Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([CH2:13][O:14][CH:15]([F:17])[F:16])[C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].C(N(CC)CC)C.[C:25](OC(=O)C)(=[O:27])[CH3:26]>C1COCC1.C(OCC)(=O)C>[C:25]([NH:1][CH:2]([CH2:13][O:14][CH:15]([F:16])[F:17])[C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4])(=[O:27])[CH3:26]
Reactant: NC(COC(F)F)C(=O)NCc1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)NC(COC(F)F)C(=O)NCc1ccccc1
Reaction time: 1 h
Yield: 59.1 %

Procedure:
2-Amino-N-benzyl-3-difluoromethoxy-propionamide (195 mg, 0.80) was mixed with triethylamine (322 mg, 3.19 mmol) in THF (5 mL). Acetic anhydride (98.5 mg, 0.96 mmol) was then added and the reaction mixture was stirred for 1 hour. The mixture was then diluted with ethyl acetate and washed with water. The organic layer was dried and concentrated. The residue was purified by column chromatography using hexanes:ethyl acetate (50:50 to 0:100). The isolated product was triturated with diethyl ether to give 2-acetylamino-N-benzyl-3-difluoromethoxy-propionamide (135 mg, 59%) as a white solid. 1H NMR (300 MHz, CDCl3): δ (ppm) 7.33 (m, 5H), 6.68 (br, 1H), 6.37 (br, 1H), 6.24 (t, 1H), 4.72 (q, 1H), 4.87 (d, 2H), 4.23 (dd, 1H), 4.01 (dd, 1H), 2.05 (s, 3H).
Reaction SMILES: [O-][N+:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C[Si]([C:21]#[N:22])(C)C.CN(C)C(Cl)=O.C(OCC)(=O)C>[N+](CC)([O-])=O.O>[C:21]([C:7]1[N:2]=[C:3]([CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:4]=[CH:5][CH:6]=1)#[N:22]
Reactant: CC(C)(C)OC(=O)CCc1cccc[n+]1[O-]
Reactant: C[Si](C)(C)C#N
Agent: CN(C)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CC[N+](=O)[O-]
Solvent: O
Product: CC(C)(C)OC(=O)CCc1cccc(C#N)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 82.8 %

Procedure:
tert-Butyl 3-(1-oxido-2-pyridyl)propanoate (0.88 g, 3.9 mmol) was dissolved in nitroethane (5 ml). Trimethylsilyl cyanide (0.78 g, 7.9 mmol) and N,N-dimethylcarbamoyl chloride (0.85 g, 7.9 mmol) were added thereto. The reaction mixture was stirred at room temperature for 48 hrs, combined with ethyl acetate and water. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried over an hydrous magnesium sulfate. The solvent was evaporated. The residue was subjected to a silica gel (50 g) column chromatography and eluted with hexane-ethyl acetate (3:1, v/v) to give the titled compound (0.75 g, 82%).
Reaction SMILES: Cl[CH2:2][CH2:3][S:4](Cl)(=[O:6])=[O:5].[CH:8]1([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[C:22]([NH2:27])=[N:23][CH:24]=[CH:25][CH:26]=3)=[CH:17][CH:16]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.O>CN(C)C(=O)C>[CH:8]1([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[C:22]4=[N:27][S:4](=[O:6])(=[O:5])[CH2:3][CH2:2][N:23]4[CH:24]=[CH:25][CH:26]=3)=[CH:17][CH:16]=2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: Nc1ncccc1-c1ccc(OC2CCCCC2)cc1
Reactant: O=S(=O)(Cl)CCCl
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=S1(=O)CCN2C=CC=C(c3ccc(OC4CCCCC4)cc3)C2=N1
Temperature: 60 °C
Reaction time: 3 h
Yield: 85.1 %

Procedure:
A solution of 2-chloroethanesulfonyl chloride (381 mg) in N,N-dimethylacetoamide (2 mL) was added dropwise to a suspension of 3-[4-(cyclohexyloxy)phenyl]pyridin-2-amine (301 mg) in N,N-dimethylacetoamide (2 mL) and additional N,N-dimethylacetoamide (1 mL) was used to complete the addition of above solution. After being stirred at 60° C. for 3 hr, the mixture was cooled to room temperature. Water (10 mL) was added dropwise to the reaction mixture and the whole was stirred at room temperature for 0.5 hr. The precipitate was collected by filtration, washed with water (10 mL) and diisopropyl ether (3 mL), and dried in vacuo at 60° C. to give the title compound (342 mg) as an off-white powder.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:28])[CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][NH:18][S:19]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)(=[O:21])=[O:20])[CH:12]=1)([CH3:6])([CH3:5])[CH3:4].[CH2:29]([O:31][C:32](=[O:44])[C:33]([C:36]1[CH:41]=[CH:40][C:39]([CH2:42]Br)=[CH:38][CH:37]=1)([CH3:35])[CH3:34])[CH3:30].O>CN(C=O)C>[CH2:29]([O:31][C:32](=[O:44])[C:33]([C:36]1[CH:41]=[CH:40][C:39]([CH2:42][N:18]([CH2:17][C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([O:10][CH2:9][C:8]([O:7][C:3]([CH3:6])([CH3:4])[CH3:5])=[O:28])[CH:12]=2)[S:19]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)(=[O:21])=[O:20])=[CH:38][CH:37]=1)([CH3:34])[CH3:35])[CH3:30]
Reactant: CC(C)(C)OC(=O)COc1cccc(CNS(=O)(=O)c2cccnc2)c1
Reactant: CCOC(=O)C(C)(C)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)c1ccc(CN(Cc2cccc(OCC(=O)OC(C)(C)C)c2)S(=O)(=O)c2cccnc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 48.7 %

Procedure:
NaH (60% by weight in oil, 23 mg, 0.55 mmol) was washed with DMF (5 mL) and fresh DMF (5 mL) was added. The reaction was cooled to 0° C. and a solution of {3-[(pyridine-3-sulfonylamino)-methyl]-phenoxy}-acetic acid tert-butyl ester (184 mg, 0.486 mmol) in DMF (1 mL) was added. The reaction was stirred for 1 h and 2-(4-bromomethyl-phenyl)-2-methyl-propionic acid ethyl ester (145 mg, 0.51 mmol) in DMF (1 mL) was added. The reaction was warmed to room temperature and was heated at 100° C. for 2 h. Water was added and the aqueous solution was washed with EtOAc (3×). The combined organic solutions were washed with water (5×), dried (MgSO4), filtered and concentrated. Flash chromatography (2:1 hexanes:EtOAc) provided 2-(4-{[(3-tert-butoxycarbonylmethoxy-benzyl)-(pyridine-3-sulfonyl)-amino]-methyl}-phenyl)-2-methyl-propionic acid ethyl ester (138 mg). 1H NMR (400 MHz, CDCl3) δ 9.01 (s, 1H), 8.76 (m, 1H), 7.97 (m, 1H), 7.40 (m, 1H), 7.19 (d, 2H), 7.13 (m, 1H), 7.02 (d, 2H), 6.76 (m, 1H), 6.67 (m, 2H), 4.41 (s, 2H), 4.33 (s, 4H), 4.10 (q, 2H), 1.52 (s, 6H), 1.49 (s, 9H), 1.17 (t, 3H).
Reaction SMILES: [CH3:1][O:2][CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][O:6][C:5]2[CH:14]=[CH:15][C:16]([C:18]([O:20]C)=[O:19])=[CH:17][C:4]1=2.[OH-].[Na+]>CO.O>[CH3:1][O:2][CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][O:6][C:5]2[CH:14]=[CH:15][C:16]([C:18]([OH:20])=[O:19])=[CH:17][C:4]1=2
Reactant: COC(=O)c1ccc2c(c1)C(OC)c1ccccc1CO2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC1c2ccccc2COc2ccc(C(=O)O)cc21

Procedure:
Dissolve 695 mg of the ester of Step A in 15 ml of methanol. Add 10 ml of 20% aqueous sodium hydroxide and reflux for 10 minutes. Dilute with 200 ml of water and extract with ether. Acidify the aqueous fraction with concentrated hydrochloric acid and extract into ether. Evaporate to dryness and crystallize from methanol to obtain the title product (m.p. 185° C. dec.).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([OH:15])=O.[NH:16]1[CH2:24][CH2:23][CH:19]([C:20]([NH2:22])=[O:21])[CH2:18][CH2:17]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[C:13]([N:16]1[CH2:24][CH2:23][CH:19]([C:20]([NH2:22])=[O:21])[CH2:18][CH2:17]1)=[O:15]
Reactant: Cc1onc(-c2ccccc2)c1C(=O)O
Reactant: NC(=O)C1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1onc(-c2ccccc2)c1C(=O)N1CCC(C(N)=O)CC1
Temperature: 25 °C

Procedure:
5-Methyl-3-phenylisooxazole-4-carboxylic acid (40 mg, 0.197 mmol), isonipecotamide (27.5 mg, 0.215 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (86.2 mg, 0.268 mmol) and diisopropylethylamine (25.4 mg, 0.197 mmol) were mixed in dimethylformamide (1.5 mL) and stirred at room temperature. Solvent was evaporated in vacuo, and the residue was taken up in methanol (1 mL), filtered and purified by preparative chromatography. The combined fractions were partitioned between NaHCO3 (sat) and ethylacetate. The organic layer was washed with water and concentrated in vacuo to afford the title compound. HRMS (ESI, pos. ion) m/z calcd for C17H19N3O3: 313.1426, found 313.1431.
Reaction SMILES: [C:1]([O:8]CC)(=O)[C:2]([O:4]CC)=O.[Br:11][C:12]1[C:13]([NH2:21])=[C:14]([NH2:20])[CH:15]=[C:16]([F:19])[C:17]=1[F:18].C>[OH-].[Na+]>[Br:11][C:12]1[C:17]([F:18])=[C:16]([F:19])[CH:15]=[C:14]2[C:13]=1[NH:21][C:2](=[O:4])[C:1](=[O:8])[NH:20]2
Reactant: Nc1cc(F)c(F)c(Br)c1N
Reactant: CCOC(=O)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: O=c1[nH]c2cc(F)c(F)c(Br)c2[nH]c1=O
Temperature: 25 °C

Procedure:
The title compound was prepared using an adaptation of the method of Cheeseman. (Cheeseman, G. W. H. J. Chem. Soc. 1171 (1962)). A mixture of diethyl oxalate (2.70 g, 18.5 mmol) and 3-bromo-4,5-difluoro-1,2-diaminobenzene (410 mg, 1.85 mmol) was heated to reflux under N2 for 15 h. The reaction was allowed to cool to room temperature and the dark-brown solid collected by vacuum filtration and rinsed with EtOH (20 mL) and air dried to give 215 mg (42%). A portion of this solid (150 mg) was taken and dissolved in 20 mL 1N NaOH with heating. The solution was treated with activated charcoal and filtered through a pad of Celite. The resulting solution was carefully acidified with 1N HCl (pH=1). Pale yellow needles slowly formed in the solution and were collected by vacuum filtration, rinsed with 20 mL of H2O and dried under vacuum (0.1 torr, 78° C.) to yield 67.8 mg of powdery pale yellow crystals, mp 306°-310° C. (dec). 1H NMR (d6 -DMSO) δ 7.09 (dd, 1H, J=7.5, H-8), 11.3 (br s, 1H, NH), 12.1 (br s, 1H, NH). EIMS m/z 278 (M+2, 75), 276 (M+, 77), 250 (56), 248 (57), 14 1 (bp). EIHRMS calc. for C8H4BrF2N2O2 275.9346, found 275.9331.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[C:45]([O:49][C:50]([N:52]1[CH2:56][CH2:55][CH2:54][C@H:53]1[CH2:57][NH:58][CH2:59][C:60]1[O:61][C:62]2[CH:68]=[CH:67][CH:66]=[CH:65][C:63]=2[CH:64]=1)=[O:51])([CH3:48])([CH3:47])[CH3:46]>O1CCCC1>[C:45]([O:49][C:50]([N:52]1[CH2:56][CH2:55][CH2:54][C@H:53]1[CH2:57][N:58]([CH2:59][C:60]1[O:61][C:62]2[CH:68]=[CH:67][CH:66]=[CH:65][C:63]=2[CH:64]=1)[C:6](=[O:8])[C:5]1[CH:4]=[CH:3][C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=1)=[O:51])([CH3:48])([CH3:46])[CH3:47]
Reactant: COc1cc(C(=O)O)cc(OC)c1OC
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CNCc1cc2ccccc2o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(C(=O)N(Cc2cc3ccccc3o2)C[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1OC

Procedure:
Experimental condition analogous to Example 1, from 3,4,5-trimethoxy benzoic acid 72 mg (0.39 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride 75 mg (0.39 mmol), 1-hydroxybenzotriazole 45 mg (0.33 mmol), triethylamine 0.05 mL (0.39 mmol), and 2-(S)-{[(benzofuran-2-ylmethyl)-amino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester, 100 mg (0.3 mmol) in 3 mL tetrahydrofuran. The compound was purified through silica gel chromatography elution with ethyl acetate: methanol 9:1, gave 93 mg of white oily compound.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13](#[N:16])[CH2:14][CH3:15].Br[C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][N:19]=1>C1COCC1>[Cl:24][C:23]1[C:18]([CH:14]([CH3:15])[C:13]#[N:16])=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: Clc1cccnc1Br
Reactant: CCC#N
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C#N)c1ncccc1Cl
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 91.2 %

Procedure:
To a −78° C. solution of diisopropylamine (3.04 g, 4.28 mL, 30 mmol) was added n-butyl lithium (13.2 mL, 2.5M in hexane, 33 mmol). The reaction mixture was stirred for 20 minutes at −78° C., followed by the addition of propionitrile (1.65 g, 2.15 mL, 30 mmol). The reaction mixture was stirred for an additional 50 minutes, followed by the slow addition of 2-bromo-3-chloropyridine (1.92 g, 10 mmol) in THF (10 mL). The reaction was then allowed to warm to ambient temperature and stirred overnight. The reaction mixture was quenched with water and extracted with two portions of diethyl ether. The combined organic phases were washed with brine, concentrated, and the residue chromatographed on silica gel eluting with 30% ethyl acetate-hexane to obtain the title compound (1.52 g, 91%). 1H NMR (300 MHz, DMSO-d6) δ ppm 8.59 (dd, J=1.5, 4.7, 1H), 8.02 (dd, J=1.5, 8.1, 1H), 7.48 (dd, J=4.7, 8.1, 1H), 4.73 (q, J=7.1, 1H), 1.59 (d, J=7.1, 3H). MS (DCI) m/z 167 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([CH3:26])=[CH:10][N:11]([C:16]3[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=3[CH3:25])[C:19](O)=[O:20])[C:12]2=[O:15])=[CH:7][CH:6]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C.[CH:42]1([NH2:46])[CH2:45][CH2:44][CH2:43]1>C(Cl)Cl.CN(C=O)C>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([CH3:26])=[CH:10][N:11]([C:16]3[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=3[CH3:25])[C:19]([NH:46][CH:42]3[CH2:45][CH2:44][CH2:43]3)=[O:20])[C:12]2=[O:15])=[CH:7][CH:6]=1
Reactant: NC1CCC1
Reactant: Cc1ccc(C(=O)O)cc1-n1cc(C)c2ccc(OCCCl)cc2c1=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CCC2)cc1-n1cc(C)c2ccc(OCCCl)cc2c1=O
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A suspension of 3-[7-(2-chloroethoxy)-4-methyl-1-oxoisoquinolin-2(1H)-yl]-4-methylbenzoic acid (550 mg) in methylene chloride (10 ml) was cooled to 0° C. and oxalyl chloride (0.26 ml) was added followed by DMF (10 μl) and the reaction mixture was left to stir at room temperature for 1 hour when N,N′-diisopropylethylamine (1.03 ml) and cyclobutylamine (0.51 ml) were added. The reaction mixture was stirred at room temperature for 4 hours and concentrated. The residue was diluted with ethyl acetate and washed with water (×3), brine, dried (magnesium sulfate) and concentrated to a brown foam which was purified by column chromatography on a silica column eluting using a gradient of iso-hexane to ethyl acetate to give 3-[7-(2-chloroethoxy)-4-methyl-1-oxoisoquinolin-2(1H)-yl]-N-cyclobutyl-4-methylbenzamide as a pale yellow solid (397 mg); NMR Spectrum: (DMSOd6) 1.66 (m, 2H), 2.06 (m, 2H), 2.12 (s, 3H), 2.21 (m, 2H), 2.28 (s, 3H), 4.01 (t, 2H), 4.38-4.46 (m, 3H), 7.12 (s, 1H), 7.49-7.54 (m, 2H), 7.74-7.76 (m, 2H), 7.81 (s, 1H), 7.89 (d, 1H), 8.60 (d, 1H); Mass Spectrum: M+ 425.
Reaction SMILES: [O:1]1[CH2:7][CH2:6][CH2:5][N:4]([CH2:8][C:9]2[N:17]3[C:12]([C:13]([NH2:18])=[N:14][CH:15]=[N:16]3)=[CH:11][CH:10]=2)[CH2:3][CH2:2]1.[Br:19]N1C(C)(C)C(=O)N(Br)C1=O>C(Cl)(Cl)Cl>[Br:19][C:11]1[CH:10]=[C:9]([CH2:8][N:4]2[CH2:5][CH2:6][CH2:7][O:1][CH2:2][CH2:3]2)[N:17]2[C:12]=1[C:13]([NH2:18])=[N:14][CH:15]=[N:16]2
Reactant: Nc1ncnn2c(CN3CCCOCC3)ccc12
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Solvent: ClC(Cl)Cl
Product: Nc1ncnn2c(CN3CCCOCC3)cc(Br)c12
Temperature: -25 °C

Procedure:
7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (1.90 g, 7.68 mmol) was suspended in chloroform (76 mL). The solution was cooled to −20 to −30° C. 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione ( 989 g, 3.46 mmol) was added. The reaction was maintained at −20° C. for 20 minutes then warmed to room temperature. An LC taken at that time showed the reaction to be essentially complete. The reaction was then quenched by the addition of saturated aqueous sodium sulfite. The resultant slurry was partitioned between ethyl acetate (300 mL) and saturated bicarbonate (100 mL). The organic layer was washed (3×100 mL) with bicarb then dried with Na2SO4 and concentrated under vacuum.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH:3]=1.[NH2:21][CH2:22][CH:23]([OH:26])[CH2:24][NH2:25]>>[ClH:1].[NH2:21][CH2:22][CH:23]([OH:26])[CH2:24][NH:25][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH:3]=1
Reactant: COc1ccc2c(Cl)cc(-c3ccc(Cl)cc3)nc2c1
Reactant: NCC(O)CN
Product: COc1ccc2c(NCC(O)CN)cc(-c3ccc(Cl)cc3)nc2c1
Product: Cl

Procedure:
The title compound, m.p. 269-271° C. and MS: m/e=358.1 (M+H+), was prepared from 4-chloro-2-(4-chloro-phenyl)-7-methoxy-quinoline and 1,3-diamino-2-propanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:39]=[CH:38][C:6]([CH2:7][NH:8][C:9]2[C:14]([C:15]([OH:17])=O)=[C:13]([NH:18][C@H:19]([C:21]3[N:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:25](=[O:33])[C:24]4=[C:34]([CH3:37])[CH:35]=[CH:36][N:23]4[N:22]=3)[CH3:20])[N:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:73][O:74][C:75]1[CH:76]=[C:77]([CH:79]=[CH:80][CH:81]=1)[NH2:78]>CN(C)C=O.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9]2[C:14]([C:15]([NH:78][C:77]3[CH:79]=[CH:80][CH:81]=[C:75]([O:74][CH3:73])[CH:76]=3)=[O:17])=[C:13]([NH:18][C@H:19]([C:21]3[N:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:25](=[O:33])[C:24]4=[C:34]([CH3:37])[CH:35]=[CH:36][N:23]4[N:22]=3)[CH3:20])[N:12]=[CH:11][N:10]=2)=[CH:38][CH:39]=1
Reactant: COc1ccc(CNc2ncnc(N[C@@H](C)c3nn4ccc(C)c4c(=O)n3-c3ccccc3)c2C(=O)O)cc1
Reactant: COc1cccc(N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CNc2ncnc(N[C@@H](C)c3nn4ccc(C)c4c(=O)n3-c3ccccc3)c2C(=O)Nc2cccc(OC)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.4 %

Procedure:
(S)-4-((4-Methoxybenzyl)amino)-6-((1-(5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carboxylic acid (300 mg, 0.51 mmol) was dissolved in 7 mL dimethylformamide. N,N-Diisopropylethylamine (150 μl, 1.10 mmol) and HATU (400 mg, 1.05 mmol) were added and the reaction mixture was stirred at room temperature for 30 min. Then, 3-methoxyaniline (95 μl, 0.85 mmol) was added and the reaction mixture stirred at room temperature overnight. The crude was diluted with water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulphate and concentrated under reduced pressure. A semi-solid was obtained and purified using SP1® Purification System (0% to 50%, hexane-ethyl acetate) to obtain 265 mg (82% yield) of the title compound. Purity 100%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH2:16])[CH2:10][CH2:9]1.[CH3:17][C:18]1[N:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:21]=[C:20]([CH:29]=O)[CH:19]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][NH:16][CH2:29][C:20]2[CH:19]=[C:18]([CH3:17])[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:21]=2)[CH2:12][CH2:13]1
Reactant: Cc1cc(C=O)nn1-c1ccccc1
Reactant: NCCN1CCN(c2ccccc2F)CC1
Product: Cc1cc(CNCCN2CCN(c3ccccc3F)CC2)nn1-c1ccccc1
Yield: 87.4 %

Procedure:
Compound 61 was prepared using the same method as that of Example 1 except that 4-(2-fluorophenyl)piperazin-1-ylethylamine and 5-methyl-1-phenylpyrazole-3-carbaldehyde were used.
Reaction SMILES: [CH:1]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)C(C)C)C.[C:33](Cl)(=[O:35])[CH3:34].CS(C)=O>C1C=CC=CC=1>[C:33]([N:14]([CH:1]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])(=[O:35])[CH3:34]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)CCCCNC(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCCN(C(C)=O)C(c1ccccc1)c1ccccc1
Yield: 97.9 %

Procedure:
Analogously to Example 19, 9 g of ethyl 5-benzhydrylaminovalerate and 4.1 g of ethyl diisopropylamine are dissolved in 100 ml of benzene and reacted with 2.5 g of acetyl chloride. As reaction product one obtains 10 g of ethyl N-acetyl-5-benzhydrylaminovalerate as a viscous non-distillable oil. The saponification of this ester gives 7.4 g (78.7%) of N-acetyl-5-benzhydrylaminovaleric acid (M.P. 135° to 136°).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][CH:28]=[CH:27][C:4]=1[C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=1[NH:14][C:15](=[O:26])[NH:16][C:17]1[S:18][CH:19]=[C:20]([CH2:22][C:23]([OH:25])=O)[N:21]=1)=[O:6].[CH3:31][O:32][CH2:33][CH2:34][NH2:35]>>[CH3:1][O:2][C:3]1[CH:30]=[CH:29][CH:28]=[CH:27][C:4]=1[C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=1[NH:14][C:15](=[O:26])[NH:16][C:17]1[S:18][CH:19]=[C:20]([CH2:22][C:23]([NH:35][CH2:34][CH2:33][O:32][CH3:31])=[O:25])[N:21]=1)=[O:6]
Reactant: COc1ccccc1C(=O)c1ccc(C)cc1NC(=O)Nc1nc(CC(=O)O)cs1
Reactant: COCCN
Product: COCCNC(=O)Cc1csc(NC(=O)Nc2cc(C)ccc2C(=O)c2ccccc2OC)n1
Yield: 70 %

Procedure:
2-(2-{3-[2-(2-Methoxy-benzoyl)-5-methyl-phenyl]-ureido}-thiazol-4-yl)-N-(methoxy-ethyl)-acetamide (169 mg, 70%) was prepared from (2-{3-[2-(2-methoxy-benzoyl)-5-methyl-phenyl]-ureido}-thiazol-4-yl)-acetic acid (213 mg, 0.5 mmol) and 2-methoxyethylamine (38 mg, 0.5 mmol) following the general procedure K.
Reaction SMILES: [CH:1]([N:3]1[CH2:7][CH2:6]C[C:4]1=O)=C.CN(CCCC=[C:16]([CH3:20])[C:17](N)=[O:18])C.CC(C(NCCC[N+](C)(C)C)=[O:25])=C.C=CN1C(=O)CCC1.[Cl-]>>[C:17]([O:25][CH2:6][CH2:7][N:3]([CH3:1])[CH3:4])(=[O:18])[CH:16]=[CH2:20]
Reactant: CC(=CCCCN(C)C)C(N)=O
Reactant: C=C(C)C(=O)NCCC[N+](C)(C)C
Reactant: C=CN1CCCC1=O
Agent: [Cl-]
Product: C=CC(=O)OCCN(C)C

Procedure:
quaternized vinylpyrrolidone/dimethylaminopropylmethacrylamide copolymers such as the product sold under the name GAFQUAT HS 100 by the company ISP, and crosslinked polymers of methacryloyloxy(C1-C4)alkyltri(C1-C4)alkylammonium salts such as the polymers obtained by homopolymerization of dimethylaminoethyl acrylate quaternized with methyl chloride, or by copolymerization of acrylamide with dimethylaminoethyl acrylate quaternized with methyl chloride, the homo- or copolymerization being followed by crosslinking with a compound containing olefinic unsaturation, such as methylenebisacrylamide. In at least one embodiment, a crosslinked acrylamide/methacryloyloxyethyltrimethylammonium chloride copolymer (20/80 by weight) in the form of a dispersion containing 50% by weight of the copolymer in mineral oil can be used. This dispersion is sold under the name SALCARE® SC 92 by the company Ciba. In some embodiments, a crosslinked methacryloyloxyethyltrimethylammonium chloride homopolymer containing about 50% by weight of the homopolymer in mineral oil or in a liquid ester can be used. These dispersions are sold under the names SALCARE® SC 95 and SALCARE® SC 96 by the company Ciba.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:5][CH:4]=1.C([O:19][C:20]1[CH2:25][CH2:24][CH2:23][C:22](=O)[CH:21]=1)C.Cl>C1COCC1.CCOCC>[CH2:9]([C:6]1[CH:7]=[CH:8][C:3]([C:22]2[CH2:23][CH2:24][CH2:25][C:20](=[O:19])[CH:21]=2)=[CH:4][CH:5]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCc1ccc(Br)cc1
Reactant: CCOC1=CC(=O)CCC1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCCCCc1ccc(C2=CC(=O)CCC2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 66 %

Procedure:
To a suspension of magnesium (1.477 g, 60.8 mmol) in THF (56 mL) was added 1-bromo-4-octylbenzene (15.00 g, 55.7 mmol). After stirring for about 6 h the reaction mixture was added with filtering to a solution of 3-ethoxycyclohex-2-enone (7.10 g, 50.6 mmol) in THF (28.0 mL) at 0° C. Following the addition the reaction mixture was allowed to warm to room temperature. After 1 h 1N HCl was added until a pH of 1 was obtained. The reaction mixture was diluted with Et2O and the organic layer was separated, washed with NaHCO3, and brine, dried with (Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (EtOAc/Hep) to provide 3-(4-octylphenyl)cyclohex-2-enone (9.5 g, 33.4 mmol, 65.9% yield) as a colorless oil.