Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][N:11]=[CH:10]3)[CH2:3][CH2:2]1.CN(C)C=O.[CH:21]1([C:25]2[C:33]([C:34](=[O:37])[NH:35][CH3:36])=[CH:32][C:28]([C:29](O)=[O:30])=[C:27]([CH3:38])[CH:26]=2)[CH2:24][CH2:23][CH2:22]1>CN(C)C1C=CN=CC=1.O>[NH:12]1[C:13]2[C:9](=[CH:8][C:7]([CH:4]3[CH2:3][CH2:2][N:1]([C:29]([C:28]4[C:27]([CH3:38])=[CH:26][C:25]([CH:21]5[CH2:24][CH2:23][CH2:22]5)=[C:33]([CH:32]=4)[C:34]([NH:35][CH3:36])=[O:37])=[O:30])[CH2:6][CH2:5]3)=[CH:15][CH:14]=2)[CH:10]=[N:11]1
Reactant: c1cc2[nH]ncc2cc1C1CCNCC1
Reactant: CNC(=O)c1cc(C(=O)O)c(C)cc1C1CCC1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(C(=O)N2CCC(c3ccc4[nH]ncc4c3)CC2)c(C)cc1C1CCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 33.7 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 5-(piperidin-4-yl)-1H-indazole (compound 62.5, 100 mg, 0.50 mmol) in N,N-dimethylformamide (3 mL) EDC.HCl (192 mg, 1.00 mmol), 4-dimethylaminopyridine (122 mg, 1.00 mmol) and 4-cyclobutyl-2-methyl-5-(methylcarbamoyl)benzoic acid (compound 62.3, 122 mg, 0.49 mmol) were added and the resulting solution was stirred for 4 h at room temperature. The reaction was diluted with water (20 mL) and extracted with of ethyl acetate (2×25 mL). The combined organic layers were washed with brine (2×15 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate as the eluent, followed by additional purification by Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% TFA and CH3CN (30% CH3CN up to 47% in 7 min, up to 100% in 3 min, down to 30% in 1 min); Detector, Waters 2489, 254 & 220 nm. The fractions containing pure compound were combined and lyophilized to yield the title compound as a white solid (71.2 mg, 33%). m/z (ES+) 431 (M+H)+.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[CH2:14][C:13]2[C:12]([F:15])=[C:11]([NH:16][C@H:17]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:18]([NH:20][CH3:21])=[O:19])[N:10]=[C:9]([C:26]3[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=3)[C:8]=2[C:7]1=[O:32]>C(O)(C(F)(F)F)=O>[F:15][C:12]1[C:13]2[CH2:14][NH:6][C:7](=[O:32])[C:8]=2[C:9]([C:26]2[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=2)=[N:10][C:11]=1[NH:16][C@H:17]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:18]([NH:20][CH3:21])=[O:19]
Reactant: CNC(=O)[C@@H](CC(C)C)Nc1nc(-c2cnn(C)c2)c2c(c1F)CN(Cc1ccc(OC)cc1OC)C2=O
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)[C@@H](CC(C)C)Nc1nc(-c2cnn(C)c2)c2c(c1F)CNC2=O

Procedure:
A solution of (R)-2-(2-(2,4-dimethoxybenzyl)-7-fluoro-4-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)-N,4-dimethylpentanamide (38 mg, 0.072 mmol) in TFA (5 mL) was heated to 65° C. for 4 h. After removal of the solvent, the residue was diluted in MeOH (2 mL) and was purified by preparative HPLC eluting with water (0.05% TFA) and ACN (25-30%, gradient, 0.035% TFA). The collected fractions were stripped to dryness to give the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 0.84-0.93 (m, 6H), 1.63-1.81 (m, 2H), 2.57 (d, J=4.39 Hz, 3H), 3.88 (s, 3H), 4.04-4.19 (m, 2H), 4.36 (s, 2H), 6.99 (d, J=7.32 Hz, 1H), 7.61-7.76 (m, 1H), 7.93 (d, J=4.39 Hz, 1H), 8.30 (s, 1H), 8.83 (s, 1H). [M+H] calc'd for C18H23FN6O2, 375. found, 375.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]2[C:31](=[CH:32][CH:33]=1)[O:30][C:11]1([CH2:16][CH2:15][N:14]([CH2:17][CH2:18][O:19][CH2:20][CH2:21][NH:22]C(=O)OC(C)(C)C)[CH2:13][CH2:12]1)[CH2:10][C:9]2=[O:34])(=[O:4])=[O:3].CO.[Cl:37]CCl>Cl.C(O)(=O)C>[ClH:37].[ClH:37].[NH2:22][CH2:21][CH2:20][O:19][CH2:18][CH2:17][N:14]1[CH2:13][CH2:12][C:11]2([CH2:10][C:9](=[O:34])[C:8]3[C:31](=[CH:32][CH:33]=[C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])[CH:7]=3)[O:30]2)[CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)NCCOCCN1CCC2(CC1)CC(=O)c1cc(NS(C)(=O)=O)ccc1O2
Reactant: ClCCl
Agent: Cl
Solvent: CC(=O)O
Solvent: CO
Product: CS(=O)(=O)Nc1ccc2c(c1)C(=O)CC1(CCN(CCOCCN)CC1)O2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Ten drops of concentrated hydrochloric acid was added to a solution of tert-butyl 2-(2-(6-(methylsulfonamido)-4-oxospiro[chroman-2,4′-piperidine]-1′-yl)ethoxy)ethylcarbamate (12, 0.51 g, 1.02 mmol) in 5 mL of glacial acetic acid and the resulting solution was stirred at room temperature. After ˜1.5 hours, TLC (silica gel, 10% methanol in dichloromethane, UV visualization) shows complete disappearance of starting compound 12 (Rf=0.2−0.3) and a new spot at the origin. Volatile components were removed under reduced pressure on the rotary evaporator. Toluene (˜10 mL) was added and evaporated under reduced pressure on the rotary evaporator. The toluene addition and evaporation was repeated two more times and the residue was dried under high vacuum. The resulting residue was triturated with 3 mL of diethyl ether, resulting in formation of a tan solid. The diethyl ether was removed under reduced pressure on the rotary evaporator followed by high vacuum to give a tan solid.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[CH3:12][O-:13].[Na+]>CO>[Br:1][C:2]1[C:3]([O:13][CH3:12])=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: C[O-]
Reactant: O=[N+]([O-])c1cnc(Cl)c(Br)c1
Agent: [Na+]
Solvent: CO
Product: COc1ncc([N+](=O)[O-])cc1Br
Temperature: 25 °C

Procedure:
To a cloudy mixture of 3-bromo-2-chloro-5-nitropyridine (Atlantic Scitech, Linden, N.J., 5.10 g, 21.48 mmol) in 50 mL anhydrous methanol at 0° C. (ice/water bath) was added sodium methoxide 5.4 M in methanol (7.96 mL, 43.0 mmol) dropwise by addition funnel The reaction became clear then a thick precipitate formed. The ice/water bath was removed and the reaction warmed to ambient temperature, quenched with water and sat'd aq. NH4Cl and DCM. The aqueous layer was extracted with DCM 2 times, and the combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 3-bromo-2-methoxy-5-nitropyridine (5.07 g, 21.76 mmol, quantitative yield) as a light yellow solid. m/z (ESI, +ve ion) 233 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 9.02 (d, J=2.3 Hz, 1H), 8.63 (d, J=2.5 Hz, 1H), 4.15 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:9])=[O:8].C([O-])([O-])=O.[K+].[K+].I[CH:30]([CH3:32])[CH3:31].O>CN(C=O)C>[CH:30]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[CH:18][C:19]([Br:22])=[CH:20][CH:21]=2)=[CH:12][CH:11]=1)(=[O:9])=[O:8])([CH3:32])[CH3:31]
Reactant: NCCCCNS(=O)(=O)c1ccc(-c2ccc(Br)cc2)cc1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)NCCCCNS(=O)(=O)c1ccc(-c2ccc(Br)cc2)cc1
Reaction time: 3 h

Procedure:
4′-Bromobiphenyl-4-sulfonic acid (4-amino-butyl) amide (0.6 g) was dissolved in DMF (30 mL). K2CO3 (1 g) was added followed by 2-iodo-propane (0.3 mL). The mixture was stirred for 3 hrs, poured into water, extracted with ether and dried. Addition of petrol and evaporation caused the title compound to precipitate as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][C:10]([C:12]2[C:17]([O:18][C:19]([C:21]3[C:26]([OH:27])=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:20])=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:28](OC(=O)C)(=[O:30])[CH3:29]>>[CH3:29][C:28]([O:27][C:26]1[C:21]([C:19]([O:18][C:17]2[C:12]([C:10]([O:9][C:8]3[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:11])=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:20])=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:30]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccccc1OC(=O)c1ccccc1OC(=O)c1ccccc1O
Product: COc1ccccc1OC(=O)c1ccccc1OC(=O)c1ccccc1OC(C)=O

Procedure:
treating the guaiacol salsalate (II) with acetic anhydride to obtain guaiacol acetylsalsalate (III) in accordance with the reaction: ##STR4## In stage (a) the 2-hydroxybenzoylchloride is dissolved in an organic solvent, preferably 1,2-dichloroethane, the solution is cooled to a temperature of between -2° and +2° C., and N,N-dimethylaniline and guaiacol salsalate are added under energetic agitation.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[OH:21].C(=O)(O)[O-].[Na+].O>C(OCC)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[OH:21])=[O:5]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1Cl
Reactant: Nc1ccccc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: O=C(Nc1ccccc1O)c1cc([N+](=O)[O-])ccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Chloro-5-nitro-benzoyl chloride in 60 mL of diethyl ether was added to an ice-cooled mixture of o-aminophenol (5.4 g) and sodium bicarbonate (8.3 g), water (36 mL) and ether (20 mL) over a period of 1 hour. The mixture was allowed to warm to room temperature and stirred overnight. The precipitate was filtered and washed sequentially with water (3×100 mL), 2N HCl (3×100 mL) and diethyl ether (3×50 mL). Yield 11.2 g (77%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:34])=[C:4]([CH:31]=[CH:32][CH:33]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:29][CH3:30])=[C:13]([O:16][C@H:17]3[CH2:21][CH2:20][N:19]([C:22](OC(C)(C)C)=O)[CH2:18]3)[CH:14]=2)[N:9]=[CH:8][N:7]=1.C=O>C(O)=O>[Cl:1][C:2]1[C:3]([F:34])=[C:4]([CH:31]=[CH:32][CH:33]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:29][CH3:30])=[C:13]([O:16][C@H:17]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18]3)[CH:14]=2)[N:9]=[CH:8][N:7]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@H]1CCN(C(=O)OC(C)(C)C)C1
Agent: C=O
Solvent: O=CO
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@H]1CCN(C)C1
Temperature: 85 °C
Yield: 53.8 %

Procedure:
4-(3-chloro-2-fluoroanilino)-6-[(3S)-1-tert-butoxycarbonylpyrrolidin-3-yloxy]-7-methoxyquinazoline (0.30 g) was dissolved in formic acid (5 ml) and formaldehyde (37% w/v in water) (2.5 ml) was added. The mixture was heated to 85° C. for one hour and then evaporated under vacuum and azeotroped with toluene. The residue was partitioned between ethyl acetate and saturated aqueous NaHCO3. The organic layer was separated, washed with brine, dried over Na2SO4, filtered and evaporated. The residue was purified by column chromatography eluting with increasingly polar mixtures of methylene chloride/methanol (saturated with ammonia) (100/0 to 9416). The fractions containing the expected product were combined, evaporated and the residue triturated with diethylether, filtered and dried under vacuum to give the title product as a white solid (0.133 g; 35%);
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1C1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=NC=1CC.Br[C:31]1[N:32]=[C:33]([CH:51]2[CH2:53][CH2:52]2)[C:34]([NH:40][C@H:41]2[C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[CH2:43][C@@H:42]2[OH:50])=[N:35][C:36]=1[CH:37]1[CH2:39][CH2:38]1>>[CH:51]1([C:33]2[C:34]([NH:40][C@@H:41]3[C:49]4[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=4)[CH2:43][C@@H:42]3[OH:50])=[N:35][C:36]([CH:37]3[CH2:39][CH2:38]3)=[C:31]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][C:6]=3[Cl:8])[N:32]=2)[CH2:53][CH2:52]1
Reactant: O[C@H]1Cc2ccccc2[C@@H]1Nc1nc(C2CC2)c(Br)nc1C1CC1
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Product: O[C@H]1Cc2ccccc2[C@H]1Nc1nc(C2CC2)c(-c2ccc(Cl)cc2Cl)nc1C1CC1

Procedure:
Following the procedure for the preparation of (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol but substituting (1S,2S)-1-[(5-bromo-3,6-dicyclopropylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol and making non-critical variations provided the title compound as a solid: 1H NMR (CDCl3) δ 0.85–0.99, 1.67, 1.82, 2.48, 3.10–3.13, 3.27–3.28, 4.79, 5.40, 5.42, 7.30–7.51; MS (ESI+) for C25H23Cl2N3O m/z 452 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][NH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:14](C(OC(C)(C)C)=O)[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=O>CC#N.CN(C1C=CN=CC=1)C>[C:18]([O:17][C:15]([N:9]1[CH2:10][CH2:11][CH2:12][CH2:13][C@H:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[O:14])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCCN1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)[C@@H]1CCCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of (S)-piperidine-2-carboxylic acid tert-butyl ester (M. Egbertson and S. J. Danishefsky, J. Org. Chem., 1989, 54, 1, 11-12) (5.78 g, 31.2 mmol) in CH3CN (30 mL) at 0° C. was added DMAP (763 mg, 6.2 mmol) followed by BOC2O (10.22 g, 46.8 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 20 h. The solvents were evaporated under reduced pressure and the residue was purified by flash chromatography (10% ethyl acetate in hexane). The title compound was obtained as a colorless oil which crystallized upon standing (8.33 g, 94%): 1H NMR (400 MHz, CDCl3) δ 1.21-1.32 (2H, m), 1.47-1.48 (18H, 2s), 1.59-1.72 (3H, m), 2.18 (1H, m), 2.85-3.00 (1H, m), 3.89-4.01 (1H, 2d, J 11.9 Hz), 4.47-4.58 (1H, 2br s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([CH3:14])([CH3:13])[C:9]([O:11]C)=[O:10].[OH-].[K+].CCO>O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([CH3:14])([CH3:13])[C:9]([OH:11])=[O:10]
Reactant: COC(=O)C(C)(C)c1ccccc1F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C(=O)O)c1ccccc1F
Temperature: 130 °C
Yield: 81.3 %

Procedure:
A flask containing a solution of methyl 2-(2-fluorophenyl)-2-methylpropanoate (5.2 g, 27 mmol), KOH (2.9 mL, 106 mmol), water (20.0 mL), and EtOH (100 mL) was sealed and heated at 130° C. for 2 hours. Removal of solvent in vacuo provided a yellow oil that was diluted with water. The aqueous mixture was extracted with DCM (1×100 mL), and the organic layer was separated. The aqueous layer was acidified to a pH of 1 with 5N HCl and then extracted with EtOAc (2×100 mL). The organic layers were dried (Na2SO4), filtered, and concentrated in vacuo to afford 4 g of the product as a solid. MS (m/z)=181 (M−1)−.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]2[CH:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]3[O:21][C:4]=2[CH:3]=1.[CH3:22]OC1C=CC2C3(C)CCN=CC3OC=2C=1>>[OH:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([CH3:22])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:10][CH:9]3[O:21][C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC2c3ccc(O)cc3OC2C1
Reactant: COc1ccc2c(c1)OC1C=NCCC21C
Product: CC(C)(C)OC(=O)N1CCC2(C)c3ccc(O)cc3OC2C1

Procedure:
Synthesized as described for tert-butyl 7-hydroxy-3,4,4a,9a-tetrahydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate starting from 7-Methoxy-4a-methyl-3,4,4a,9a-tetrahydro[1]benzofuro[2,3-c]pyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:21]=[CH:20][C:12]([O:13][C:14]([CH3:19])([CH3:18])[C:15](O)=[O:16])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:24])=O>C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:21]=[CH:20][C:12]([O:13][C:14]([CH3:19])([CH3:18])[C:15]([Cl:24])=[O:16])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: CC(C)(Oc1ccc(Sc2ccc(Cl)cc2)cc1)C(=O)O
Solvent: c1ccccc1
Product: CC(C)(Oc1ccc(Sc2ccc(Cl)cc2)cc1)C(=O)Cl

Procedure:
A mixture of 15 g (0.0465 mol) of p-(p-chlorophenylthio)-phenoxy-isobutyric acid (CRL 40,201) and of 16.75 ml (0.232 mol) of thionyl chloride is heated to the reflux temperature for 10 minutes. After having taken up the reaction mixture in benzene, filtered the solution in the presence of carbon black and evaporated the solvent, 16 g of an orange-coloured oil are obtained.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.Cl.Cl.[CH:23]12[NH:31][CH2:30][CH:27]([NH:28][CH2:29]1)[CH2:26][CH2:25][CH2:24]2.N12CCCN=C1CCCCC2>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:28]4[CH2:29][CH:23]5[NH:31][CH2:30][CH:27]4[CH2:26][CH2:25][CH2:24]5)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: C1CC2CNC(C1)CN2
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CC4CCCC3CN4)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.1 %

Procedure:
A mixture of 0.71 g (2.5 mmol) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 0.54 g (2.7 mmol) of 6,8-diazabicyclo[3.2.2]nonane, dihydrochloride, 1.13 ml (7.5 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene and 15 ml of acetonitrile was heated under reflux for 1.5 hr. The reaction mixture was stirred overnight at room temperature and filtered to obtain 0.40 g of the title compound, mp 268°-271° dec.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][NH:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.CN1CCCC1=O.F[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1[N+:30]([O-:32])=[O:31]>O>[CH:9]1([N:8]([CH3:7])[C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=2[N+:30]([O-:32])=[O:31])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Reactant: CNC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CN(c1ccc(F)cc1[N+](=O)[O-])C1CCCCC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 88.4 %

Procedure:
Potassium carbonate (6.0 g, 43.5 mmol) and N-methylcyclohexylamine (4.6 g, 40.6 mmol) were added to a N-methylpyrolidone (NMP) solution (20 ml) of 2,5-difluoronitrobenzene (5.0 g, 31.4 mmol), and stirred at 100° C. for 3 hours. The reaction mixture was cooled to room temperature, water was added, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water, and then dried over anhydrous magnesium sulfate. The resulting dry product was concentrated under reduced pressure to thereby obtain 7.0 g of oily yellow N-cyclohexyl-4-fluoro-2-nitro-N-methylaniline (yield: 89%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH2:5]([N:7]1[C:26]2[C:14](=[CH:15][C:16]3[C:17]([CH2:28][CH3:29])([CH3:27])[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=4[C:24]=3[CH:25]=2)[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH3:6].[C:30](Cl)(=[O:32])[CH3:31]>ClCCl>[C:30]([C:21]1[CH:20]=[CH:19][C:18]2[C:17]([CH2:28][CH3:29])([CH3:27])[C:16]3[CH:15]=[C:14]4[C:13]5[C:8]([N:7]([CH2:5][CH3:6])[C:26]4=[CH:25][C:24]=3[C:23]=2[CH:22]=1)=[CH:9][CH:10]=[CH:11][CH:12]=5)(=[O:32])[CH3:31]
Reactant: CCn1c2ccccc2c2cc3c(cc21)-c1ccccc1C3(C)CC
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCn1c2ccccc2c2cc3c(cc21)-c1cc(C(C)=O)ccc1C3(C)CC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Aluminum chloride (3.43 g, 25.6 mmol) was slowly added into a dichloromethane solution (80 mL) in which were dissolved 6,12-diethyl-12-methyl-6,12-dihydro-6-aza-indeno[1,2-b]fluorene (5.95 g, 20.0 mmol) and acetyl chloride (1.83 mL, 25.7 mmol) at 0° C. under nitrogen atmosphere. After stirring at room temperature overnight, the reaction mixture was poured into ice-water. The product was extracted twice with dichloromethane. The combined organic layer was washed with brine, and dried over MgSO4. The dichloromethane was removed under high vacuum and the product thus obtained was used for the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[N:8][CH:9]([CH3:13])[NH:10][C:11]=1[CH3:12])=[O:5])[CH3:2].C(N(CC)CC)C.[CH2:30]([O:32][C:33](Cl)=[O:34])[CH3:31].C(Cl)(Cl)Cl>>[CH3:13][C:9]1[N:8]([C:33]([O:32][CH2:30][CH3:31])=[O:34])[CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:11]([CH3:12])[N:10]=1
Reactant: CCOC(=O)Cl
Reactant: CCOC(=O)C1=C(C)NC(C)N=C1c1ccccc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1=C(C)N=C(C)N(C(=O)OCC)C1c1ccccc1[N+](=O)[O-]

Procedure:
To a solution of 5-ethoxycarbonyl-2,6-dimethyl-4-(2'-nitrophenyl)-dihydropyrimidine (756 mg, 2.49 millimole) and triethylamine (374 mg, 3.7 millimole) in 30 ml of chloroform ethyl chlorocarbonate (406 mg, 3.74 millimole) was added dropwise with stirring in ice and the mixture was stirred at room temperature for 3 hours. The reaction mixture was washed with 2% aqueous NaOH solution and water, dried and evaporated to remove the solvent. The obtained oil (730 mg) was purified on silica gel by column chromatography and eluted with 1% MeOH/CHCl3 to obtain the title product as crystals. The crystals were recrystallized from acetone-n-hexane to obtain colorless prisms (m.p. 130°-131.5°, 290 mg, 31% yield).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][N:11]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=3)[N:16]=[C:10]2[CH:9]=1)(C)(C)C.Cl>C(Cl)Cl.O1CCOCC1>[CH3:24][O:23][C:19]1[CH:18]=[C:17]([C:15]2[N:16]=[C:10]3[CH:9]=[C:8]([NH2:7])[CH:13]=[CH:12][N:11]3[N:14]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: COc1cccc(-c2nc3cc(NC(=O)OC(C)(C)C)ccn3n2)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1cccc(-c2nc3cc(N)ccn3n2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 128.5 %

Procedure:
To a solution of [2-(3-methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl]-carbamic acid tert-butyl ester (5.5 g, 16.2 mmol) in DCM (100 ml) was added a solution of HCl in dioxane (4 N, 20 ml). The resultant reaction mixture was stirred at 25° C. for 16 h. Volatiles were removed in vacuum, and the resultant residue was dried under vacuum to give 2-(3-methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-7-ylamine (5 g, quant) as light yellow solid. LC-MS: m/z=241.0 [M+H]+.
Reaction SMILES: C([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:24]3[C:23](=[O:25])[NH:22][C:21]([CH2:26][CH3:27])=[N:20][C:19]=3[N:18]=[C:17]([S:28][CH2:29][C:30]3[N:31]=[C:32]([C:35]4[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=4)[S:33][CH:34]=3)[C:16]=2[C:42]#[N:43])=[CH:11][CH:10]=1)(=O)CC.[OH-].[Li+]>O1CCOCC1.O>[Cl:41][C:38]1[CH:37]=[CH:36][C:35]([C:32]2[S:33][CH:34]=[C:30]([CH2:29][S:28][C:17]3[C:16]([C:42]#[N:43])=[C:15]([C:12]4[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][OH:5])=[CH:10][CH:11]=4)[C:24]4[C:23](=[O:25])[NH:22][C:21]([CH2:26][CH3:27])=[N:20][C:19]=4[N:18]=3)[N:31]=2)=[CH:40][CH:39]=1
Reactant: CCC(=O)OCCOc1ccc(-c2c(C#N)c(SCc3csc(-c4ccc(Cl)cc4)n3)nc3nc(CC)[nH]c(=O)c23)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCc1nc2nc(SCc3csc(-c4ccc(Cl)cc4)n3)c(C#N)c(-c3ccc(OCCO)cc3)c2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
40 mg (0.063 mmol) of 2-{4-[7-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)-6-cyano-2-ethyl-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-5-yl]phenoxy}ethyl propanoate were initially charged in 4 ml of a dioxane/water mixture 2:1, 3 mg (0.127 mmol) of lithium hydroxide were added and the mixture was stirred at RT. After 3 h, the reaction mixture was purified by preparative HPLC (mobile phase gradient: acetonitrile/water 10:90→95:5, with 0.1% TFA added). This gave 27 mg (70% of theory) of the target compound.