Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([NH:11][C:12](=[N:20][C:21]#[N:22])OC2C=CC=CC=2)[CH:7]=[C:8]([Cl:10])[CH:9]=1)=[N+:2]=[N-:3].[C:23]([NH2:28])([CH2:26][CH3:27])([CH3:25])[CH3:24]>C(O)(C)C>[N:1]([C:4]1[CH:5]=[C:6]([NH:11][C:12]([NH:20][C:21]#[N:22])=[N:28][C:23]([CH3:25])([CH3:24])[CH2:26][CH3:27])[CH:7]=[C:8]([Cl:10])[CH:9]=1)=[N+:2]=[N-:3]
Reactant: N#CN=C(Nc1cc(Cl)cc(N=[N+]=[N-])c1)Oc1ccccc1
Reactant: CCC(C)(C)N
Solvent: CC(C)O
Product: CCC(C)(C)N=C(NC#N)Nc1cc(Cl)cc(N=[N+]=[N-])c1
Yield: 65.4 %

Procedure:
Step B-2. To a stirred suspension of N-(3-azido-5-chlorophenyl)-N'-cyanocarbamimidic acid, phenyl ester (B-1, 0.705 g, 2.25 mmol) in 10 mL of isopropanol is added tert-amylamine (1.0 mL, 9.02 mmol). The reaction mixture is heated at reflux for 4 hours, cooled and concentrated. The organic residue is purified by flash chromatography using 30% ethyl acetate in hexane as the eluent to afford 0.45 g of N-(3-azido-5-chlorophenyl)-N'-cyano-N"-(1,1-dimethylpropyl)guanidine. (B-2) Mp 147°-149° C.; IR (mull) 3325, 3234, 2925, 2159, 2121, 2108, 1611, 1595, 1578, 1558, 1495, 1414, 1228, 853 cm-1 ; 1H NMR (DMSO) δ7.10 (bs, 1 H), 6.80 (m, 1 H), 6.74 (m, 1 H), 6.65 (m, 1 H), 1.55 (q, 2 H, J=7 Hz), 1.14 (s, 6 H), 0.68(t, 3 H, J=7 Hz).; 13 C NMR (DMSO) δ156.3, 141.8, 141.7, 134.5, 116.5, 116.2, 113.4, 109.2, 54.7, 32.3, 26.1, 8.4; Melt Solvate: 0.63% Chloroform; Analysis calculated for C13H16ClN7 plus 0.63% CHCl3 :C, 50.81; H, 5.23; N, 31.86; Cl, 12.08. Found: C, 50.73; H, 5.15; N, 31.57; Cl, 12.35.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:19]=[C:18]([O:20][C:21]([F:24])([F:23])[F:22])[CH:17]=[CH:16][C:15]=2[S:25]([CH3:28])(=[O:27])=[O:26])[C:3]=1[CH3:29].[O:30]1[CH2:35][CH2:34][N:33]([C:36]2[CH:37]=[C:38]([NH2:42])[CH:39]=[N:40][CH:41]=2)[CH2:32][CH2:31]1>C1(C)C=CC=CC=1>[F:12][C:10]1[CH:9]=[C:8]([F:13])[CH:7]=[C:6]2[C:11]=1[C:2]([NH:42][C:38]1[CH:39]=[N:40][CH:41]=[C:36]([N:33]3[CH2:34][CH2:35][O:30][CH2:31][CH2:32]3)[CH:37]=1)=[C:3]([CH3:29])[C:4]([C:14]1[CH:19]=[C:18]([O:20][C:21]([F:22])([F:23])[F:24])[CH:17]=[CH:16][C:15]=1[S:25]([CH3:28])(=[O:27])=[O:26])=[N:5]2
Reactant: Cc1c(-c2cc(OC(F)(F)F)ccc2S(C)(=O)=O)nc2cc(F)cc(F)c2c1Cl
Reactant: Nc1cncc(N2CCOCC2)c1
Solvent: Cc1ccccc1
Product: Cc1c(-c2cc(OC(F)(F)F)ccc2S(C)(=O)=O)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1

Procedure:
Essentially prepared according to Procedure H using 4-chloro-5,7-difluoro-3-methyl-2-(2-(methylsulfonyl)-5-(trifluoromethoxy)phenyl)quinoline (50.0 mg, 0.11 mmol) and 5-morpholinopyridin-3-amine in toluene to give 5,7-difluoro-3-methyl-2-(2-(methylsulfonyl)-5-(trifluoromethoxy)phenyl)-N-(5-morpholinopyridin-3-yl)quinolin-4-amine. 1H NMR (CDCl3) δ ppm 8.25 (1H, d, J=8.8 Hz), 7.91 (1H, d, J=2.3 Hz), 7.87 (1H, d, J=2.3 Hz), 7.44-7.54 (2H, m), 7.25 (1H, d, J=1.6 Hz), 7.20 (1H, d, J=14.5 Hz), 7.10 (1H, ddd, J=13.9, 8.6, 2.5 Hz), 6.54 (1H, t, J=2.3 Hz), 3.79 (4H, t, J=4.8 Hz), 3.07-3.22 (7H, m), 1.89 (3H, s). Mass Spectrum (ESI) m/e=595.2 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[S:18][C:17]([C:19](O)=[O:20])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+:22]([C:25]1[CH:30]=[CH:29][C:28]([C:31]2[S:32][CH:33]=[CH:34][CH:35]=2)=[CH:27][C:26]=1[NH2:36])([O-:24])=[O:23].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[H-].[Na+]>N1C=CC=CC=1>[N+:22]([C:25]1[CH:30]=[CH:29][C:28]([C:31]2[S:32][CH:33]=[CH:34][CH:35]=2)=[CH:27][C:26]=1[NH:36][C:19]([C:17]1[S:18][C:14]([C:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:13][CH:12]=2)=[CH:15][CH:16]=1)=[O:20])([O-:24])=[O:23]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(C(=O)O)s2)CC1
Reactant: Nc1cc(-c2cccs2)ccc1[N+](=O)[O-]
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [H-]
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(C(=O)Nc3cc(-c4cccs4)ccc3[N+](=O)[O-])s2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.7 %

Procedure:
Compound 353 (270 mg, 0.87 mmol), 2-nitro-5-(thiophen-2-yl)benzenamine (3, 193 mg, 0.87 mmol), and BOP (386 mg, 0.87 mmol) were dissolved in dry pyridine (10 mL). Sodium hydride (140 mg, 3.50 mmol) was added and the resulting solution was stirred at room temperature for 2 hours, quenched with glacial acetic acid (1 mL), and the pyridine was removed under reduced pressure. Water (50 mL) was added and the mixture was extracted with ethyl acetate (2×50 mL). The extract was dried with sodium sulphate and evaporated to yield a residue which was triturated with ethyl acetate for 15 minutes, to afford the title compound 354 as a yellow solid (270 mg, 61% yield). 1H NMR: (DMSO) δ 10.79 (s, 1H), 8.06-8.04 (m, 2H), 7.86 (d, J=3.9 Hz, 1H), 7.75-7.68 (m, 3H), 7.25-7.20 (m, 2H), 6.32 (s, 1H), 4.04-4.01 (m, 2H), 3.54 (t, J=5.3 Hz, 2H), 1.43 (s, 9H).
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)=[O:5])[CH3:2].[CH:11](=[O:13])C>C1COCC1.CCCCC>[CH2:1]([NH:3][C:4]([C:6]1[S:7][CH:8]=[CH:9][C:10]=1[CH2:11][OH:13])=[O:5])[CH3:2]
Reactant: CC=O
Reactant: CCNC(=O)c1cccs1
Solvent: CCCCC
Solvent: C1CCOC1
Product: CCNC(=O)c1sccc1CO
Temperature: 25 °C
Reaction time: 3 h
Yield: 500 %

Procedure:
A solution of thiophene-2-carboxylic acid ethylamide (465 mg, 3 mmol) in dry THF (12 mL) is cooled to −78° C. under an argon atmosphere. Tert-BuLi (5.3 mL of a 1.7 M solution in pentane, 9.0 mmol) is added dropwise at −78° C. and the reaction mixture is stirred for 3 h. The reaction mixture is treated with neat acetaldehyde (3 mL, 53 mmol) and is stirred at −78° C. for 2 h and then warmed to room temperature overnight. The reaction mixture is quenched by the addition of water (35 mL). The reaction mixture is transferred to a separatory funnel and the organic phase is collected. The aqueous layer is extracted 5 times with Dichloromethane. The combined organic extracts are washed with water, and saturated aqueous NaCl, dried over Na2SO4 and concentrated. The residue is purified by chromatography (silica gel, 25% EtOAc/hexane) to give the title compound (298 mg, 15 mmol) in 50% yield.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[OH:22][CH2:23][CH2:24][NH:25][CH2:26][CH2:27][OH:28]>>[OH:22][CH2:23][CH2:24][N:25]([CH2:26][CH2:27][OH:28])[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21]
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Reactant: OCCNCCO
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(N(CCO)CCO)cc2c1=O
Yield: 55 %

Procedure:
N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (30 mg, 0.0943 mmol) is reacted with 2-(2-hydroxy-ethylamino)-ethanol according to the GPA affording 21 mg (55%) of a red powder. Rt=2.36 min.
Reaction SMILES: N[C:2]1[C:7]([Br:8])=[CH:6][C:5]([CH3:9])=[CH:4][N:3]=1.N.[ClH:11]>O>[Br:8][C:7]1[C:2]([Cl:11])=[N:3][CH:4]=[C:5]([CH3:9])[CH:6]=1
Reactant: Cl
Reactant: Cc1cnc(N)c(Br)c1
Agent: N
Solvent: O
Product: Cc1cnc(Cl)c(Br)c1
Reaction time: 1.5 h

Procedure:
The product from (a) (145 g) was dissolved in concentrated hydrochloric acid (750 ml) and water (450 ml) and the solution cooled to -10° C. Sodium nitride (54 g) in cold water (450 ml) was added dropwise with stirring over a period of 90 minutes while the mixture was kept at -5° C. The solution was stirred for a further 2 hours, and then basified with concentrated ammonia, keeping the temperature below 20° C. The solid which separated was washed with water, dried, dissolved in ether (1500 ml) and washed with cold sodium hydroxide solution (1 M; 1 liter). The ether solution was washed twice with water (1 liter portions), dried, and evaporated to give the required 3-bromo-2-chloro-5-methylpyridine.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[O:10])=[CH:4][CH:3]=1.Cl.[NH2:24][OH:25]>C1(C)C=CC=CC=1>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:24][OH:25])[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)C(=O)c1ccc(O)cc1
Reactant: NO
Agent: Cl
Solvent: Cc1ccccc1
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)C(=NO)c1ccc(O)cc1

Procedure:
To a mixture of 0.176 g. of p-nitrobenzyl p-hydroxyphenylglyoxylate and 1 g. of hydroxylamine hydrochloride were added 9 ml. of N,O-bis-trimethylsilyltrifluoroacetamide and the solution was stirred at a temperature of 140° C. for 2 hours. The reaction mixture was evaporated under reduced pressure and the residue was taken up in ethyl acetate. The ethyl acetate solution was washed with water and was then dried and evaporated. The oxime product was purified and isolated over silica gel preparative plates using toluene:ethyl acetate, 7:3, for elution. The product was located on the plate by means of UV light and the silica gel was scraped from the plate and the product extracted therefrom with ethyl acetate. The ethyl acetate was evaporated to yield 186 mg. of product. The product was crystallized from methylene chloride to yield 103 mg. of the crystalline material. The filtrate from the crystallization was diluted with petroleum ether to yield a second crop of 20 mg.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][CH2:13][C:14]([CH3:17])([CH3:16])[N:15]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].N#N.C1C[O:23][CH2:22]C1.C([Li])CCC>CCCCCC.CN(C=O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[O:12][CH2:13][C:14]([CH3:17])([CH3:16])[N:15]=2)=[C:9]([CH:10]=1)[CH:22]=[O:23])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)COC(c2ccc(C(C)(C)C)cc2)=N1
Reactant: C1CCOC1
Agent: N#N
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CC1(C)COC(c2ccc(C(C)(C)C)cc2C=O)=N1

Procedure:
An oven dried 250 mL 3-neck round bottom flask was fitted with a thermometer, stir bar, septum, and nitrogen inlet. Added 8.02 g (34.7 mmol) of 2-(4-tert-butyl-phenyl)-4,4-dimethyl-4,5-dihydro-oxazole. Established and maintained N2 atmosphere. Added 100 mL of anhydrous THF. Cooled the clear solution to −78°. Stirred rapidly and added 17 mL (43 mmol) of a 2.5 M solution of n-butyllithium in hexane dropwise over 10 minutes. Stirred the clear amber solution at −20° for 4 hr. The reaction mixture became red-amber and cloudy. Cooled the mixture to −78°. Stirred rapidly and added 12 mL of DMF dropwise at a rate to keep the temperature below −60°. Stirred at −78° for 15 min. Stirred at −20° for 1 hr. Stirred at room temperature for 1 hr. Quenched with 100 mL of 0.5 M aqueous KHSO4. The aqueous phase was still strongly basic. Added more 1.0 M KHSO4 until the pH was ˜2. Diluted the two phase solution with 300 mL Et2O. Separated phases and extracted the aqueous phase with 100 mL Et2O. Washed the combined organic phases with 200 mL brine and dried over K2CO3. Filtered through 120 g of silica gel and washed through with 300 mL Et2O to remove baseline impurities. Removed the solvent on rotavap to obtain 8.18 g of the title compound as a clear yellow liquid. MS (ESI) 260 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7](=[O:8])[NH:6][C:5](=[S:9])[N:4]([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:3]=1[NH:15][C:16]([CH:18]1[CH2:21][CH2:20][CH2:19]1)=O.[OH-].[Na+]>O.CO>[CH:18]1([C:16]2[NH:1][C:2]3[C:7](=[O:8])[NH:6][C:5](=[S:9])[N:4]([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:3]=3[N:15]=2)[CH2:21][CH2:20][CH2:19]1
Reactant: CCCCCn1c(NC(=O)C2CCC2)c(N)c(=O)[nH]c1=S
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCCn1c(=S)[nH]c(=O)c2[nH]c(C3CCC3)nc21
Temperature: 70 °C
Reaction time: 1 h
Yield: 74.3 %

Procedure:
The mixture of N-(5-amino-6-oxo-3-pentyl-2-thioxo-1,2,3,6-tetrahydropyrimidin-4-yl)cyclobutanecarboxamide (720 mg, 2.3 mmol) and 2.5 M of sodium hydroxide in water (25 mL) and methanol (25 mL) was stirred at 70° C. for 1 hour. After cooling to room temperature, The reaction mixture was concentrated to remove methanol and then acidified to pH=5. The precipitate formed was filtered and dried to yield the desired product (500 mg, 73.7%). LCMS calculated for C14H21N4OS (M+H): 293.1. Found: 293.1.
Reaction SMILES: CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH3:34][C@H:35]1[C:43]2[C:42]([CH:44]3[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]3)=[N:41][CH:40]=[N:39][C:38]=2[CH2:37][CH2:36]1.[C:50]([O:54][C:55]([N:57]1[C:61]([CH3:63])([CH3:62])[CH2:60][CH2:59][C@H:58]1[C@H:64]([C:68]1[CH:73]=[CH:72][C:71]([Cl:74])=[CH:70][CH:69]=1)[C:65](O)=[O:66])=[O:56])([CH3:53])([CH3:52])[CH3:51]>C(Cl)Cl>[Cl:74][C:71]1[CH:70]=[CH:69][C:68]([C@@H:64]([C@H:58]2[N:57]([C:55]([O:54][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:56])[C:61]([CH3:63])([CH3:62])[CH2:60][CH2:59]2)[C:65]([N:47]2[CH2:48][CH2:49][CH:44]([C:42]3[C:43]4[C@H:35]([CH3:34])[CH2:36][CH2:37][C:38]=4[N:39]=[CH:40][N:41]=3)[CH2:45][CH2:46]2)=[O:66])=[CH:73][CH:72]=1
Reactant: C[C@@H]1CCc2ncnc(C3CCNCC3)c21
Reactant: CC(C)(C)OC(=O)N1[C@H]([C@@H](C(=O)O)c2ccc(Cl)cc2)CCC1(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CCc2ncnc(C3CCN(C(=O)[C@@H](c4ccc(Cl)cc4)[C@@H]4CCC(C)(C)N4C(=O)OC(C)(C)C)CC3)c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.9 %

Procedure:
DIPEA (174 μL, 1.00 mmol) and O-(benzotriazol-1yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (25 mg, 0.065 mmol) were added to a solution of (R)-5-methyl-4-(piperidin-4-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (22 mg, 0.10 mmol) and (S)-2-((S)-1-(tert-butoxycarbonyl)-5,5-dimethylpyrrolidin-2-yl)-2-(4-chlorophenyl)acetic acid (20 mg, 0.054 mmol) in DCM (2 mL). The mixture was stirred at room temperature for 2 hours. The reaction was quenched with saturated NH4Cl and extracted with DCM (2×10 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude product was purified by flash chromatography (0-5% MeOH/DCM gradient elution) to give (S)-tert-butyl 5-((S)-1-(4-chlorophenyl)-2-(4-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperidin-1-yl)-2-oxoethyl)-2,2-dimethylpyrrolidine-1-carboxylate as a solid (26 mg, 84%). 1H NMR. (CD3OD, 500 MHz) δ 8.73 (s, 3H), 7.42 (d, J=8.5 Hz, 2H), 7.25 (d, J=8.5 Hz, 2H), 4.73-4.70 (m, 2H), 4.40-4.35 (m, 1H), 3.89-3.86 (m, 1H), 3.76-3.70 (m, 2H), 3.49-3.43 (m, 1H), 3.25-3.20 (m, 2H), 3.18-2.97 (m, 2H), 2.86-2.70 (m, 3H), 2.34-2.25 (m, 1H), 2.16-2.13 (m, 1H), 1.83-1.67 (m, 2H), 1.54 (s, 9H), 1.38 (s, 3H), 1.36 (s, 3H), 1.25-1.20 (m, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]#[CH:10])[CH2:4][CH2:3]1.Br[C:12]1[CH:13]=[C:14]2[C:18](=[C:19]([Cl:21])[CH:20]=1)[C:17](=[O:22])[N:16]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1)[CH2:15]2.C(Cl)(Cl)Cl.CO>C(NC(C)C)(C)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:21][C:19]1[CH:20]=[C:12]([C:10]#[C:9][CH2:8][N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[CH:13]=[C:14]2[C:18]=1[C:17](=[O:22])[N:16]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:26][CH:25]=1)[CH2:15]2
Reactant: O=C1c2c(Cl)cc(Br)cc2CN1Cc1ccc(C(F)(F)F)cc1
Reactant: C#CCN1CCN(C)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CN1CCN(CC#Cc2cc(Cl)c3c(c2)CN(Cc2ccc(C(F)(F)F)cc2)C3=O)CC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 90.2 %

Procedure:
A mixture of 1-methyl-4-prop-2-ynyl-piperazine (0.122 mL, 0.79 mmol), 5-bromo-7-chloro-2-(4-trifluoromethyl-benzyl)-2,3-dihydro-isoindol-1-one (0.240 g, 0.6 mmol), PdCl2(PPh3)2 (0.023 g, 0.03 mmol), and CuI (0.006 g, 0.03 mmol) in diisopropyl amine (4 mL) was stirred at 100° C. for 2 h. Workup and silica gel column chromatography using 10:1 CHCl3-MeOH afforded 7-chloro-5-[3-(4-methyl-piperazin-1-yl)-prop-1 ynyl)-2-(4-trifluoromethyl-benzyl)-2,3-dihydro-isoindol-1-one (0.250 g, 90%). 1H NMR (300 MHz, CDCl3): δ (ppm) 2.34 (s, 3H), 2.32-2.54 (m, 8H), 3.57 (s, 2H), 4.20 (s, 2H), 4.81 (s, 2H), 7.34 (s, 1H), 7.41-7.63 (m, 5H).
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[N:10]=[CH:11][S:12][C:13]=2[Cl:14])=[N:6][CH:5]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])[C:4]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH:29]1[C:34]([OH:36])=[O:35]>>[Cl:14][C:13]1[S:12][CH:11]=[N:10][C:9]=1[C:7]1[NH:8][C:3]([CH2:2][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH:29]2[C:34]([OH:36])=[O:35])=[C:4]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:5]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])[N:6]=1
Reactant: CCOC(=O)C1=C(CBr)NC(c2ncsc2Cl)=NC1c1ccc(Cl)cc1Cl
Reactant: O=C(O)C1COCCN1
Product: CCOC(=O)C1=C(CN2CCOCC2C(=O)O)NC(c2ncsc2Cl)=NC1c1ccc(Cl)cc1Cl
Yield: 33.9 %

Procedure:
Ethyl 6-(bromomethyl)-2-(5-chlorothiazol-4-yl)-4-(2,4-dichlorophenyl)-1,4-dihydropyrimidine-5-carboxylate (0.78 g, 1.53 mmol) was reacted with morpholine-3-carboxylic acid (0.2 g, 1.53 mmol) according to the procedure as described in Example 28 to give the title compound as a yellow solid (0.29 g, 34%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: ICC.C([O-])([O-])=O.[K+].[K+].[C:10]([O:13][C:14]1[CH:19]=[C:18]([I:20])[CH:17]=[C:16]([OH:21])[C:15]=1[Cl:22])(=O)[CH3:11]>CN(C=O)C.C(OCC)C>[Cl:22][C:15]1[C:14]([O:13][CH2:10][CH3:11])=[CH:19][C:18]([I:20])=[CH:17][C:16]=1[OH:21]
Reactant: CC(=O)Oc1cc(I)cc(O)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCI
Product: CCOc1cc(I)cc(O)c1Cl
Temperature: 60 °C
Reaction time: 1 h
Yield: 57.6 %

Procedure:
Iodoethane (0.78 mL, 9.6 mmol) and K2CO3 (1.3 g, 9.6 mmol) were added to a solution of 2-chloro-3-hydroxy-5-iodophenyl acetate (6) (2.0 g, 6.4 mmol) in DMF (5 mL) and the mixture was stirred at 60° C. for 1 h. The reaction mixture was cooled to RT, diluted with diethyl ether (100 mL) and washed with brine (3×100 mL). The solvent was removed in vacuo and the residue was dissolved in MeOH (20 mL). K2CO3 (1.0 g, 7.2 mmol) was added and the mixture was stirred at RT for 20 h. The solvent was removed in vacuo and the residue was partitioned between EtOAc (100 mL) and water (100 mL). The organic layer was washed with water (100 mL) and evaporated in vacuo. The residue was purified by silica gel chromatography (40 g, 0-30% EtOAc in isohexane) to afford 2-chloro-3-ethoxy-5-iodophenol (7) (1.1 g, 58% yield) as a colourless solid: m/z 297 [M−H]− (ES−); 1H NMR (400 MHz, DMSO-d6) δ: 10.45 (1H, s), 6.89 (2H, d), 4.04 (2H, br s), 1.32 (3H, br s).
Reaction SMILES: [CH3:1][NH2:2].[CH2:3]([CH:19]1O[CH:20]1[CH2:21][O:22][CH2:23][CH:24]1[O:42][CH:25]1CCCCCCCCCCCCCCCC)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]CCC>O1CCCC1>[CH2:21]([O:22][CH2:23][CH:24]([OH:42])[CH2:25][NH:2][CH3:1])[CH2:20][CH2:19][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CN
Reactant: CCCCCCCCCCCCCCCCC1OC1COCC1OC1CCCCCCCCCCCCCCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCOCC(O)CNC

Procedure:
A cooled mixture of 15.5 g of methylamine, 50 cc. of tetrahydrofurane and 15 g of hexadecyl-2.3-epoxypropylether is heated to 60° C. for 2 hours in an autoclave, cooled and evaporated in a vacuo. The residue is purified by column chromatography (silicic acid gel//chloroform/methanol).
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([O:13][C:14]3[CH:27]=[CH:26][C:17]([O:18][CH:19]([CH3:25])[C:20](OCC)=[O:21])=[CH:16][CH:15]=3)[CH:9]=[N:10]2)=[CH:5][CH:4]=1>CC(C)=O>[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([O:13][C:14]3[CH:27]=[CH:26][C:17]([O:18][CH:19]([CH3:25])[C:20]([NH2:1])=[O:21])=[CH:16][CH:15]=3)[CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)C(C)Oc1ccc(Oc2cnc3cc(Cl)ccc3c2)cc1
Reactant: N
Solvent: CC(C)=O
Product: CC(Oc1ccc(Oc2cnc3cc(Cl)ccc3c2)cc1)C(N)=O
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Concentrated ammonia was added at 20° C. to a solution of ethyl 2-[4-(7-chloroquinolin-3-yloxy)phenoxy]propionate (3.0 g) (see Example 5) in acetone (50 ml) until the mixture just began to turn cloudy. The mixture was then heated at 60° C. for 8 hours and allowed to cool and stand overnight. Colourless crystals (1.5 g) 2-[4-(7-chloroquinolin-3-yloxy)phenoxy]propionamide were collected by filtration. The compound was characterised by its proton magnetic resonance spectrum. (Table 3).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][C:6]([O:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([OH:16])=O)=[N:5]2.[F:20][C:21]([F:30])([F:29])[C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>CN(C)C=O>[N:1]1[CH:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][C:6]([O:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([NH:25][C:24]1[CH:26]=[CH:27][CH:28]=[C:22]([C:21]([F:20])([F:29])[F:30])[CH:23]=1)=[O:16])=[N:5]2
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: O=C(O)c1cccc(Oc2ccc3nccn3n2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1cccc(Oc2ccc3nccn3n2)c1
Yield: 58 %

Procedure:
Using 3-(imidazo[1,2-b]pyridazin-6-yloxy)benzoic acid (128 mg, 0.50 mmol), 3-(trifluoromethyl)aniline (97 mg, 0.60 mmol), 1-hydroxybenzotriazole hydrate (92 mg, 0.60 mmol), N,N-dimethylformamide (5 mL), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (192 mg, 1.00 mmol) and triethylamine (0.209 mL, 1.50 mmol), and in the same manner as in Example 448, the title compound (114 mg, 0.29 mmol, yield 57%) was obtained.
Reaction SMILES: [CH2:1]([C:13]1[C:14](=[O:25])[C:15]2[C:20]([C:21](=[O:24])[C:22]=1[OH:23])=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(N(CC)CC)C.[C:33](Cl)(=[O:35])[CH3:34].C(Cl)Cl>O>[C:33]([O:23][C:22]1[C:21](=[O:24])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=[O:25])[C:13]=1[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])(=[O:35])[CH3:34]
Reactant: CCCCCCCCCCCCC1=C(O)C(=O)c2ccccc2C1=O
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCCCCCCCCCC1=C(OC(C)=O)C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 30 h

Procedure:
A mixture of 2.0 parts of 2-n-dodecyl-3-hydroxy-1,4-naphthoquinone, 0.81 parts of triethylamine, 0.63 parts of acetyl chloride and 50 parts of methylene chloride was stirred at room temperature for 30 hours. The resulting mixture was distributed between methylene chloride and water. The methylene chloride layer was separated, dried over magnesium sulfate, then filtered and evaporated under reduced pressure. The residue was crystallized from petroleum ether (b.p. 30°-60°) to give 1.2 parts of 3-acetoxy-2-n-dodecyl-1,4-naphthoquinone, m.p.57°-58° C.