([O:17][C@@H:18]([C:23]([O:36][CH3:37])([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:19]([O:21]C)=[O:20])[N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>CO.O>[CH2:1]([O:8][CH2:9][C:10]1[CH:15]=[C:14]([CH3:16])[N:13]=[C:12]([O:17][C@@H:18]([C:23]([O:36][CH3:37])([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:19]([OH:21])=[O:20])[N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H](Oc1nc(C)cc(COCc2ccccc2)n1)C(OC)(c1ccccc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(c1ccccc1)(c1ccccc1)[C@H](Oc1nc(C)cc(COCc2ccccc2)n1)C(=O)O
Temperature: 25 °C
Yield: 87.9 %

Procedure:
To a solution of the compound of Example 13 (1.17 g, 2.34 mmol) in methanol (20 mL) is added a solution of potassium hydroxide (0.987 g, 23.4 mmol) in water (10 mL) and the reaction stirred at reflux for 5 hr. The reaction is cooled to room temperature and the methanol removed under reduced pressure on a rotary evaporator. The aqueous residue is washed with ethyl acetate (2×25 mL) and then the pH is adjusted to 2-3 with 2N HCl. The aqueous phase is extracted with ether (2×50 mL) to yield the title compound (0.997 g, 88%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:17])[CH:11]=[C:12]([CH2:15]O)[O:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=S(Cl)[Cl:20]>CCOCC>[CH2:1]([O:8][C:9]1[C:10](=[O:17])[CH:11]=[C:12]([CH2:15][Cl:20])[O:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1cc(CO)occ1OCc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: CCOCC
Product: O=c1cc(CCl)occ1OCc1ccccc1
Reaction time: 1 h

Procedure:
To a suspension of 5-(benzyloxy)-2-(hydroxymethyl)-4H-pyran-4-one (18.5 g, 80 mmol) in Et2O (130 mL) was added SOCl2 (18 mL, 110 mmol) at r.t. and the mixture was stirred for 1 h. The reaction mixture was poured onto ice-water and more Et2O was added. Then the Et2O phase was collected and water phase was extracted by Et2O twice, the combined Et2O layer was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel chromatography to give 5-(benzyloxy)-2-(chloromethyl)-4H-pyran-4-one 1HNMR (DMSO, 400 MHZ) δ 8.27 (s, 1H), 7.32-7.41 (m, 5H), 6.55 (s, 1H), 4.92 (s, 2H), 4.65 (s, 2H). MS (M+H)+ 250.1/252.1.
Reaction SMILES: Br[C:2]1[CH:15]=[N:14][C:5]2[NH:6][C:7]3[CH:12]=[N:11][C:10]([Cl:13])=[CH:9][C:8]=3[C:4]=2[CH:3]=1.Cl.CC1(C)C(C)(C)OB([C:25]2[CH:37]=[CH:36][C:28]([CH2:29][N:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)=[CH:27][CH:26]=2)O1>C(#N)C.[F-].[K+]>[Cl:13][C:10]1[N:11]=[CH:12][C:7]2[NH:6][C:5]3[N:14]=[CH:15][C:2]([C:25]4[CH:26]=[CH:27][C:28]([CH2:29][N:30]5[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]5)=[CH:36][CH:37]=4)=[CH:3][C:4]=3[C:8]=2[CH:9]=1
Reactant: Clc1cc2c(cn1)[nH]c1ncc(Br)cc12
Reactant: CC1(C)OB(c2ccc(CN3CCCCC3)cc2)OC1(C)C
Agent: Cl
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Product: Clc1cc2c(cn1)[nH]c1ncc(-c3ccc(CN4CCCCC4)cc3)cc12
Temperature: 140 °C
Yield: 65 %

Procedure:
A degassed mixture of 3-bromo-6-chloro-9H-dipyrido[2,3-b;4′,3′-d]pyrrole (1.00 g, 3.55 mmol), 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-piperidine hydrochloride (1.24 g, 3.67 mmol) and 1,1′-[bis(diphenylphosphino) ferrocene]dichloro palladium(II) (0.29 g, 0.35 mmol) in acetonitrile (20 mL) and 2N aqueous potassium fluoride solution (10 mL) was heated under microwave irradiation at 140° C. for 30 minutes. The cooled reaction mixture was concentrated under reduced pressure and taken up in DCM/methanol and loaded onto an SCX-2 cartridge (20 g) which was then washed with methanol (50 mL) then 2N ammonia in methanol (50 mL). The combined basic fractions were concentrated in vacuo and the residue purified by flash chromatography (silica, 80 g column, ISCO, 0-10% methanol in DCM) to afford the title compound as a pink solid (0.87 g, 66%). 1H NMR (DMSO-D6, 400 MHz): 12.38 (s, 1H), 9.03 (d, J=2.3 Hz, 1H), 8.95 (d, J=2.3 Hz, 1H), 8.71 (d, J=1.0 Hz, 1H), 8.38 (d, J=0.9 Hz, 1H), 7.75 (d, J=7.9 Hz, 2H), 7.44 (d, J=7.9 Hz, 2H), 3.49 (s, 2H), 2.39-2.33 (m, 4H), 1.56-1.48 (m, 4H), 1.45-1.37 (m, 2H). LCMS (Method B): RT=2.27 min, M+H+=377.
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH3:9])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[C:10](=O)([O-])[O-].[K+].[K+].IC>O1CCCC1>[CH3:10][CH:3]([C:2](=[O:1])[CH2:8][CH3:9])[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C([O-])[O-]
Reactant: CCC(=O)CC(=O)OC
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: CCC(=O)C(C)C(=O)OC
Temperature: 0 °C
Reaction time: 6 h
Yield: 99.9 %

Procedure:
Methyl 3-oxopentanoate (6.27 ml, 50 mmol) in tetrahydrofuran (100 ml) and potassium carbonate (20.73 g, 150 mmol) was heated at reflux under argon for 3 hours, reaction mixture was cooled in an ice bath and and iodomethane (3.75 ml, 60.0 mmol) was added dropwsie. The reaction mixture was stirred at 0° C. for 6 hours, and allowed to warm to room temperature while stirring overnight. The reaction mixture was filtered through a celite and the filtrate was evaporated under reduced pressure to give the title compound as an oil (7.2 g);
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11](CC3C=CC=CC=3)[CH2:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1.[H][H]>C(O)C.[Pd]>[N:3]1[CH:4]=[CH:5][C:6]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:7][CH:2]=1
Reactant: Clc1nccc(N2CCN(Cc3ccccc3)CC2)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: c1cc(N2CCNCC2)ncn1

Procedure:
A solution of 7.4 g (0.0256 mol) of 1-(2-chloro-4-pyrimidinyl)-4-(phenylmethyl)piperazine in 100 ml of ethanol was hydrogenated in the presence of 2 g of 10% palladium/charcoal for 4 hours at 40° C. under 5 bar of hydrogen pressure. The crude product obtained after conventional working up was purified by column chromatography over silica gel (30-60 μm) using FM1/cyclohexane 9/1 (v/v) as eluant. Colourless crystals, Rf=0.3 (FM1/cyclohexane 9/1 (v/v)); Macherey-Nagel POLYGRAM® SIL G/UV254, ready-made films for TLC). Yield: 1.7 g (40.7% of theory).
Reaction SMILES: Cl.[F:2][C:3]1([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[C:14]1(=O)[CH2:17][CH2:16][CH2:15]1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C(Cl)Cl>[CH2:12]([O:11][C:9]([C:3]1([F:2])[CH2:4][CH2:5][N:6]([CH:14]2[CH2:17][CH2:16][CH2:15]2)[CH2:7][CH2:8]1)=[O:10])[CH3:13]
Reactant: O=C1CCC1
Reactant: CCOC(=O)C1(F)CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)C1(F)CCN(C2CCC2)CC1
Temperature: 25 °C
Reaction time: 0.12 h

Procedure:
To a 250 mL round bottle was added compound B1(I) ethyl 4-fluoropiperidine-4-carboxylate, hydrochloride (1.25 g, 5.91 mmol, 1.0 eq), CH2Cl2 (40 mL), cyclobutanone B1(II) (1.30 g, 7.68 mmol, 1.30 eq), and glacial HOAc (0.338 mL, 5.91 mmol, 1.0 eq). After stirring at rt for 5 to 10 min, sodium triacetoxyborohydride (2.00 g, 9.45 mmol, 1.60 eq) was added in one portion. A cloudy solution was obtained. The reaction mixture was stirred at rt for 2 h. To the reaction mixture, 100 mL aqueous NaOH (1 M) was added, and the resulting suspension was stirred at rt for 10 min. The reaction was extracted with EtOAc (150 mL). The organic layer was collected, washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated to afford the desired product, B1(III), as a colorless oil. The crude product was cleaned and subjected to the next step without purification (see next step for the overall reaction yield). 1H NNR (400 MHz, CDCl3, ppm) δ 1.28 (t, J=7.20 Hz, 3H), 1.64-1.73 (m, 2H), 1.82-1.99 (m, 4H), 2.01-2.21 (m, 6H), 2.72-2.80 (m, 3H), 4.22 (q, J=7.2 Hz, 2H); 19F NMR (376 Hz, CDCl3, ppm) δ-166.83.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[C:8]([CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[OH:13])[CH:9]=[CH:10][CH:11]=1.C1OCCOCCOCCOCCOCCOC1.[Mn]([O-])(=O)(=O)=O.[K+].S([O-])(O)=O.[Na+]>ClCCl.O>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[C:8]([C:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:13])[CH:9]=[CH:10][CH:11]=1
Reactant: OC(c1ccccc1)c1cccc(C2OCCO2)c1
Agent: O=[Mn](=O)(=O)[O-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=S([O-])O
Solvent: O
Solvent: ClCCl
Product: O=C(c1ccccc1)c1cccc(C2OCCO2)c1
Temperature: 40 °C
Reaction time: 4 h

Procedure:
Combine (3-[1,3]dioxolan-2-ylphenyl)phenyl-methanol (5.0 g, 18.5 mmol) and 18-crown-6 (160 mg, 0.6 mmol) in dichloromethane. Add potassium permanganate (8.8 g, 55.5 mmol). Heat to about 40° C. After 4 hours, cool to room temperature add water and sodium hydrogensulfite (6.0 g). Basify with a solution of 1N sodium hydroxide (about 60 ml) and extract with dichloromethane. Combine the organic layers and wash sequentially with distilled water and brine and then dry (Na2SO4), filter, and concentrate to give a residue. Chromatograph the residue eluting with EtOAc to give the title compound.
Reaction SMILES: [BH4-].[Na+].CS(O)(=O)=O.[O:8]=[C:9]([N:23]1[CH2:28][CH2:27][N:26]2[C:29]([C:32]([F:35])([F:34])[F:33])=[N:30][N:31]=[C:25]2[CH2:24]1)[CH:10]=[C:11]([NH2:22])[CH2:12][C:13]1[CH:18]=[C:17]([F:19])[C:16]([F:20])=[CH:15][C:14]=1[F:21].Cl.C([O-])(O)=O.[Na+]>CC(O)C.C1COCC1>[O:8]=[C:9]([N:23]1[CH2:28][CH2:27][N:26]2[C:29]([C:32]([F:35])([F:34])[F:33])=[N:30][N:31]=[C:25]2[CH2:24]1)[CH2:10][CH:11]([NH2:22])[CH2:12][C:13]1[CH:18]=[C:17]([F:19])[C:16]([F:20])=[CH:15][C:14]=1[F:21]
Reactant: NC(=CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Agent: CS(=O)(=O)O
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: CC(C)O
Product: NC(CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Temperature: -12.5 °C
Reaction time: 0.75 h

Procedure:
In a 500 mL round bottom flask dry THF (112 mL) and NaBH4 (2.81 g) were taken. It was cooled to −15 to −10° C. After that methanesulfonic acid (17.7 g) was added dropwise at −15 to −5° C. over a period of 1.5 h. 4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)but-2-en-2-amine (10.0 g) was mixed in a solvent mixture of dry THF (25 mL) and IPA (11 mL) and added into the reaction mixture over a period of 45-60 min. at −10 to −5. It was stirred for 30-60 min. at −10 to −5° C. Reaction mixture was poured into cold 10% aq. HCl solution. It was basified by adding aq. NaHCO3 solution. Product was extracted in ethyl acetate. The organic layer was collected, washed with water and brine solution. It was dried over anhydrous sodium sulfate. Solvent was evaporated at reduced pressure to obtain the product. (Wt.-12.4 g, % Purity by HPLC-94.9%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](OS(C(F)(F)F)(=O)=O)=[N:8][C:9]2[C:14]([C:15]=1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])=[CH:13][C:12]([Cl:24])=[CH:11][CH:10]=2)=[O:5])[CH3:2].[CH2:33]([NH:35][CH2:36][CH3:37])[CH3:34]>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([N:35]([CH2:36][CH3:37])[CH2:33][CH3:34])=[N:8][C:9]2[C:14]([C:15]=1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])=[CH:13][C:12]([Cl:24])=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(OS(=O)(=O)C(F)(F)F)nc2ccc(Cl)cc2c1Cc1ccccc1Cl
Reactant: CCNCC
Product: CCOC(=O)c1c(N(CC)CC)nc2ccc(Cl)cc2c1Cc1ccccc1Cl

Procedure:
This compound was prepared in analogy to example 29 step D from 6-chloro-4-(2-chloro-benzyl)-2-trifluoromethanesulfonyloxy-quinoline-3-carboxylic acid ethyl ester (prepared as described in example 29 step C, 100 mg, 0.2 mmol) and diethyl amine (0.047 ml, 0.39 mmol). Pale yellow solid (52 mg, 61%). LC-MS (ESI): 431 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:3]=1[O:4][C:5]1[C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:8]([CH3:14])[NH:7][N:6]=1.[C:20](Cl)(=[O:23])[O:21][CH3:22]>C(N(CC)CC)C>[CH3:22][O:21][C:20]([N:7]1[C:8]([CH3:14])=[C:9]([C:10]([O:12][CH3:13])=[O:11])[C:5]([O:4][C:3]2[CH:15]=[CH:16][CH:17]=[C:18]([CH3:19])[C:2]=2[CH3:1])=[N:6]1)=[O:23]
Reactant: COC(=O)Cl
Reactant: COC(=O)c1c(Oc2cccc(C)c2C)n[nH]c1C
Solvent: CCN(CC)CC
Product: COC(=O)c1c(Oc2cccc(C)c2C)nn(C(=O)OC)c1C

Procedure:
A mixture of 5.6 g of triethylamine, 13 g of 3-(2',3'-dimethylphenoxy)-5-methyl-4-methoxycarbonyl pyrazole and 100 ml of tetahydrofuran is prepared, and, while stirring and cooling, 4.9 g of methyl chlorocarbonate is dripped in. After stirring for 16 hours, the precipitated hydrochloride is filtered off. The filtrate is concentrated and the residue is recrystallized from ethyl acetate. Melting point: 115° C.
Reaction SMILES: [C:1]([C:3]1[C:8]2[C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Br:22])=[N:10][CH2:11][C:12]([NH:14][NH2:15])=[N:13][C:7]=2[CH:6]=[CH:5][C:4]=1[C:23]#[N:24])#[N:2].[Cl:25][CH:26]([CH3:30])[C:27](Cl)=O.C([O-])(=O)C.[Na+]>>[C:1]([C:3]1[C:8]2[C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Br:22])=[N:10][CH2:11][C:12]3[N:13]([C:27]([CH:26]([Cl:25])[CH3:30])=[N:15][N:14]=3)[C:7]=2[CH:6]=[CH:5][C:4]=1[C:23]#[N:24])#[N:2]
Reactant: N#Cc1ccc2c(c1C#N)C(c1ccccc1Br)=NCC(NN)=N2
Reactant: CC(Cl)C(=O)Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Product: CC(Cl)c1nnc2n1-c1ccc(C#N)c(C#N)c1C(c1ccccc1Br)=NC2

Procedure:
In the manner given in Example 1, 6,7-dicyano-5-(o-bromophenyl)-3H-1,4-benzodiazepin-2-yl hydrazine was reacted with α-chloropropionyl chloride and after 1.5 hours with sodium acetate, then refluxed to give 7,8-dicyano-1-(α-chloroethyl)-6-(o-bromophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]2[CH2:16][C:11]3[C:12]4=[C:13]2[C:4](=[CH:5][CH:6]=[C:7]4[CH:8]=[C:9]([Br:17])[CH:10]=3)[CH:3]=1.CC([O-])(C)C.[K+].CS(C)=O.CN(P(N(C)C)(N(C)C)=O)C>C(Cl)Cl.O>[Br:1][C:2]1[CH:15]=[C:14]2[CH2:16][C:11]3[C:12]4[C:13]2=[C:4]([CH2:5][CH2:6][C:7]=4[CH:8]=[C:9]([Br:17])[CH:10]=3)[CH:3]=1
Reactant: Brc1cc2c3c(ccc4cc(Br)cc(c43)C2)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: Brc1cc2c3c(c1)Cc1cc(Br)cc(c1-3)CC2
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 133.6 %

Procedure:
2,6-dibromo-4H-cyclopenta[def]phenanthrene (2.6 g, 7.7 mmol), t-BuOK(20.8 g, 61.6 mmol), DMSO(20 ml), and HMPA(20 ml) was placed in 50 ml round bottom flask with a syringe. The mixture was stirred for 50 minutes at room temperature and cooled to 0° C. CH3l(3.75 ml, 61.6 mmol) was dropped to the mixture with a syringe and the resultant solution was stirred for 30 minutes at 0° C. Then, water(50 ml) and methylene chloride(50 ml) were added to the solution to separate an organic layer. The organic layer was purified by silica gel column chromatography to obtain compound 2(3.6 g, 80%). 1H NMR (300 MHz, CDCl3, δ): 7.98(2H, s), 7.79(2H, s), 7.73(2H, s), 1.93(m, 6H).
Reaction SMILES: C(N(CC)CC)C.[NH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.O1CCCC1.[Br:19][C:20]1[C:21](Cl)=[N:22][CH:23]=[C:24]([N+:26]([O-:28])=[O:27])[CH:25]=1>O>[Br:19][C:20]1[C:21]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:22][CH:23]=[C:24]([N+:26]([O-:28])=[O:27])[CH:25]=1
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1cnc(Cl)c(Br)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: O=[N+]([O-])c1cnc(N2CCOCC2)c(Br)c1
Reaction time: 0.67 h
Yield: 95.1 %

Procedure:
Triethylamine (191 mg) and morpholine (120 mg) were added to a tetrahydrofuran (4 ml) solution containing 3-bromo-2-chloro-5-nitropyridine (300 mg), followed by stirring for 40 minutes. Water was added to the reaction solution, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (chloroform:methanol=1:0 to 3:1), and a yellow solid of 4-(3-bromo-5-nitropyridin-2-yl)morpholine (346 mg) was thus obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH:16]2[CH2:17][CH2:18][CH2:19][CH:12]1[C:13](=[O:31])[N:14]([CH2:21][CH2:22][O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:15]2=[O:20])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].Cl.[CH3:35]O>O1CCOCC1>[CH2:1]([O:8][C:9]([N:11]1[CH:12]2[CH2:19][CH2:18][CH2:17][CH:16]1[CH:15]([O:20][CH3:35])[N:14]([CH2:21][CH2:22][O:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:13]2=[O:31])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO
Reactant: O=C1C2CCCC(C(=O)N1CCOCc1ccccc1)N2C(=O)OCc1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COC1C2CCCC(C(=O)N1CCOCc1ccccc1)N2C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 85 %

Procedure:
3-(2-Benzyloxyethyl)-2,4-dioxo-3,9-diaza-bicyclo[3.3.1]nonane-9-carboxylic acid benzyl ester (Compound 3, 0.46 g, 1.11 mmol) was dissolved in methanol (15 mL). The mixture was cooled to 0° C., and NaBH4 (0.06 g, 1.66 mmol) was added in portions from the top. The reaction was stirred for 10 minutes at 0° C., and then 4N HCl in dioxane was added to obtain a pH in the range of 1 to 2, and the reaction was stirred overnight at room temperature. The methanol was evaporated, and the residue was dissolved in EtOAc and poured into NaHCO3 saturated aqueous solution, then extracted with EtOAc (3×10 mL). The combined extracts were washed with brine (10 mL), passed over a short plug of Na2SO4, and the solvents were evaporated to give Compound 4 (0.40 g, 85%, mixture of isomers) as a thick pale-yellow oil, which was of sufficiently good quality to be advanced to the next step without further purification. Rf (40% EtOAc/hexanes): 0.45.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[C:20]([CH:22]=[O:23])[CH:19]=[CH:18][C:17]=1[O:24][CH3:25])=[CH:13][CH:12]=[C:11]([C:26]([F:29])([F:28])[F:27])[CH:10]=2)=[O:5])[CH3:2].[BH4-].[Na+]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[C:20]([CH2:22][OH:23])[CH:19]=[CH:18][C:17]=1[O:24][CH3:25])=[CH:13][CH:12]=[C:11]([C:26]([F:29])([F:27])[F:28])[CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1-c1cc(C=O)ccc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1-c1cc(CO)ccc1OC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4-(5-Formyl-2-methoxy-phenyl)-7-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester (30 mg, 0.074 mmol) was dissolved in ethanol (1 mL) and treated with sodium borohydride (26 mg) in one portion. After stirring at room temperature for 15 min, the reaction mixture was quenched with an aqueous solution of ammonium chloride. The reaction mixture was then extracted with ethyl acetate and the organic layer was dried over sodium sulfate, concentrated. The crude compound was purified by column chromatography eluted with 30% ethyl acetate to yield 4-(5-hydroxymethyl-2-methoxy-phenyl)-7-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester as a white solid.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].C[Al](C)C.CO[C:12](=[O:34])[CH2:13][CH2:14][CH2:15][C:16]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:17]=1[CH:18]=[CH:19][C:20]([NH:26][CH2:27][C:28]1[O:29][C:30]([CH3:33])=[CH:31][CH:32]=1)=[N:21]2>O1CCOCC1>[CH2:1]([N:3]([CH2:4][CH3:5])[C:12](=[O:34])[CH2:13][CH2:14][CH2:15][C:16]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:17]=1[CH:18]=[CH:19][C:20]([NH:26][CH2:27][C:28]1[O:29][C:30]([CH3:33])=[CH:31][CH:32]=1)=[N:21]2)[CH3:2]
Reactant: COC(=O)CCCc1cccc2nc(NCc3ccc(C)o3)ccc12
Reactant: CCNCC
Agent: C[Al](C)C
Solvent: C1COCCO1
Product: CCN(CC)C(=O)CCCc1cccc2nc(NCc3ccc(C)o3)ccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Diethylamine (89 mg, 1.22 mmol) was dissolved in 5 mL dioxane. Trimethylaluminium (2M solution in heptane, 0.61 mL, 1.22 mmol) was added and the mixture was stirred for 1 hour at room temperature. 4-{2-[(5-Methyl-furan-2-ylmethyl)-amino]-quinolin-5-yl}-butyric acid methyl ester (137 mg, 0.4 mmol) 7 mL dioxane was added and stirring was continued at 90° C. for 5 hours. The reaction mixture was quenched by addition of 0.6 mL water. The solvent was evaporated off. The residue was purified by flash chromatography on silica gel (heptane/ethyl acetate 100:0->0:100 gradient). The title compound was obtained as a yellow oil (40 mg, 26%), MS: m/e=380.5 (M+H+).