Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[S:27]1[CH:31]=[N:30][N:29]=[C:28]1[NH2:32].Cl>N1C=CC=CC=1>[CH2:1]([C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH:32][C:28]2[S:27][CH:31]=[N:30][N:29]=2)(=[O:25])=[O:24])=[CH:19][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: Nc1nncs1
Reactant: CCCCCCCCCCCCCCCCc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCc1ccc(S(=O)(=O)Nc2nncs2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 46 %

Procedure:
To a solution of p-hexadecylbenzenesulfonyl chloride (600 mg, 1.50 mmol) in pyridine (8 mL) was added 1,3,4-thiadiazol-2-amine (228 mg, 2.25 mmol). The reaction mixture was stirred at room temperature for 6 hours, then 2 M HCl (40 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (3×50 mL), the organic layer was washed with water (40 mL) and brine (40 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by chromatography over silica gel (70-230 mesh) eluted with methanol:DCM 1:19 to give the product as a solid (320 mg, 0.69 mmol, 46% yield), mp 118-119° C.; 1H NMR (300 MHz, CDCl3) δ 0.88 (t, 3H, J=6.9 Hz), 1.25 (m, 26H), 1.59 (m, 2H), 2.64 (t, 2H, J=8.1 Hz), 7.29 (d, 2H, J=7.8 Hz), 7.84 (d, 2H, J=7.8 Hz), 8.23 (s, 1H); 13C NMR (75 MHz, CDCl3) 14.1, 22.7, 29.2, 29.3, 29.4, 29.6, 29.7, 31.1, 31.9, 35.9, 126.5, 128.9, 138.1, 142.5, 148.7, 167.5; MS (LCQ, ESI+) Calcd for C24H40N3O2S2 466.3, found 466.3 (M+H)+; HRMS (ESI+, m/z) Calcd for C24H40N3O2S2 466.2556, found 466.2558 (M+H)+.
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[CH2:11][CH2:10][CH2:9][NH:8]2)[CH:2]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[F:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:8]2[CH2:9][CH2:10][CH2:11][CH:7]2[C:3]2[CH:2]=[C:1]([CH3:12])[CH:6]=[CH:5][CH:4]=2)(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: Cc1cccc(C2CCCN2)c1
Product: Cc1cccc(C2CCCN2S(=O)(=O)c2ccc(F)cc2)c1

Procedure:
The title compound, off-white solid, m.p. 80° C. and MS: m/e=319(M+) was prepared in accordance with the general method of example 1e from (RS)-2-m-tolyl-pyrrolidine and 4-fluoro-benzenesulfonyl chloride.
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([N+:14]([O-:16])=[O:15])=[CH:7][N:6]=1.[Cl-].[NH4+]>CO>[CH3:1][O:2][C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([N+:14]([O-:16])=[O:15])=[CH:7][N:6]=1
Reactant: O=[N+]([O-])c1cnc(Cl)c([N+](=O)[O-])c1
Reactant: C[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: COc1ncc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80 %

Procedure:
A 14% methanol solution of sodium methoxide was added to 25.0 g (120 mmol) of 2-chloro-3,5-dinitropyridine, and the mixture was stirred for 15 minutes at room temperature. The mixture was added to 200 ml of a saturated aqueous ammonium chloride solution, and extracted with 200 ml of ethyl acetate. Washing with saturated saline, drying over anhydrous sodium sulfate, filtering and distilling under reduced pressure (bath temp. 40°-60° C., 40-20 mmHg) yielded yellow crystals, which were recrystallized from methanol to obtain 19.5 g (91.8 mmol) of 2-methoxy-3,5-dinitropyridine as pale yellow crystals (yield: 80%).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](OCC)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]1=[O:23])(=O)C.[N:24]1([CH2:30][C:31]([N:33]([C:35]2[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=2)[CH3:34])=[O:32])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.[OH-].[Na+]>CN(C=O)C.CO>[N:24]1([CH2:30][C:31]([N:33]([C:35]2[CH:36]=[CH:37][C:38]([NH:39]/[C:13](=[C:6]3\[C:5](=[O:23])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[CH:10][CH:11]=4)/[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:40][CH:41]=2)[CH3:34])=[O:32])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccccc21)c1ccccc1
Reactant: CN(C(=O)CN1CCCCC1)c1ccc(N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: CN(C(=O)CN1CCCCC1)c1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 43 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and 4-(N-piperidinomethylcarbonyl-N-methyl-amino)-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])/[C:5](/[N+:10]#[C-:11])=[CH:6]/[N:7]([CH3:9])C)[CH3:2].[CH:13]1(N)[CH2:16]C[CH2:14]1>>[CH2:1]([O:3][C:4]([C:5]1[N:10]=[CH:11][N:7]([CH:9]2[CH2:16][CH2:13][CH2:14]2)[CH:6]=1)=[O:12])[CH3:2]
Reactant: [C-]#[N+]/C(=C\N(C)C)C(=O)OCC
Reactant: NC1CCC1
Product: CCOC(=O)c1cn(C2CCC2)cn1
Temperature: 70 °C

Procedure:
The stirred mixture of (Z)-3-dimethylamino-2-isocyano-acrylic acid ethyl ester (17.0 g, 100 mmol) and cyclobutaneamine (21.79 g, 300 mmol) was heated for 2.5 h at 70° C. The reaction mixture was cooled to rt and concentrated. The residue was purified by flash chromatography (EtOAc/hexane, 5:1) to afford the title compound as an orange oil. tR: 0.70 min (LC-MS 2); ESI-MS: 195.2 [M+H]+ (LC-MS 2); 1H-NMR (DMSO-d6, 400 MHz) δ ppm 8.03 (s, 1H), 7.83 (s, 1H), 4.73 (m, 1H), 4.18 (q, 2H), 2.36 (m, 4H), 1.74 (m, 2H), 1.24 (t, 3H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:15]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:16]=1[CH2:17][CH2:18][N:19]([S:25]([NH:28][C:29]1[S:33][N:32]=[CH:31][N:30]=1)(=[O:27])=[O:26])[CH2:20]2.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>O>[S:33]1[C:29]([NH:28][S:25]([N:19]2[CH2:18][CH2:17][C:16]3[C:21](=[CH:22][CH:23]=[CH:24][C:15]=3[C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=3)[CH2:20]2)(=[O:26])=[O:27])=[N:30][CH:31]=[N:32]1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: O=S(=O)(Nc1ncns1)N1CCc2c(Br)cccc2C1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=S(=O)(Nc1ncns1)N1CCc2c(cccc2-c2ccc(C(F)(F)F)cc2)C1
Temperature: 120 °C

Procedure:
A vial charged with Cl2Pd(AmPhos) (Sigma-Aldrich, St. Louis, Mo., 9.43 μg, 0.013 μmol), (4-(trifluoromethyl)phenyl)boronic acid (0.200 μmol), 5-bromo-N-(1,2,4-thiadiazol-5-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide (0.050 mg, 0.133 μmol), and potassium phosphate (0.085 mg, 0.400 μmol) was treated with 2 mL dioxane and 1 mL water. The reaction mixture was heated to 120° C. for 2 hours at which time the mixture was cooled to room temperature then concentrated and purified by reverse phase column chromatography [RediSep Gold C-18 50 g, 5 to 75% (0.1% NH4OH in MeOH)/(0.1% NH4OH in water)] to provide N-(1,2,4-thiadiazol-5-yl)-5-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide. [M+H]+=441.0. 1H NMR (400 MHz, MeOH-d4) δ ppm: 8.03 (s, 1H), 7.72 (d, J=8.1 Hz, 2H), 7.49 (d, J=7.9 Hz, 2H), 7.22-7.28 (m, 1H), 7.12 (dd, J=15.5, 7.1 Hz, 2H), 4.40 (s, 2H), 3.33-3.38 (m, 2H), 2.77 (m, 2H)
Reaction SMILES: [Cl:1][C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.N1C=CC=CC=1.[C:19]1([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][OH:30])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[C:19]1([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][C:2]([Cl:1])=[O:4])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OCCCCCc1ccccc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: O=C(Cl)OCCCCCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 188.5 %

Procedure:
In a four necked round bottom flask, triphosgene (22.0 g, 74.2 mmol) was dissolved in toluene (325 mL) under argon. After cooling at 0° C., pyridine (19.2 mL, 237.5 mmol) was added dropwise during 1 h and the resulting suspension stirred for 1 h at 0° C. 5-phenylpentanol (25 mL, 148.4 mmol) was added drop wise in 30 min. After stirring at rt for 16 h the solid was filtered-off and the solvent removed under vacuum yielding the title compound (31.7 g, 94%), which was used in the next step without further purification. Rf=0.75 (Cy/AcOEt 8:2). FTIR (cm−1): 3087, 3063, 3027, 2936, 2859, 1778, 1744, 1604, 1496, 1455, 1382, 1260, 1146, 1031, 941, 835, 731, 696.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[CH3:11][C:12]1[C:13]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[N:14][C:15]([CH3:19])=[C:16]([CH3:18])[CH:17]=1>>[Br:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([N:23]2[CH2:24][CH2:25][N:20]([C:13]3[C:12]([CH3:11])=[CH:17][C:16]([CH3:18])=[C:15]([CH3:19])[N:14]=3)[CH2:21][CH2:22]2)=[O:8])=[CH:9][CH:10]=1
Reactant: Cc1cc(C)c(N2CCNCC2)nc1C
Reactant: O=C(O)c1ccc(Br)nc1
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(Br)nc3)CC2)nc1C
Yield: 79 %

Procedure:
To 1-(3,5,6-trimethylpyridin-2-yl)piperazine hydrochloride described in Preparation Example 52 were added ethyl acetate and 1N aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate and washed with saturated brine. The solvent was evaporated to give 1-(3,5,6-trimethylpyridin-2-yl)piperazine (470 mg). By reaction and treatment in the same manner as in Preparation Example 27 and using 6-bromonicotinic acid (407 mg) and 1-(3,5,6-trimethylpyridin-2-yl)piperazine (470 mg), the title compound (620 mg) was obtained.
Reaction SMILES: [Li+].[OH-].C[O:4][C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[CH2:12][CH2:11][C@H:10]2[NH:16][C:17](=[O:25])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24])=[O:6]>CO.O>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:17]([NH:16][C@H:10]1[C:9]2[C:13](=[CH:14][CH:15]=[C:7]([C:5]([OH:6])=[O:4])[CH:8]=2)[CH2:12][CH2:11]1)=[O:25]
Reactant: COC(=O)c1ccc2c(c1)[C@H](NC(=O)c1ccccc1Cl)CC2
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2c(c1)[C@H](NC(=O)c1ccccc1Cl)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Method 1 LiOH (5 eq) was added to a suspension of (3R)-3-[(2-chloro-benzoyl)amino]-2,3-dihydro-1H-indene-5-carboxylic acid methyl ester (B-01) (8.569 mmol, 1 eq) in methanol (35 ml) and water (8 ml), and the reaction mixture was stirred overnight at 25° C. Methanol was removed in vacuo and the residue was taken up in diethyl ether and water. The phases were separated and the aqueous phase was adjusted to pH 2 with 1N HCl. The aqueous phase was extracted with ethyl acetate (2×) and the combined organic phases were then dried over magnesium sulfate. After concentration, the desired product (3R)-3-[(2-chloro-benzoyl)amino]-2,3-dihydro-1H-indene-5-carboxylic acid (E-01) was obtained. Yield: 93%
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=O)[CH:6]=[C:7]([CH:9]=[O:10])[CH:8]=1.[C:13]([O-])([O-])=O.[K+].[K+].O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:6]=[C:5]([CH:11]=[CH2:13])[CH:4]=1)[CH:9]=[O:10]
Reactant: O=C([O-])[O-]
Reactant: COc1cc(C=O)cc(C=O)c1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: C=Cc1cc(C=O)cc(OC)c1
Yield: 47.9 %

Procedure:
A mixture of the 5-methoxy-benzene-1,3-dicarbaldehyde (3.68 g, 22.4 mmol) obtained in Example 198.1, methyl-triphenylphosphonium bromide (8.17 g, 22.4 mmol), K2CO3 (3.10 g, 22.4 mmol), water (0.68 ml) and dioxan (51 ml) was heated for 2 h. to 90° C. The reaction mixture was concentrated and the product was purified by chromatography (SiO2, hexane/CH2Cl2 4:1). There were obtained 1.74 g (48%) of 3-methoxy-5-vinyl-benzaldehyde as a colorless oil; MS: 162 ([M]+).
Reaction SMILES: CCN(S(F)(F)[F:7])CC.[Cl:10][C:11]1[N:16]=[CH:15][N:14]=[C:13]([CH2:17]O)[C:12]=1[CH3:19]>ClCCl>[Cl:10][C:11]1[C:12]([CH3:19])=[C:13]([CH2:17][F:7])[N:14]=[CH:15][N:16]=1
Reactant: Cc1c(Cl)ncnc1CO
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: Cc1c(Cl)ncnc1CF
Temperature: -78 °C
Reaction time: 3 h
Yield: 74.9 %

Procedure:
DAST (1.5 mL, 11.35 mmol) was added to dichloromethane (DCM) (64 mL), cooled to −78° C. and treated dropwise with a solution of (6-chloro-5-methyl-4-pyrimidinyl)methanol (Intermediate 50, 1.70 g, 10.72 mmol) in DCM (24 mL) under argon. The resulting mixture was allowed to warm to room temperature and stirred for 3 hours. The reaction was quenched by adding water (45 ml) and extracted with DCM (×2). The DCM layers were separated, combined, dried under magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (SP4, 40+M) eluting with a gradient of 0-50% ethyl acetate and iso-hexane. Product containing fractions were combined and evaporated under reduced pressure to give the title compound as a yellow oil (1.29 g) m/z (ES+) 161 (M+1), title compound is 42% pure by LCMS. Also contains 4-bromo-6-(fluoromethyl)-5-methylpyrimidine, m/z (ES+) 205, 207 (M+1) (44% by LCMS)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH2:15][CH2:14][CH2:13][NH:12][C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[F:17][C:18]([F:31])([F:30])[O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](O)=[O:28])=[CH:22][CH:21]=1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[CH2:15][CH2:14][CH2:13][N:12]([C:27](=[O:28])[CH2:26][C:23]4[CH:24]=[CH:25][C:20]([O:19][C:18]([F:30])([F:17])[F:31])=[CH:21][CH:22]=4)[C:11]=3[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(-n2ncc3c2CCCN3)cc1
Reactant: O=C(O)Cc1ccc(OC(F)(F)F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(OC(F)(F)F)cc1)N1CCCc2c1cnn2-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.4 %

Procedure:
To a mixture of 1-(4-fluorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridine (0.023 g, 0.10 mmol), 4-(trifluoromethoxy)phenylacetic acid (0.025 g, 0.11 mmol) and Et3N (0.060 mL, 0.43 mmol) in DMF (0.6 mL) was added HATU (0.060 g, 0.15 mmol). The mixture was stirred at rt for 30 min. It was then quenched with water. The mixture was partitioned between EtOAc (50 mL) and sat. NaHCO3 (30 mL). The organic layer was separated, dried over Na2SO4, concentrated in vacuo, and purified by reverse phase HPLC to afford the desired product (0.040 g, 95%). 1H NMR (400 MHz, CDCl3) δ 8.51 (s, 1H), 7.43 (m, 2H), 7.30 (m, 2H), 7.18 (m, 4H), 3.91 (s, 2H), 3.76 (m, 2H), 2.79 (t, J=6.4 Hz, 2H), 2.00 (m, 2H); MS: (ES) m/z calculated for C21H17F4N3O2 [M+H]+ 420.1, found 420.1.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([C:18]3[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH:19]=3)[CH:12]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].[K+].[C:27]([C:29]1[N:30]=[C:31]([C:42]([O-])=[O:43])[N:32]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[CH:33]=1)#[N:28]>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:42]([C:31]3[N:32]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[CH:33]=[C:29]([C:27]#[N:28])[N:30]=3)=[O:43])=[C:13]([C:18]3[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH:19]=3)[CH:12]=2)[CH2:6][CH2:7][O:8][CH2:9][CH2:10]1)=[O:4]
Reactant: COC(=O)C1(c2ccc(N)c(C3=CCC(C)(C)CC3)c2)CCOCC1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Product: COC(=O)C1(c2ccc(NC(=O)c3nc(C#N)cn3COCC[Si](C)(C)C)c(C3=CCC(C)(C)CC3)c2)CCOCC1
Yield: 90 %

Procedure:
The title compound was prepared by the coupling procedure of Example 1, step (f) using 4-[4-amino-3-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-tetrahydro-pyran-4-carboxylic acid methyl ester (as prepared in the previous step, 650 mg, 1.89 mmol) and potassium 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate (as prepared in Example 1, step (d), 636 mg, 2.08 mmol). Silica gel chromatography (DCM) afforded the title compound (1.01 g, 90%) as a colorless oil. Mass spectrum (ESI, m/z): Calcd. for C32H44N4O5Si, 593.3 (M+H). found 593.0.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:14]=[C:13]([C:15](OC)=[O:16])[O:12][N:11]=2)=[CH:6][CH:5]=1.[NH2:21][NH2:22].O>CCO>[F:1][C:2]([F:20])([F:19])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:14]=[C:13]([C:15]([NH:21][NH2:22])=[O:16])[O:12][N:11]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1cc(-c2ccc(OC(F)(F)F)cc2)no1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)c1cc(-c2ccc(OC(F)(F)F)cc2)no1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.5 %

Procedure:
To a solution of methyl 3-(4-(trifluoromethoxy)phenyl)isoxazole-5-carboxylate (3.0 g, 10.5 mmol) in EtOH (80 mL) was added NH2NH2.H2O (3.3 mL, 52.3 mmol). The resulting mixture was stirred at RT for 16 h and then concentrated under reduced pressure. The residue was crystallized from CHCl3 and petroleum ether to afford the title compound (2.7 g, 90%). MS (ES+) C11H8F3N3O3 requires: 287. found: 288 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:14]=[CH:13][C:6]([CH2:7][N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)=[CH:5][CH:4]=1)#[N:2].[Li]CCCC.CCCCCC.[F:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][CH2:35]Br)=[CH:29][CH:28]=1.[Cl-].[NH4+]>C1COCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:7]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)[CH2:35][CH2:34][CH2:33][C:30]2[CH:31]=[CH:32][C:27]([F:26])=[CH:28][CH:29]=2)=[CH:13][CH:14]=1)#[N:2]
Reactant: N#Cc1ccc(Cn2ccnc2)cc1
Reactant: Fc1ccc(CCCBr)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: N#Cc1ccc(C(CCCc2ccc(F)cc2)n2ccnc2)cc1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
1-(4-cyanobenzyl)-imidazole (1 g, 0.0054 mol) is dissolved into dry tetrahydrofuran (30 ml) and cooled to -70° C. n-BuLi in hexane (0.0054 mol) is added dropwise into the reaction mixture. After stirring for additional 30 min at -70° C. 3-(4-fluorophenyl)propyl bromide (1.5 g, 0,0069 mol) in THF (10 ml) is added to the mixture and stirring is continued for 2 hours. Then the mixture is allowed to warm to room temperature. Saturated aqueous ammonium chloride solution is added to the mixture, shaked and then the layers are separated. THF-phase is dried and evaporated to dryness. The residue is crystallized from isopropanol as hydrogen chloride salt. The filtrate is purified by flash chromatography.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH:13]2[CH2:18][C:17]([CH3:20])([CH3:19])[N:16]([CH3:21])[C:15]([CH3:23])([CH3:22])[CH2:14]2)[CH2:9][CH2:10][CH2:11][CH3:12])[N:5]=[C:4]([N:24]([CH:29]2[CH2:34][C:33]([CH3:36])([CH3:35])[N:32]([CH3:37])[C:31]([CH3:39])([CH3:38])[CH2:30]2)[CH2:25][CH2:26][CH2:27][CH3:28])[N:3]=1.[NH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][NH2:47].[OH-].[Na+]>C1(C)C(C)=CC=CC=1.O>[NH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][NH:47][C:2]1[N:7]=[C:6]([N:8]([CH:13]2[CH2:18][C:17]([CH3:20])([CH3:19])[N:16]([CH3:21])[C:15]([CH3:22])([CH3:23])[CH2:14]2)[CH2:9][CH2:10][CH2:11][CH3:12])[N:5]=[C:4]([N:24]([CH:29]2[CH2:30][C:31]([CH3:38])([CH3:39])[N:32]([CH3:37])[C:33]([CH3:35])([CH3:36])[CH2:34]2)[CH2:25][CH2:26][CH2:27][CH3:28])[N:3]=1
Reactant: CCCCN(c1nc(Cl)nc(N(CCCC)C2CC(C)(C)N(C)C(C)(C)C2)n1)C1CC(C)(C)N(C)C(C)(C)C1
Reactant: NCCCCCCN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1C
Product: CCCCN(c1nc(NCCCCCCN)nc(N(CCCC)C2CC(C)(C)N(C)C(C)(C)C2)n1)C1CC(C)(C)N(C)C(C)(C)C1
Reaction time: 8 h
Yield: 89.9 %

Procedure:
56.4 g of 2-chloro-4,6-bis-(1,2,2,6,6-pentamethyl-4-piperidyl-butylamino)-1,3,5-triazine are introduced into a melt of 120 g of hexamethylenediamine at 80°. The reaction mixture is then stirred for 8 hours at 100° and after adding 50 ml of xylene is then stirred for 16 hours at 140°. The reaction mixture is diluted with 200 ml of xylene, a solution of 4.4 g of sodium hydroxide in 50 ml of water is added and the resulting mixture is stirred vigorously for 4 hours at room temperature. The xylene solution is separated off from the aqueous phase in a separating funnel, dried over sodium sulphate and evaporated in vacuo. 57.9 g of the 2-(6-aminohexylamino)-4,6-bis-(1,2,2,6,6-pentamethyl-4-piperidyl-butylamino)-1,3,5-triazine thus obtained are dissolved in 200 ml of xylene and the resulting solution is cooled to 5°. 5.5 g of cyanuric chloride are introduced at this temperature and the reaction mixture is stirred at 5°-10° for 1 hour. After adding 1.2 g of finely powdered sodium hydroxide, the temperature is raised to 35°-40° and the mixture is stirred for 2 hours at this temperature. After adding a further portion of 1.2 g of sodium hydroxide, the reaction mixture is slowly heated to the reflux temperature. After 3 hours under reflux, a final portion of 1.4 g of sodium hydroxide is added and the reaction mixture is then stirred under reflux for 16 hours. After cooling, 200 ml of water are added, the mixture is stirred well for 15 minutes, the aqueous solution is separated off and the xylene solution is washed with 3 times 100 ml of water. The xylene solution is evaporated in vacuo and the residue is then dried under a high vacuum (130°/0.001 mm Hg). The resulting, pale yellowish mass can be comminuted to a virtually colourless powder. The light stabiliser having the above structural formula melts at about 125°.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16](Cl)=[O:17].[NH:19]=[C:20]1[NH:24][CH2:23][CH2:22][S:21]1>N1C=CC=CC=1>[S:21]1[CH2:22][CH2:23][N:24]=[C:20]1[NH:19][C:16]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[OH:1])=[CH:10][CH:9]=[CH:8][C:7]=2[C:12]([F:15])([F:14])[F:13])=[O:17]
Reactant: N=C1NCCS1
Reactant: O=C(Cl)c1cnc2c(C(F)(F)F)cccc2c1O
Solvent: c1ccncc1
Product: O=C(NC1=NCCS1)c1cnc2c(C(F)(F)F)cccc2c1O
Reaction time: 18 h
Yield: 24.7 %

Procedure:
6.3 g of 4-hydroxy-8-trifluoromethyl-quinoline-3-carboxylic acid chloride were added with stirring under an inert gas to 90 ml of pyridine and a solution of 2.35 g of 2-imino-2,3,4,5-tetrahydrothiazole in 15 ml of pyridine were added thereto. The mixture was stirred for 18 hours and was evaporated to dryness. The 11.5 g of residue were taken up in 40 ml of a 10% potassium carbonate solution and the solution was extracted with ethyl acetate. The combined organic phases were chromatographed over silica gel and the product was eluted with a 9-1 benzene-ethanol mixture. The elute was dried and the product was crystallized from ethanol to obtain 1.93 g of N-(4,5-dihydro-2-thiazolyl)-4-hydroxy-8-trifluoromethyl-quinoline-3-carboxamide melting at 267°-268° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[O:12]CCO2)=[CH:4][C:3]=1[CH:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=1)O.[SH:29][CH2:30][C:31]([OH:33])=[O:32]>Cl>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:12])[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:4][C:3]=1[CH:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=1)[S:29][CH2:30][C:31]([OH:33])=[O:32]
Reactant: O=C(O)CS
Reactant: Nc1ccc(C2(c3ccc(Cl)cc3)OCCO2)cc1C(O)c1cccc(Cl)c1
Agent: Cl
Product: Nc1ccc(C(=O)c2ccc(Cl)cc2)cc1C(SCC(=O)O)c1cccc(Cl)c1
Temperature: 0 °C
Yield: 95.1 %

Procedure:
A mixture of intermediate (9) (0.088 mol) and mercapto-acetic acid (0.0836 mol) in HCl 6N (500 ml) was stirred and refluxed for 1 hour, then cooled and poured out into ice water. The precipitate was filtered off, washed with water and taken up in DCM. The organic solution was dried (MgSO4), filtered and the solvent was evaporated till dryness. The product was used without further purification, yielding 35.5 g (90.5%) of [[[2-amino-5-(4-chlorobenzoyl)phenyl](3-chlorophenyl)methyl]thio]-acetic acid (intermediate 19).