Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:10]O.CS(OS(C)(=O)=O)(=O)=O.CCN(C(C)C)C(C)C.[N:30]1([C:36]2[CH:43]=[CH:42][CH:41]=[CH:40][C:37]=2[C:38]#[N:39])[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>C(Cl)Cl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:10][N:33]1[CH2:32][CH2:31][N:30]([C:36]2[CH:43]=[CH:42][CH:41]=[CH:40][C:37]=2[C:38]#[N:39])[CH2:35][CH2:34]1
Reactant: OCc1cc2ccccc2s1
Reactant: N#Cc1ccccc1N1CCNCC1
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: N#Cc1ccccc1N1CCN(Cc2cc3ccccc3s2)CC1

Procedure:
The product from Example 8A (150 mg 0.9 mmol), methane sulfonic anhydride (159 mg, 0.9 mmol), and DIEA (475 μL 2.7 mmol) were combined. After stirring, 2-(1-piperazinyl)benzonitrile (181 mg, 1.0 mmol) in 2 ml DCM was also combined and stirred at room temperature for 18 hours. The mixture was concentrated and the residue was taken up in hot methanol. The methanol was filtered and the filter cake washed with cold methanol to provide the title compound. 1H NMR (300 MHz, CDCl3) δ 2.69 (m, 4H) 3.04 (s, 4H) 3.76 (m, 4H) 3.86 (s, 1H) 6.74 (m, 2H) 7.29 (m, 3H) 7.75 (m, 1H); (ESI) m/z 334 (M+H)+.
Reaction SMILES: C1(CC(Cl)=O)C=CC=CC=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][CH:17]=[C:16]2[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[C:28]([CH3:33])[C:27]=1[CH3:34].[C:35]1([CH2:41][C:42]([N:44]=[C:45]=[S:46])=[O:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C1(C)C=CC=CC=1.C(O)C>[C:35]1([CH2:41][C:42]([N:44]=[C:45]=[S:46])=[O:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][CH:17]=[C:16]2[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH:30][C:45]([NH:44][C:42](=[O:43])[CH2:41][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)=[S:46])=[C:28]([CH3:33])[C:27]=1[CH3:34]
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Agent: O=C(Cc1ccccc1)N=C=S
Agent: O=C(Cl)Cc1ccccc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)c(C)c3C)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
2-Phenylethanoyl isothiocyanate was prepared using commercially available 2-phenylethanoyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 2-phenylethanoyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (44 mg, yield 58%).
Reaction SMILES: [N:1]1([CH:10]([NH:14][C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[C:11](O)=[O:12])C2C=CC=CC=2N=N1.C(Cl)(=O)C(Cl)=O.[NH2:31][C:32]1[CH:37]=[C:36]([Br:38])[CH:35]=[CH:34][C:33]=1[C:39](=O)[CH3:40].CN1CCOCC1.C([O-])(=O)C.[NH4+].[OH-].[Na+]>C(Cl)Cl.O1CCCC1.CO.O.CN(C)C=O>[Br:38][C:36]1[CH:35]=[CH:34][C:33]2[C:39]([CH3:40])=[N:1][CH:10]([NH:14][C:15](=[O:16])[O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11](=[O:12])[NH:31][C:32]=2[CH:37]=1
Reactant: CC(=O)c1ccc(Br)cc1N
Reactant: O=C(NC(C(=O)O)n1nnc2ccccc21)OCc1ccccc1
Agent: CC(=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Agent: [NH4+]
Solvent: CN1CCOCC1
Solvent: CO
Solvent: O
Product: CC1=NC(NC(=O)OCc2ccccc2)C(=O)Nc2cc(Br)ccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 53.2 %

Procedure:
Under an argon atmosphere 1H-1,2,3-benzotriazol-1-yl{[(benzyloxy)carbonyl]amino}acetic acid (6.71 g, 20.6 mmol) was suspended in anhydrous methylene chloride (92 ml) and cooled to 0° C. in an ice bath. Oxalyl chloride (2.61 g, 20.6 mmol), then N,N-dimethylformamide (38 ml) were added dropwise to the suspension. The reaction mixture was stirred at 0° C. in an ice bath for 30 minutes, at which point no further gas evolution was noted. Then a solution of 1-(2-amino-4-bromophenyl)ethanone (4.0 g, 18.7 mmol) and 4-methylmorpholine (2.84 g, 28.0 mmol) in anhydrous methylene chloride (60 ml) was added dropwise. The reaction mixture was allowed to warm to room temperature over 12 hours, then quenched with water (200 ml), and extracted with ethyl acetate (3×250 ml). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated to give a semi-solid which was dissolved in tetrahydrofuran (120 ml) and methyl alcohol (35 ml). Ammonia gas was bubbled through this solution for 2.5 hours. The reaction was then concentrated to a viscous light brown oil. The oil was dissolved in acetic acid (120 ml) and ammonium acetate (4.3 g, 56.1 mmol) was added in one portion and stirred for 12 hours. The reaction mixture was diluted with water (100 ml) and then made basic (pH=10) with 25% sodium hydroxide, while stirring in an ice bath. The aqueous solution was then extracted with ethyl acetate (3×500 ml) and the organic layers combined, dried over magnesium sulfate, filtered and concentrated. The resulting residue was purified on silica gel, eluting with 40% ethyl acetate in hexanes to give the title compound (4 g, 53%). 1H NMR (CDCl3, 300 MHz): δ 9.90 (s-br, 1H), 7.42-7.31 (m, 6H), 7.12 (d, 1H, 1.5 Hz), 7.06-7.03 (m, 1H), 5.18-5.08 (m, 3H), 2.50 (s, 3H) ppm.
Reaction SMILES: FC(F)(F)S([O:6][Si:7]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9])(=O)=O.[F:19][C:20]1[CH:21]=[CH:22][C:23]2[N:24]([C:26]([N:29]3[CH2:34][CH2:33][C:32]([CH3:36])(O)[CH2:31][CH2:30]3)=[N:27][N:28]=2)[CH:25]=1.CCN(CC)CC>C(Cl)Cl>[F:19][C:20]1[CH:21]=[CH:22][C:23]2[N:24]([C:26]([N:29]3[CH2:34][CH2:33][C:32]([CH3:36])([O:6][Si:7]([CH:8]([CH3:9])[CH3:10])([CH:11]([CH3:12])[CH3:13])[CH:14]([CH3:15])[CH3:16])[CH2:31][CH2:30]3)=[N:27][N:28]=2)[CH:25]=1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: CC1(O)CCN(c2nnc3ccc(F)cn23)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)[Si](OC1(C)CCN(c2nnc3ccc(F)cn23)CC1)(C(C)C)C(C)C
Yield: 96.3 %

Procedure:
Triisopropylsilyl trifluoromethanesulfonate (550 mg, 1.81 mmol) was added to a solution of Intermediate 79c (150 mg, 0.60 mmol) and Et3N (242 mg, 2.40 mmol) in a DCM (5 mL) and the mixture stirred at reflux for 1 h. The reaction mixture was diluted with DCM (30 mL), washed with water (2×), brine, dried (MgSO4), and then concentrated in vacuo. The residue was purified by FCC, using 0-10% MeOH in DCM, to give the title compound (235 mg, 96%). 1H NMR (400 MHz, CDCl3): 1.00-1.20 (21H, m), 1.40 (3H, s), 1.76-1.93 (4H, m), 3.18-3.29 (2H, m), 3.44-3.58 (2H, m), 7.03-7.12 (1H, m), 7.58-7.69 (2H, m).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:14]C[CH2:12][N:11]3[C:15](=[O:25])[CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:18]=[C:10]23)[CH:6]=[CH:5][N:4]=1.C1(C2C=C3NCCN3C(=O)C=2)C=CC=CC=1.CC(C)([O-])C.[Na+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.ClC1C=CN=C(SC)N=1>C1(C)C=CC=CC=1>[CH3:1][S:2][C:3]1[N:8]=[C:7]([N:9]2[C:10]3=[CH:18][C:17]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)=[CH:16][C:15](=[O:25])[N:11]3[CH2:12][CH2:14]2)[CH:6]=[CH:5][N:4]=1
Reactant: CSc1nccc(N2CCCn3c2cc(-c2ccccc2)cc3=O)n1
Agent: CC(C)(C)[O-]
Agent: CSc1nccc(Cl)n1
Agent: O=c1cc(-c2ccccc2)cc2n1CCN2
Solvent: Cc1ccccc1
Product: CSc1nccc(N2CCn3c2cc(-c2ccccc2)cc3=O)n1

Procedure:
Following the procedure described for the synthesis of 1-(2-methylsulfanyl-pyrimidin -4-yl)-8-phenyl-1,2,3,4-tetrahydro-pyrido[1,2-a]pyrimidin-6-one, but using 7-phenyl-2,3-dihydro-1H-imidazo[1,2-a]pyridin-5-one (1 g, 4.7 mmol), sodium tert-butoxide (1.26 g, 13.16 mmol), BINAP (0.43 g, 0.7 mmol), Pd (OAc)2 (0.16 g, 0.7 mmol), toluene (20 mL) and 4-chloro-2-methylthiopyrimidine (0.66 mL, 0.56 mmol). The title compound was isolated as a yellow solid. MS m/e 337 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5](=O)[C:6]2[C:14]=1[C:13]1[C:8](=[CH:9][CH:10]=[CH:11][C:12]=1[CH3:15])[CH:7]=2.CO.C(OCC)(=O)C.[H][H]>[OH-].[Pd+2].[OH-].C(OCC)(=O)C.CCCCCC.C(O)(=O)C>[CH3:15][C:12]1[C:13]2[C:14]3[C:6](=[CH:5][CH:4]=[CH:3][C:2]=3[CH3:1])[CH2:7][C:8]=2[CH:9]=[CH:10][CH:11]=1
Reactant: CC1=C2C(=Cc3cccc(C)c32)C(=O)C=C1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CCCCCC
Solvent: CC(=O)O
Product: Cc1cccc2c1-c1c(C)cccc1C2
Yield: 91 %

Procedure:
A mixture of 4,5-dimethylfluorenone (7.0 g, 32.8 mmol), methanol (100 mL), ethyl acetate (50 mL), acetic acid (20 mL) and palladium hydroxide (20% on carbon, water content 44.43%, 1.0 g) was hydrogenated in a shaker at 35-40psi of hydrogen for 3.5 hr. The reaction was monitored by TLC (silica, 10% ethyl acetate/hexane). The catalyst was filtered off and the solvent was removed in vacuum, the residue was diluted with water (150 mL). The product was extracted with ethyl acetate (3×50 mL) and dried over magnesium sulfate. Evaporation of the solvent afforded 5.8 g (91.2%) of 4,5-dimethylfluorene.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:27]=[CH:26][C:17]([C:18]([NH:20][CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH2:28])[CH2:6][C@@H:5]1[CH3:29])(=[O:3])[CH3:2].Br[C:31]1[N:36]=[CH:35][CH:34]=[CH:33][N:32]=1.CC(C)([O-])C.[Na+].CN(C)C1C=CC=CC=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.[ClH:71]>O1CCOCC1.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]>[ClH:71].[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:27]=[CH:26][C:17]([C:18]([NH:20][CH2:21][CH2:22][N:23]([CH3:24])[CH3:25])=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:28][C:31]2[N:36]=[CH:35][CH:34]=[CH:33][N:32]=2)[CH2:6][C@@H:5]1[CH3:29])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(-c3ccc(C(=O)NCCN(C)C)cc3)cc2[C@H](N)C[C@@H]1C
Reactant: Brc1ncccn1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)NCCN(C)C)cc3)cc2[C@H](Nc2ncccn2)C[C@@H]1C
Temperature: 100 °C
Yield: 36.5 %

Procedure:
To a flask charged with 4-((2S,4R)-1-acetyl-4-amino-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-N-(2-(dimethylamino)ethyl)benzamide (for a preparation see Intermediate 32) (197 mg, 0.5 mmol), 2-bromopyrimidine (238 mg, 1.500 mmol), sodium tert-butoxide (240 mg, 2.500 mmol), 2-(dimethylamino)-2′-(dicyclohexylphosphino)biphenyl (197 mg, 0.500 mmol) and tris(dibenzylideneacetone)dipalladium(0) (229 mg, 0.250 mmol) was added degassed toluene (4 mL) and the resulting mixture was stirred under nitrogen at 100° C. After 2 h the mixture was cooled to room temperature and most of the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and saturated NaHCO3 solution and the layers were separated. The aqueous phase was extracted with EtOAc and the combined organic phases were washed with saturated aqueous NaHCO3 (×3), dried over MgSO4 and concentrated in vacuo. The residue was dissolved in DCM and loaded on a SCX column (20 g). The cartridge was eluted with DCM then ammonia in MeOH (2N). The methanolic ammonia fractions were concentrated in vacuo and further purified on by chromatography (25 g column, elution with 2N ammonia in MeOH/DCM gradient) to give a residue which was dissolved in 1,4-dioxane (4 ml) and the solution treated with hydrogen chloride in 1,4-dioxane (4N, 0.5 mL). The precipitate which formed was isolated by filtration and dried at 60° C. under vacuum for 2 h to give 4-((2S,4R)-1-acetyl-2-methyl-4-(pyrimidin-2-ylamino)-1,2,3,4-tetrahydroquinolin-6-yl)-N-(2-(dimethylamino)ethyl)benzamide, hydrochloride (93 mg, 0.183 mmol, 36.5% yield) as a pale yellow solid. LCMS (HpH, 2 min), Rt=0.79 min, MH+=473.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:12]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH:22]=2)([CH3:20])[CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].OC1[CH2:38][C:37](C)([CH3:39])[NH:36][C:35]([CH3:42])([CH3:41])[CH2:34]1.C([Sn](=O)CCCC)CCC.C(O)C>C1(C)C(C)=CC=CC=1>[C:28]([C:23]1[CH:22]=[C:21]([C:12]([C:7]2[CH:8]=[CH:9][C:10]([OH:11])=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH:6]=2)([CH3:20])[CH2:13][CH2:14][C:15]([O:17][CH:18]2[CH2:34][C:35]([CH3:42])([CH3:41])[NH:36][C:37]([CH3:39])([CH3:38])[CH2:19]2)=[O:16])[CH:26]=[CH:25][C:24]=1[OH:27])([CH3:30])([CH3:29])[CH3:31]
Reactant: CCOC(=O)CCC(C)(c1ccc(O)c(C(C)(C)C)c1)c1ccc(O)c(C(C)(C)C)c1
Reactant: CC1(C)CC(O)CC(C)(C)N1
Agent: CCCC[Sn](=O)CCCC
Solvent: CCO
Solvent: Cc1ccccc1C
Product: CC1(C)CC(OC(=O)CCC(C)(c2ccc(O)c(C(C)(C)C)c2)c2ccc(O)c(C(C)(C)C)c2)CC(C)(C)N1
Temperature: 25 °C

Procedure:
8.5 g (0.02 mol) of ethyl 4,4-bis-(3-tert.-butyl-4-hydroxyphenyl)-valerate and 3.1 g (0.02 mol) of 4-hydroxy-2,2,6,6-tetramethylpiperidine are dissolved in 200 ml of xylene. 0.1 g of dibutyltin oxide is added, and the mixture is heated at the boil under nitrogen for about 6 hours, during which the resulting ethanol is distilled off continuously. When no more ethanol distils off, the reaction solution is cooled down to room temperature, is admixed with 200 ml of water and is efficiently mixed. The organic phase is separated off, is dried over magnesium sulfate and is evaporated. The resulting oil is purified by column chromatography to give 2,2,6,6-tetramethylpiperidin-4-yl 4,4-bis-(3-tert.-butyl-4-hydroxyphenyl)-valerate in the form of a colourless solid having a melting point of 100°.
Reaction SMILES: O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.C1C=[N+]([C@@H]2O[C@H](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](OP(O)(O)=O)[C@@H]3O)(O)=O)(O)=O)[C@@H](O)[C@H]2O)C=C(C(N)=O)C=1.[Cl:61][CH2:62][C:63](=[O:80])[C@@H:64]([NH:72][C:73]([O:75][C:76]([CH3:79])([CH3:78])[CH3:77])=[O:74])[CH2:65][C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:61][CH2:62][C@H:63]([OH:80])[C@@H:64]([NH:72][C:73]([O:75][C:76]([CH3:78])([CH3:77])[CH3:79])=[O:74])[CH2:65][C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)CCl
Agent: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CCl
Temperature: 30 °C
Reaction time: 40 h
Yield: 99.1 %

Procedure:
Glucose 3 g, NADP 3 mg, toluene 0.25 ml, and (3S)-1-chloro-3-tert-butoxycarbonylamino-4-phenyl-2-butanone 2.5 g were added to 25 ml of a cultured medium of E. coli HB101 (pNTOM4G1) prepared in the same manner as in Example 7, and the mixture was stirred at 30° C. for 40 hr while adjusting to pH 6.5 by dropwise addition of 5 M sodium hydroxide. After completion of the reaction, the reaction mixture was extracted with toluene, desolvated and the extract was analyzed in the same manner as in Example 8. As a result, (2R,3S)-1-chloro-3-tert-butoxycarbonylamino-4-phenyl-2-butanol (yield 99.1%, diastereomeric excess 99.8% d.e.) was obtained.
Reaction SMILES: [CH3:1][Si:2]([CH3:7])([CH3:6])[C:3]#[C:4][CH3:5].[Li]CCCC.CCCCCC.Cl[CH2:20][CH:21]1[CH2:23][O:22]1>C1COCC1>[CH3:1][Si:2]([CH3:7])([CH3:6])[C:3]#[C:4][CH2:5][CH2:20][CH:21]1[CH2:23][O:22]1
Reactant: ClCC1CO1
Reactant: CC#C[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C[Si](C)(C)C#CCCC1CO1
Temperature: -75 °C
Yield: 102 %

Procedure:
To a stirred solution of trimethyl(prop-1-ynyl)silane (3 g, 26.7 mmol) in dry THF (100 mL) cooled at −72° C., was added drop by drop 2.5 N nBuLi in hexane solution (10.5 mL, 26.2 mmol). The resulting mixture was stirred at −75° C. for 1 h30. Then 2-(chloromethyl)oxirane (2.42 g, 26.2 mmol) in dry THF (2 mL) was slowly added. The resulting mixture was stirred at −72° C. for 1 h30, then warmed up to room temperature for an additional 1 h. The reaction mixture was quenched with water and extracted with diethyl ether. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure to afford 4.50 g trimethyl(4-(oxiran-2-yl)but-1-ynyl)silane (Yield: 100%) as a yellow oil which was used in the next step without further purification.
Reaction SMILES: [CH:1]([C:4]1[S:5][C:6]([C:9](OCC)=[O:10])=[CH:7][N:8]=1)([CH3:3])[CH3:2].CO>C(Cl)(Cl)Cl>[OH:10][CH2:9][C:6]1[S:5][C:4]([CH:1]([CH3:3])[CH3:2])=[N:8][CH:7]=1
Reactant: CCOC(=O)c1cnc(C(C)C)s1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(C)c1ncc(CO)s1
Yield: 25 %

Procedure:
Using the procedure of Example 5B, but replacing ethyl 2-isopropyl-4-thiazolecarboxylate with ethyl 2-isopropylthiazole-5-carboxylate provided, after silica gel chromatography using 3% methanol in chloroform, the desired compound, Rf 0.3, (5% methanol in chloroform) in 25% yield. 1H NMR (d6 -DMSO) δ 1.30 (d, J=7 Hz, 6H), 3.22 (heptet, J=7 Hz, 1H), 4.61 (dd, J=6, 1 Hz, 2H), 5.45 (t, J=6 Hz, 1H), 7.48 (br s, 1H).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]([CH2:7][C:8]1[CH:33]=[CH:32][C:11]([C:12]([NH:14][C:15]2[S:16][C:17]3[C:23]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[CH:22][CH:21]=[C:20]([O:30][CH3:31])[C:18]=3[N:19]=2)=[O:13])=[CH:10][CH:9]=1)[CH3:6])=[O:4].[NH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1>>[CH3:31][O:30][C:20]1[C:18]2[N:19]=[C:15]([NH:14][C:12](=[O:13])[C:11]3[CH:32]=[CH:33][C:8]([CH2:7][N:5]([CH3:6])[C:3](=[O:4])[CH2:2][N:34]4[CH2:38][CH2:37][CH2:36][CH2:35]4)=[CH:9][CH:10]=3)[S:16][C:17]=2[C:23]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:22][CH:21]=1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccc(CN(C)C(=O)CCl)cc3)nc12
Reactant: C1CCNC1
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccc(CN(C)C(=O)CN4CCCC4)cc3)nc12

Procedure:
Using 4-[(Chloroacetyl-methyl-amino)-methyl]-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-benzamide and pyrrolidine the title compound was obtained as white crystals (61% yield), mp 114-116° C.). MS: m/e=524 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([F:12])[CH:4]=1)#[N:2].[C:13](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O.O>CC(C)=O>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:9][CH3:13])=[O:8])=[C:5]([F:12])[CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C(=O)O)c(F)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)c1ccc(C#N)cc1F

Procedure:
13.20 g (79.9 mmol) of 4-cyano-2-fluorobenzoic acid are dissolved in 300 ml of acetone. Then 22.10 g (159.9 mmol) of potassium carbonate and 9.08 ml (95.9 mmol) of dimethyl sulfate are successively added. The mixture is stirred at reflux temperature for 20 h. The reaction mixture is then mixed with 300 ml of water and the acetone is removed in a rotary evaporator. Several extractions with dichloromethane are carried out. The combined organic phases are washed with saturated sodium chloride solution and dried over sodium sulfate. The solvent is then removed in vacuo. The remaining solid is used further without further purification. 16.1 g (84% of theory) of the title compound are obtained as a colorless solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[Cl:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C(#N)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:11][C:12]1[CH:17]=[C:16]([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=2)[C:7]([OH:9])=[O:8])[CH:15]=[CH:14][CH:13]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: O=C(O)c1cncc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=C(O)c1cncc(-c2cccc(Cl)c2)c1
Temperature: 25 °C

Procedure:
A three neck flask was charged with 5-bromonicotinic acid (2 g, 9.90 mmol), 3-chlorophenylboronic acid (1.55 g, 9.90 mmol), a 0.4 M solution of sodiumcarbonate in water (37 mL, 14.8 mmol) and Acetonitrile (37 mL). The solution was degassed under vacuum and tetrakistriphenylphoshine Pd(0) (0.57 g, 0.495 mmol) was added and the reaction refluxed overnight under nitrogen. The reaction was cooled to room temperature and filtered through a celite pad. The filtrate was partially evaporated under reduced pressure and the remaining solution acidified to pH=2 with 1N HCl. The resulting solid was collected by filtration and dried under vacuum. 1H NMR [(CD3)2SO]: δ 9.15-9.05 (m, 2H), 8.45 (s, 1H), 7.85 (s, 1H), 7.80-7.65 (m, 1H), 7.60-7.42 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:6][C:5]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:4][C:3]=1[N:16]1[N+:20]([O-])=[C:19]2[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:18]2=[N:17]1.C1(C)C=CC=CC=1.N12CCCCC1CNCC=C2.[H][H]>[Ni].CC(O)CC>[OH:1][C:2]1[C:7]([C:8]([CH3:10])([CH3:11])[CH3:9])=[CH:6][C:5]([C:12]([CH3:13])([CH3:14])[CH3:15])=[CH:4][C:3]=1[N:16]1[N:20]=[C:19]2[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:18]2=[N:17]1
Reactant: [H][H]
Reactant: CC(C)(C)c1cc(-n2nc3cc(Cl)ccc3[n+]2[O-])c(O)c(C(C)(C)C)c1
Agent: [Ni]
Agent: C1=CN2CCCCC2CNC1
Solvent: CCC(C)O
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(-n2nc3ccc(Cl)cc3n2)c(O)c(C(C)(C)C)c1
Yield: 78.8 %

Procedure:
37.4 g (0.1 mol) of 2-(2'-hydroxy-3',5'-di-t-butylphenyl)-5-chlorobenzotriazole-N-oxide, 0.25 g of Raney nickel catalyst, 150 ml of toluene, 100 ml of 2-butanol and 0.5 g of 1,5-diazabicyclo[5.4.0]undecene were charged into a 500-ml stainless autoclave equipped with an agitator. After the air in the autoclave had been replaced by nitrogen, hydrogen was charged to a pressure of 8 kg/cm2. The temperature of the resultant mixture was increased to 60° C. under agitation, and reaction was been effected while agitation being continued until no hydrogen gas was absorbed by the mixture. After the reaction had been completed, after treatment was performed in the same way as that employed in Example 9 to obtain 28.2 g of 2-(2'-hydroxy-3',5'-di-t-butylphenyl)-5-chlorobenzotriazole as a target substance (yield, 79%; melting point, 153° to 155° C.).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:12](O)[CH2:13][OH:14].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH2:1]([O:8][CH2:9][CH:10]1[O:14][CH2:13][CH2:12][O:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCO
Reactant: O=CCOCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: c1ccc(COCC2OCCO2)cc1
Temperature: 140 °C
Reaction time: 2 h
Yield: 77.5 %

Procedure:
A mixture of benzyloxyacetaldehyde (3 g, 20 mmol), ethylene glycol (1.23 ml, 22 mmol), p-toluenesulfonic acid monohydrate (344 mg, 1.8 mmol), and toluene (15 ml) was stirred at 140° C. for 2 hours and further stirred at 150° C. for 3 hours. After cooled on ice, a 2N aqueous sodium hydroxide solution and ethyl acetate were added to the reaction mixture. An organic layer was separated, washed with water (three times) and a saturated saline solution. The organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography (NH silica gel, elution solvent: heptane/ethyl acetate=1/0 to 9/1 gradient). Desired fractions were concentrated to obtain the title compound (3.01 g, 77.5% yield) as a light yellow oil.