Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]([CH2:34][CH2:35][CH2:36][CH3:37])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH:26]([CH2:31][CH3:32])[CH2:27][CH2:28][CH2:29][CH3:30])=[CH:20][CH:19]=3)[N:15]=[C:14](O)[N:13]=2)=[CH:8][CH:7]=1)[CH3:2].S(Cl)(Cl)=O.[C:42]1([CH:49]=[CH:48][CH:47]=[C:45]([OH:46])[CH:44]=1)[OH:43].Cl>C1(C)C(C)=CC=CC=1.CN(C)C=O>[CH2:1]([CH:3]([CH2:34][CH2:35][CH2:36][CH3:37])[CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:17]=[C:16]([C:18]3[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH:26]([CH2:31][CH3:32])[CH2:27][CH2:28][CH2:29][CH3:30])=[CH:22][CH:23]=3)[N:15]=[C:14]([C:47]3[CH:48]=[CH:49][C:42]([OH:43])=[CH:44][C:45]=3[OH:46])[N:13]=2)=[CH:10][CH:11]=1)[CH3:2]
Reactant: Oc1cccc(O)c1
Reactant: CCCCC(CC)COc1ccc(-c2nc(O)nc(-c3ccc(OCC(CC)CCCC)cc3)n2)cc1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1C
Solvent: CN(C)C=O
Product: CCCCC(CC)COc1ccc(-c2nc(-c3ccc(OCC(CC)CCCC)cc3)nc(-c3ccc(O)cc3O)n2)cc1
Reaction time: 0.25 h
Yield: 51.1 %

Procedure:
55.6 g (0.11 mol) of 4,6-bis[4-(2-ethylhexyloxy)phenyl]-s-triazin-2-ol in 300 ml of xylene, to which 1 ml of dimethylformamide has been added, are placed in a 1.5 l sulfonating flask fitted with stirrer, cooler, internal thermometer, dropping funnel and gas outlet. 17.0 g (0.14 mol) of thionyl chloride are added dropwise at an internal temperature of 75-80 C. with vigorous stirring over the course of 15 minutes. After the evolution of gas has subsided, the temperature is raised to 100 C. The reaction is complete after 2 hours (checking by thin-layer chromatography). Excess thionyl chloride is distilled off from the reaction vessel under a slight vacuum, and the intermediate 2-chloro-4,6-bis[4-(2-ethylhexyloxy)phenyl]-s-triazine is reacted further directly. 16.2 g (0.12 mol) of dry, sublimed aluminium chloride are introduced at 50 C. (about 1 minute), whereby the temperature rises to 65 C. The initially clear, yellow solution becomes a red, then olive suspension. 13.3 g (0.12 mol) of resorcinol are added in portions at 50-55 C. (about 10 minutes) and the mixture is then heated to 85 C. After 3 hours the thin-layer chromatogram shows no further starting material. The mixture is cooled to 70 C. and the aluminium complex is hydrolysed by slow dropwise addition of 300 ml of 5% hydrochloric acid, during which the temperature should not exceed 80 C. The solvent (xylene) is removed by steam distillation, and the oily residue is stirred with 500 ml of hot toluene and filtered over silica gel. The filtrate is digested with active charcoal and filtered again. The filtrate is dried over sodium sulfate and the solvent is distilled off. For further purification, the viscous brown residue (69 g) is dissolved in 150 ml of toluene/ethyl acetate (95/5) and subjected to column chromatography (6 cm×60 cm silica gel 60), to give 33.6 g (51% of theory) of 4-{4,6-bis[4-(2-ethylhexyloxy)phenyl]-s-triazin-2-yl}-1,3-dihydroxybenzene as a viscous yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N+:6]([O-])=[CH:5][CH:4]=1.[Si]([C:14]#[N:15])(C)(C)C.CN(C)C(Cl)=O.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:14]#[N:15])[CH:4]=1
Reactant: C[Si](C)(C)C#N
Reactant: COc1cc[n+]([O-])cc1
Agent: CN(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COc1ccnc(C#N)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 73.2 %

Procedure:
To a stirring mixture of 1.2 g (9.67 mmol) of 4-methoxypyridine-N-oxide in 18 mL of CH2Cl2 at r.t. was added 1.6 mL (12.0 mmol) of TMSCN. After 5 min. 0.9 mL (9.8 mmol) of dimethylcarbamoyl chloride. The solution was stirred at r.t. for 13 h and CHCl3 and 20 mL of 10% K2CO3 was added. The aqueous layer was extracted with CHCl3 3 times, and the combined extracts were dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (38-44% EtOAc/hexanes) provided 949 mg of 4-methoxypicolinonitrile as a colorless solid in 73% yield.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[NH2:6][C@H:7]([CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][CH:29]=1)[CH2:8][N:9]1[CH2:15][CH:14]2[CH:16]([N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:11]([CH2:12][CH2:13]2)[CH2:10]1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[C:20]([O:19][C:18]([N:17]([CH3:25])[CH:16]1[CH:11]2[CH2:12][CH2:13][CH:14]1[CH2:15][N:9]([CH2:8][C@H:7]([NH:6][C:2](=[O:3])[O:4][CH3:5])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][CH:29]=1)[CH2:10]2)=[O:24])([CH3:22])([CH3:21])[CH3:23]
Reactant: COC(=O)Cl
Reactant: CN(C(=O)OC(C)(C)C)C1C2CCC1CN(C[C@H](N)COc1ccc(C#N)cc1)C2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)N[C@H](COc1ccc(C#N)cc1)CN1CC2CCC(C1)C2N(C)C(=O)OC(C)(C)C

Procedure:
Methyl chloroformate (0.24 mL, 3.2 mmol) was added, at 0° C., to a mixture of tert-butyl 3-[(2S)-2-amino-3-(4-cyanophenoxy)propyl]-3-azabicyclo[3.2.1]oct-8-yl(methyl)carbamate (see step (vii) above; 1.2 g, 2.9 mmol) and TEA (1.2 mL, 9 mmol) in DCM (30 mL). The mixture was allowed to reach rt over the course of 3 h, after which time a saturated solution of Na2CO3 was added. The organic phase was separated, dried and evaporated to give a crude product that was purified by chromatography on silica gel. This gave 0.6 g (45%) of the sub-title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.Cl[CH2:16][CH2:17][S:18](Cl)(=[O:20])=[O:19]>C1(C)C=CC=CC=1.CCOC(C)=O>[C:2]1([NH:1][S:18]([CH:17]=[CH2:16])(=[O:20])=[O:19])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: O=S(=O)(Cl)CCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C=CS(=O)(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Aniline (0.98 mL, 10.7 mmol) and Et3N (1.8 mL, 12.9 mmol) in toluene (25 mL) were treated with 2-chloro-1-ethanesulfonylchloride (1.1 mL, 10.5 mmol). The exothermic reaction was stirred for 14 hours at room temperature. After stirring, the solution was diluted with EtOAc and washed with HCl (˜10% aq. soln.). The organic layer concentrated and purified via flash column chromatography (4:1 hexane/EtOAc) to afford two lots of phenyl(vinylsulfonyl)amine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]([S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH:10]=2)[N:6]=[C:5]([NH:27][CH2:28][C:29]2[CH:30]=[C:31]([OH:35])[CH:32]=[CH:33][CH:34]=2)[N:4]=1.O[CH2:37][CH2:38][CH2:39][NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]([S:18]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)(=[O:20])=[O:19])[CH:10]=2)[N:6]=[C:5]([NH:27][CH2:28][C:29]2[CH:30]=[C:31]([CH:32]=[CH:33][CH:34]=2)[O:35][CH2:37][CH2:38][CH2:39][NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[N:4]=1
Reactant: COc1cc(-c2cn(S(=O)(=O)c3ccccc3)c3ncccc23)nc(NCc2cccc(O)c2)n1
Reactant: CC(C)(C)OC(=O)NCCCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc(-c2cn(S(=O)(=O)c3ccccc3)c3ncccc23)nc(NCc2cccc(OCCCNC(=O)OC(C)(C)C)c2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of Example 63A (0.510 g, 1.05 mmol), tert-butyl 3-hydroxypropylcarbamate (0.275 g, 1.57 mmol) and triphenylphosphine (0.412 g, 1.57 mmol) in tetrahydrofuran (13 ml) was added dropwise diisopropyl azodicarboxylate (DIAD) (0.305 ml, 1.57 mmol). The reaction mixture was stirred at room temperature for 3 hours and then concentrated in vacuo. Flash chromatography isolation (gradient elution, ethyl acetate/hexane 0-50%) gave the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[CH2:14]([O:21][CH2:22][C:23](Cl)=[O:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CC(C)=O>[CH2:14]([O:21][CH2:22][C:23]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1)=[O:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)COCc1ccccc1
Reactant: Nc1ccc(O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(COCc1ccccc1)Nc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 48.8 %

Procedure:
To mixture of 4-aminophenol (20 g, 183.2 mmol) and sodium bicarbonate (17 grams, 202 mmol) in acetone (150 ml) at 0° C. was added benzyloxy acetyl chloride (40 g, 216.8 mmol) drop wise, followed by stirring at room temperature for 20 hours. The solids were filtered off, and cold water (500 ml) was added. Crude 26 was extracted into chloroform, washed with 5% sodium bicarbonate solution (2×100 ml), water (2×100 ml), dried over sodium sulphate and distilled. The crude 26 was purified by column chromatography on silica gel using chloroform as eluant to get pure 26 (23 g, 48.9%) as a light orange syrup.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C:9]1([CH3:15])[CH3:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:16](=O)[C:17]1C=CC=CC=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1([CH2:14][CH2:16][CH3:17])[CH2:15][CH2:13][CH2:12][NH:11][CH2:10]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCCC1(NC(=O)OC(C)(C)C)CCCNC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 2.20 g of 2,2-Dimethyl-piperazine-1-carboxylic acid tert-butyl ester in 50 ml DCM was added 1.15 ml of benzaldehyde, followed by the addition of 2.61 g of sodium triacetoxyborohydride in small portions. The reaction was stirred at r.t. overnight. To the reaction was then added water. The layers were separated and the organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. 3.30 g (100%) of the title compound were obtained and used without further purification.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:7]([N:21]2[N:30]=[CH:29][C:28]3[C:23](=[C:24]([F:35])[CH:25]=[C:26]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH:27]=3)[C:22]2=[O:36])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16](Br)[C:15](=[O:19])[N:14]([CH3:20])[CH:13]=1)(=[O:3])[CH3:2].Cl.O=[S:39]1[C:43]([CH3:44])=[CH:42][C:41]([NH2:45])=[N:40]1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CN(C=O)C>[C:1]([O:4][CH2:5][C:6]1[C:7]([N:21]2[N:30]=[CH:29][C:28]3[C:23](=[C:24]([F:35])[CH:25]=[C:26]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH:27]=3)[C:22]2=[O:36])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:45][C:41]2[CH:42]=[C:43]([CH3:44])[S:39][N:40]=2)[C:15](=[O:19])[N:14]([CH3:20])[CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC1=CC(N)=NS1=O
Reactant: CC(=O)OCc1c(-c2cc(Br)c(=O)n(C)c2)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: Cl
Solvent: CN(C)C=O
Product: CC(=O)OCc1c(-c2cc(Nc3cc(C)sn3)c(=O)n(C)c2)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Temperature: 110 °C
Yield: 38.8 %

Procedure:
A 25-mL sealed tube was charged with (4-(5-bromo-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)pyridin-3-yl)methyl acetate 142c (155 mg, 0.28 mmol), 4-fluoro-2-(1-oxo-5-methylisothiazol-3-amine hydrochloride (55 mg, 0.33 mmol), Cs2CO3 (183 mg, 0.56 mmol), Pd2(dba)3 (27 mg, 0.030 mmol), XantPhos (35 mg, 0.060 mmol), and DMF (10 mL). After three cycles of vacuum/argon flush, the mixture was heated at 110° C. under microwave irradiation for 1 hour. It was then cooled to room temperature and evaporated under reduced pressure. The residue was purified by silica-gel column eluting with 20:1 methylene chloride/methanol to afford 157a as a yellow solid (64 mg, 39%). MS-ESI: [M+H]+ 589.2
Reaction SMILES: [CH3:1][C:2](=[CH2:5])[CH2:3][Cl:4].[Br:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1.S(=O)(=O)(O)O>CCOCC>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([C:2]([CH3:5])([CH3:1])[CH2:3][Cl:4])[CH:8]=1
Reactant: COc1ccc(Br)cc1
Reactant: C=C(C)CCl
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: COc1ccc(Br)cc1C(C)(C)CCl
Reaction time: 5 h

Procedure:
2-Methylallyl chloride (108 parts) was added dropwise to a mixture of 4-bromoanisole (240 parts) and a concentrated sulphuric acid (20 parts) over a period of 2 hours at a temperature of 25°-35° C. Stirring was continued for 5 hours and the mixture was then kept for 24 hours at room temperature. Ether (400 parts) was then added and the resulting solution washed with water, aqueous sodium bicarbonate solution and water again. After drying with sodium sulphate and evaporating off the solvent the brown oil which remained was distilled yielding 4-bromo-2-(2-chloro-1,1-dimethylethyl)anisole (118 parts), boiling point 106°-120°/0.4 mm Hg. Recrystallisation from petroleum ether (b.p. 80°-100° C.) gave the pure product (98 parts), melting point 86°-88° C.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].C([N:14]1[CH2:19][CH2:18][C:17](=[O:20])[CH:16]([CH2:21][CH3:22])[CH2:15]1)C1C=CC=CC=1>C1C=CC=CC=1>[C:2]([N:14]1[CH2:19][CH2:18][C:17](=[O:20])[CH:16]([CH2:21][CH3:22])[CH2:15]1)([O:4][CH2:5][CH3:6])=[O:3]
Reactant: CCOC(=O)Cl
Reactant: CCC1CN(Cc2ccccc2)CCC1=O
Solvent: c1ccccc1
Product: CCOC(=O)N1CCC(=O)C(CC)C1
Reaction time: 16 h

Procedure:
Ethyl chloroformate (37.49 g, 346 mmol) was added to a stirred solution of 1-benzyl-3-ethyl-4-piperidone (24.0 g, 110 mmol) in benzene (200 ml) at ambient temperature. The obtained reaction mixture was refluxed with stirring for 16 hr and concentrated to dryness to give 1-carbethoxy-3-ethylpiperidin-4-one as oil. Yield 21 g (96%), C10H17NO3, m/z 200 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[CH:22]=[C:21]3[C:17]([CH2:18][CH2:19][NH:20]3)=[CH:16][CH:15]=2)=[O:13])=[CH:7][C:6]=1[F:23])[CH3:2].[Cl:25][C:26]1[CH:27]=[C:28]([S:32](Cl)(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1>>[CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[CH:22]=[C:21]3[C:17]([CH2:18][CH2:19][N:20]3[S:32]([C:28]3[CH:29]=[CH:30][CH:31]=[C:26]([Cl:25])[CH:27]=3)(=[O:34])=[O:33])=[CH:16][CH:15]=2)=[O:13])=[CH:7][C:6]=1[F:23])[CH3:2]
Reactant: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)NCC3)cc1F
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cccc(Cl)c2)CC3)cc1F

Procedure:
4-{[1-(3-Chloro-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carbonyl]-amino}-2-fluoro-benzoic acid, m/z (ES+): 475.18 (M+H+.), was prepared in analogy to example 1, steps 1 to 5. Step 2 was performed using 4-amino-2-fluorobenzoic acid ethyl ester and yielded 2-fluoro-4-[(1H-indole-6-carbonyl)-amino]-benzoic acid ethyl ester. This was reduced to 4-[(2,3-dihydro-1H-indole-6-carbonyl)-amino]-2-fluoro-benzoic acid ethyl ester in step 3. Step 4 was performed using 3-chloro-benzenesulfonyl chloride, yielding 4-{[1-(3-chloro-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carbonyl]-amino}-2-fluoro-benzoic acid ethyl ester, which was hydrolyzed in step 5.
Reaction SMILES: [CH2:1]([N:3]([CH2:30][CH3:31])[C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:20]=[C:19]([CH3:21])[C:18]([CH2:22][CH2:23][C:24]([OH:26])=O)=[C:17]([CH2:27][CH3:28])[CH:16]=3)[N:11]=2)[CH:7]=[C:6]([CH3:29])[N:5]=1)[CH3:2].[CH2:32]([CH2:34][NH2:35])[OH:33].Cl>>[CH2:1]([N:3]([CH2:30][CH3:31])[C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:20]=[C:19]([CH3:21])[C:18]([CH2:22][CH2:23][C:24]([NH:35][CH2:34][CH2:32][OH:33])=[O:26])=[C:17]([CH2:27][CH3:28])[CH:16]=3)[N:11]=2)[CH:7]=[C:6]([CH3:29])[N:5]=1)[CH3:2]
Reactant: CCc1cc(-c2noc(-c3cc(C)nc(N(CC)CC)c3)n2)cc(C)c1CCC(=O)O
Reactant: NCCO
Agent: Cl
Product: CCc1cc(-c2noc(-c3cc(C)nc(N(CC)CC)c3)n2)cc(C)c1CCC(=O)NCCO

Procedure:
The title compound is prepared by coupling 3-{4-[5-(2-diethylamino-6-methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenyl}-propionic acid with ethanolamine as described in Example 26 omitting the treatment with HCl; LC-MS: tR=0.80 min; [M+1]+=466.26.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[CH:42]=[C:43]([NH2:47])[CH:44]=[N:45][CH:46]=2)[CH2:37][CH2:36]1.Cl[C:49]1[C:58]2[C:53](=[CH:54][C:55]([F:60])=[CH:56][C:57]=2[F:59])[N:52]=[C:51]([C:61]2[CH:62]=[N:63][CH:64]=[C:65]([O:67][CH3:68])[CH:66]=2)[C:50]=1[CH3:69].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:59][C:57]1[CH:56]=[C:55]([F:60])[CH:54]=[C:53]2[C:58]=1[C:49]([NH:47][C:43]1[CH:44]=[N:45][CH:46]=[C:41]([N:38]3[CH2:39][CH2:40][O:35][CH2:36][CH2:37]3)[CH:42]=1)=[C:50]([CH3:69])[C:51]([C:61]1[CH:62]=[N:63][CH:64]=[C:65]([O:67][CH3:68])[CH:66]=1)=[N:52]2
Reactant: Nc1cncc(N2CCOCC2)c1
Reactant: COc1cncc(-c2nc3cc(F)cc(F)c3c(Cl)c2C)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: COc1cncc(-c2nc3cc(F)cc(F)c3c(Nc3cncc(N4CCOCC4)c3)c2C)c1

Procedure:
The Buchwald coupled product was prepared according to Procedure H using dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.024 g, 0.050 mmol), 5-morpholinopyridin-3-amine (0.067 g, 0.37 mmol), 4-chloro-5,7-difluoro-2-(5-methoxypyridin-3-yl)-3-methylquinoline (0.1 g, 0.31 mmol), Pd2dba3 (0.011 g, 0.012 mmol) and sodium tert-butoxide (0.075 g, 0.78 mmol) in toluene (3.1 mL) at 100° C. for 1.6 h. The crude product was purified by column chromatography on silica gel (0 to 100% DCM/MeOH/ammonium hydroxide (90/9/1)) to give the desired product 5,7-difluoro-2-(5-methoxypyridin-3-yl)-3-methyl-N-(5-morpholinopyridin-3-yl)quinolin-4-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.51 (1H, d, J=1.8 Hz), 8.39-8.45 (2H, m), 7.80 (1H, d, J=2.3 Hz), 7.59-7.69 (3H, m), 7.43-7.51 (1H, m), 6.60 (1H, t, J=2.3 Hz), 3.90 (3H, s), 3.67-3.77 (4H, m), 3.05-3.17 (4H, m), 2.11 (3H, s). Mass Spectrum (ESI) m/e=464.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:16]2[C:15](=[O:17])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][C:13]=3[O:18][CH3:19])[C:8](=[O:20])[C:7]=2[CH:6]=[C:5]([C:21]([OH:23])=[O:22])[CH:4]=1.[N+:24]([O-])([O-:26])=[O:25].[K+]>S(=O)(=O)(O)O>[CH3:1][O:2][C:3]1[C:16]2[C:15](=[O:17])[C:14]3[C:9](=[C:10]([N+:24]([O-:26])=[O:25])[CH:11]=[CH:12][C:13]=3[O:18][CH3:19])[C:8](=[O:20])[C:7]=2[CH:6]=[C:5]([C:21]([OH:23])=[O:22])[CH:4]=1
Reactant: O=[N+]([O-])[O-]
Reactant: COc1cccc2c1C(=O)c1c(OC)cc(C(=O)O)cc1C2=O
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COc1cc(C(=O)O)cc2c1C(=O)c1c(OC)ccc([N+](=O)[O-])c1C2=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Concentrated sulphuric acid (20 ml) was cooled to 5° C., and 9,10-dihydro-4,5-dimethoxy-9,10-dioxoanthracene-2-carboxylic acid (1 g) was added portionwise during fifteen minutes, resulting in a deep crimson coloration. Maintaining the cool temperature, potassium nitrate (0.36 g) was added portionwise during 10 minutes. Stirring continued at 5° C. for a further 15 minutes before the mixture was allowed to warm to room temperature. Upon reaching room temperature, the mixture was heated to 40° C. for 1 hour. The material was then poured onto ice/water (100 ml), generating a yellow precipitate. This solid was collected by filtration and washed with water (1×100 ml). Drying in vacuo over silica gel yielded 9,10-dihydro-4,5-dimethoxy-9,10-dioxo-8-nitro-anthracene-2-carboxylic acid as a signal yellow powder, decomposition point 230° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]([NH2:17])=O)=[C:13]([CH3:18])[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[C:11](=[O:29])[NH:10]2)=[C:5]([S:30][CH3:31])[CH:4]=1)#[N:2].[OH-].COC(NS([N+](CC)(CC)CC)(=O)=O)=O>C1COCC1.C(OCC)(=O)C.O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]#[N:17])=[C:13]([CH3:18])[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:27])([F:28])[F:26])[CH:20]=3)[C:11](=[O:29])[NH:10]2)=[C:5]([S:30][CH3:31])[CH:4]=1)#[N:2]
Reactant: CSc1cc(C#N)ccc1[C@H]1NC(=O)N(c2cccc(C(F)(F)F)c2)C(C)=C1C(N)=O
Agent: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CSc1cc(C#N)ccc1[C@H]1NC(=O)N(c2cccc(C(F)(F)F)c2)C(C)=C1C#N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The reaction was carried out under argon. (4S)-4-[4-Cyano-2-(methylsulfanyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide (95.0 mg, 0.213 mmol) was dissolved in THF (4 ml), and methoxycarbonylsulfamoyltriethylammonium hydroxide (Burgess reagent; 101 mg, 0.426 mmol) was added. After 30 min of stirring at room temperature, HPLC showed complete conversion. The mixture was diluted with ethyl acetate (4 ml), and water (1 ml) was added. The mixture was then applied to a Merck Extrelut® NT3 column and the filtrate was purified by preparative HPLC. Concentration of the product fractions gave 96.0 mg (quant.) of the title compound.
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Li]CCCC.[C:34]([CH:39]1[CH2:44][CH2:43][CH:42]([CH2:45][CH:46]=O)[CH2:41][CH2:40]1)([CH2:37][CH3:38])([CH3:36])[CH3:35]>>[C:34]([CH:39]1[CH2:44][CH2:43][CH:42]([CH2:45][CH:46]=[CH:2][CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:41][CH2:40]1)([CH2:37][CH3:38])([CH3:36])[CH3:35]
Reactant: c1ccc(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCC(C)(C)C1CCC(CC=O)CC1
Agent: [Br-]
Agent: [Li]CCCC
Product: CCC(C)(C)C1CCC(CC=CCc2ccccc2)CC1
Yield: 48.8 %

Procedure:
Starting from phenethyltriphenylphosphonium bromide (2.00 g, 4.47 mmol, 1.0 equiv.), n-BuLi (1.6 M in hexanes, 2.8 mL, 4.47 mmol, 1.0 equiv.) and 2-(4-tert-pentylcyclohexyl)acetaldehyde (1.32 g, 6.71 mmol, 1.5 equiv.), 0.62 g (48%) of the title compound as a colorless oil was obtained after purification by flash chromatography on SiO2 (cyclohexane).
Reaction SMILES: [Cl:1][C:2]1([C:7]([O:9]CC)=O)[CH2:4][C:3]1([Cl:6])[Cl:5].[NH2:12][NH2:13]>C(O)C>[Cl:1][C:2]1([C:7]([NH:12][NH2:13])=[O:9])[CH2:4][C:3]1([Cl:6])[Cl:5]
Reactant: NN
Reactant: CCOC(=O)C1(Cl)CC1(Cl)Cl
Solvent: CCO
Product: NNC(=O)C1(Cl)CC1(Cl)Cl

Procedure:
A solution of ethyl 1,2,2-trichlorocyclopropane carboxylate (3 grams), ethanol (25 ml), and anhydrous hydrazine (0.48 grams) was heated to reflux for approximately 2 hours. The reaction mixture was cooled, the solvent was stripped from solution, and the residue was recrystallized using a small volume of ethanol to produce 1,2,2-trichlorocyclopropane carboxylic acid hydrazide (mp 122°-123° C.). The identity of the final product was confirmed by NMR analysis.