Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.O.[C:3]1([CH:11]=[C:9]([OH:10])[CH:8]=[C:6]([OH:7])[CH:5]=1)[OH:4].[CH2:12]([CH:19]([C:25]([CH3:27])=O)[C:20](OCC)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>C(O)C>[CH2:12]([C:19]1[C:20](=[O:21])[O:4][C:3]2[CH:11]=[C:9]([OH:10])[CH:8]=[C:6]([OH:7])[C:5]=2[C:25]=1[CH3:27])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Oc1cc(O)cc(O)c1
Reactant: CCOC(=O)C(Cc1ccccc1)C(C)=O
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1c(Cc2ccccc2)c(=O)oc2cc(O)cc(O)c12

Procedure:
A solution of phloroglucinol dihydrate (20 g) and ethyl 2-benzylacetoacetate (27.5 ml) in ethanol (320 ml) was treated with dry HCl at 0° C. for five hours and the solution was kept at that temperature overnight. The yellow solution was concentrated and triturated with water, the solids filtered, washed with water and dried. The resulting hydrate was thrice evaporated to dryness from toluene, triturated with petroleum ether (bp. 40-60° C.) and filtered. Yield 33,4 g (96%). Melting point 258-260° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]([C:15]([O:17]CCC#N)=[O:16])=[C:13]([CH3:22])[N:12]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)[C:11](=[S:33])[NH:10]2)=[CH:5][CH:4]=1)#[N:2].N12CCCN=C1CCCCC2>O1CCOCC1.Cl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[C:14]([C:15]([OH:17])=[O:16])=[C:13]([CH3:22])[N:12]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)[C:11](=[S:33])[NH:10]2)=[CH:7][CH:8]=1)#[N:2]
Reactant: CC1=C(C(=O)OCCC#N)C(c2ccc(C#N)cc2)NC(=S)N1c1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: CC1=C(C(=O)O)C(c2ccc(C#N)cc2)NC(=S)N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-Cyanoethyl 4-(4-cyanophenyl)-6-methyl-2-thioxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate (Example 16; 47 mg, 0.1 mmol) is dissolved in 0.5 ml dioxane. After addition of 1,8-diazabicyclo[5.4.0]undec-7-ene (15 μl, 15 mg, 0.1 mmol), the reaction mixture is stirred at room temperature for 3 hours. The reaction mixture is diluted with 1 N hydrochloric acid and extracted with ethyl acetate. After drying with magnesium sulfate and evaporating off the solvent the residue is purified by preparative HPLC (column: Nucleosil 100-5 C 18 Nautilus 20 mm×50 mm, 5 μm; solvent A: acetonitrile, solvent B: water+0.1% formic acid; flow rate: 25 ml/min; gradient: 0 min 10% A, 2 min 10% A, 6 min 90% A, 7 min 90% A, 7.1 min 10% A, 8 min 10% A; wavelength: 220 nm; injection volume: approx. 550 μl; number of injections: 1). The product containing fractions are combined and concentrated in vacuo.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[N:11][C:12]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)(=[O:18])=[O:17])=[CH:13][CH:14]=2)=[CH:4][C:3]=1[NH:26][C:27]([C:29]1[N:33]([CH3:34])[N:32]=[C:31]([CH3:35])[CH:30]=1)=[O:28].C(N(CC)C(C)C)(C)C.I[CH2:46][C:47]([NH2:49])=[O:48]>CN(C)C=O>[NH2:49][C:47](=[O:48])[CH2:46][N:11]1[C:12](=[N:15][S:16]([C:19]2[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:13]=[CH:14][C:9]([O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([NH:26][C:27]([C:29]3[N:33]([CH3:34])[N:32]=[C:31]([CH3:35])[CH:30]=3)=[O:28])[CH:4]=2)=[CH:10]1
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(Oc3ccc(Cl)c(NC(=O)c4cc(C)nn4C)c3)cn2)cc1
Reactant: NC(=O)CI
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)N=c2ccc(Oc3ccc(Cl)c(NC(=O)c4cc(C)nn4C)c3)cn2CC(N)=O)cc1
Yield: 75.4 %

Procedure:
In the same manner as in Reference Example 5 and using N-{2-chloro-5-[(6-{[(4-methylphenyl)sulfonyl]amino}pyridin-3-yl)oxy]phenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide (364 mg, 0.711 mmol), N,N-diisopropylethylamine (161 μl, 0.924 mmol), iodoacetamide (171 mg, 0.924 mmol) and N,N-dimethylformamide (5 mL) as starting materials, the title compound (305 mg, 75%) was obtained as a white solid.
Reaction SMILES: [OH:1][C:2]([CH3:8])([CH2:6][OH:7])[C:3](=[O:5])[CH3:4].[CH3:9][C:10]([CH3:12])=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCCC(C)C>[CH3:9][C:10]1([CH3:12])[O:1][C:2]([C:3](=[O:5])[CH3:4])([CH3:8])[CH2:6][O:7]1
Reactant: CC(C)=O
Reactant: CC(=O)C(C)(O)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCC(C)C
Solvent: O
Product: CC(=O)C1(C)COC(C)(C)O1
Yield: 92 %

Procedure:
A mixture of 3,4-dihydroxy-3-methylbutan-2-one (4.13 g, 35 mmol), acetone (25 ml) and p-toluenesulfonic acid monohydrate (33 mg, 0.18 mmol) in isohexane (75 ml) was heated in a Dean-Stark apparatus for 10 h. The solvent was removed by distillation at atmospheric pressure and the residue purified by chromatography on silica gel. Elution with 50% ether in isohexane afforded 1-(2,2,4-trimethyl-[1,3]dioxolan-4-yl)ethanone as a pale yellow liquid (5.1 g, 92%): δH (360 MHz, d6-DMSO) 1.29 (3H, s), 1.34 (3H, s), 1.36 (3H, s), 2.20 (3H, s), 3.69 (1H, d, J 9), 4.18 (1H, d, J 9).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[NH:6][C:7](S(C)=O)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1>ClC1C=C(C)C=CC=1>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[NH:6][C:7]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1
Reactant: CS(=O)C1=NS(=O)(=O)c2cc(Cl)ccc2N1
Reactant: Nc1ccccn1
Solvent: Cc1cccc(Cl)c1
Product: O=S1(=O)N=C(Nc2ccccn2)Nc2ccc(Cl)cc21

Procedure:
7-Chloro-3-methylsulfinyl-4H-1,2,4-benzothiadiazine 1,1-dioxide (0.25 g) and 2-aminopyridine (0.25 g) in 3-chlorotoluene (5 mL) was heated at 150° C. for 1 h. After cooling, the white precipitate was collected by filtration and washed with diethylether. The insoluble material was dissolved in 1M NaOH (20 mL), treated with charcoal, filtered, and the filtrate was adjusted to pH 3 with 6N HCl. The precipitate was collected by filtration, washed with water, dissolved in hot DMF (15 mL), mixed with an equal volume of distilled water and cooled. The white precipitate was collected by filtration, washed with water and dried (yield: 0.12 g); m.p. >310° C.
Reaction SMILES: [OH-:1].[Na+].[Cl:3][C:4]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:5]=1[CH2:6]Cl>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)(=O)C>[Cl:3][C:4]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:5]=1[CH2:6][OH:1]
Reactant: [OH-]
Reactant: ClCc1ccc(Cl)cc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)O
Product: OCc1ccc(Cl)cc1Cl
Reaction time: 7 h
Yield: 95 %

Procedure:
Aqueous sodium hydroxide (36 ml. of 70% w/v solution) was added slowly with stirring to glacial acetic acid (39 g). The solution was then heated to reflux and a mixture of 2,4-dichlorobenzyl chloride (100 g) and tetrabutylammonium iodide (1 g) added. The mixture was heated under reflux with stirring for 7 hours. The mixture was then treated with aqueous sodium hydroxide and worked up as described in Example 1 to give 2,4-dichlorobenzyl alcohol, having a purity of 98.5% in a yield of 95.0%.
Reaction SMILES: [NH:1]([CH2:6][C:7]([OH:9])=[O:8])[CH2:2][C:3]([OH:5])=[O:4].[CH2:10](O)[CH:11]=[CH2:12].[C:14]1(C)[CH:19]=CC(S(O)(=O)=O)=C[CH:15]=1>C1C=CC=CC=1>[C:3]([O:5][CH2:19][CH:14]=[CH2:15])(=[O:4])[CH2:2][NH:1][CH2:6][C:7]([O:9][CH2:10][CH:11]=[CH2:12])=[O:8]
Reactant: O=C(O)CNCC(=O)O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: C=CCO
Solvent: c1ccccc1
Product: C=CCOC(=O)CNCC(=O)OCC=C
Temperature: 25 °C
Yield: 170.8 %

Procedure:
A solution of iminodiacetic acid 8 (3.0 g, 22.54 mmol), allyl alcohol (18.43 mL, 270 mmol) and p-toluenesulfonic acid (8.57 g, 45.0 mmol) in benzene (60 mL) was heated at reflux with a Dean-Stark distilling trap for 16 h. The mixture was cooled to room temperature and the solvent was evaporated in vacuo. The residue was crystallized from diethyl ether and dried in vacuo to give the compound 9 (8.21 g, 94.6%). 1H NMR (400 MHz, CDCl3) δ 2.34 (s, 3H), 4.17 (s, 4H), 4.61 (d, J=6.2, 4H), 5.24 (d, J=11.7, 2H), 5.31 (d, J=17.2, 2H), 5.82 (m, 2H), 7.15 (d, J=7.8, 2H), 7.68 (d, J=8.2, 2H).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][NH:13][CH2:14][CH2:15][CH2:16][NH2:17].[OH2:18]>CN(C)C=O>[CH3:12][N:13]([CH2:14][CH2:15][CH2:16][NH:17][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:8])=[O:18])[S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O
Reactant: CNCCCN
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)NCCCN(C)S(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 79 %

Procedure:
--A freshly prepared solution of p-toluenesulfonyl chloride (90.8 g, 0.476 mole) in N,N-dimethylformamide (200 ml) is added during 45 min. with moderate external cooling to a stirred solution of N-methyl-1,3-propanediamine (41.9 g, 0.476 mole) in N,N-dimethylformamide (150 ml) at such a rate that the temperature does not exceed 40° C. The mixture is stirred 45 min. longer at room temperature and then poured into cold water (1.2 1.). The white gum that precipitated, solidifies on standing. The crude product is collected, pulverized, and washed thoroughly with water. Recrystallization from ethanol affords the pure product, m.p. 93° C. (Kofler Heizbank), in 79% yield (74.4 g).
Reaction SMILES: [NH2:1][CH:2]([C:5]1([CH2:10][CH2:11][CH3:12])[CH2:9][CH:8]=[CH:7][CH2:6]1)[CH2:3][CH3:4].B.[OH:14]O.[OH-].[Na+]>C1COCC1.O>[NH2:1][CH:2]([C:5]1([CH2:10][CH2:11][CH3:12])[CH2:9][CH2:8][CH:7]([OH:14])[CH2:6]1)[CH2:3][CH3:4]
Reactant: CCCC1(C(N)CC)CC=CC1
Reactant: OO
Agent: B
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCC1(C(N)CC)CCC(O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(1-aminopropyl)-1-propylcyclopent-3-ene (63, 1.4 g, 8.25 mmol) was dissolved in THF (15 mL) at 0° C. under argon. Borane (9.1 mL, 9.07 mmol, 1M in THF) was added dropwise over 10 minutes. The reaction mixture was allowed to warm to room temperature before stirring overnight. After cooling to 0° C., water was added (4 mL), followed by hydrogen peroxide (5.8 mL, 30% solution in water) and sodium hydroxide solution (9.1 mL, 1M aqueous solution). After stirring for 5 minutes the mixture was extracted with ethyl acetate, dried over sodium sulphate and evaporated to give 1.54 g of desired product as a mixture of isomers. Rt=0.81, 0.84, 0.88 min (Method M). Detected mass: 186.2 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH:7]=1.Cl[C:20]1[CH2:25][CH2:24][C:23]([C:26]([O:28]CC)=[O:27])=[C:22]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:21]=1.C[O-].[Na+]>CO>[C:13]1([C:4]2[CH:3]=[CH:2][CH:7]=[CH:6][C:5]=2[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1.[C:31]1([C:22]2[CH:21]=[CH:20][CH:25]=[CH:24][C:23]=2[C:26]([OH:28])=[O:27])[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CCOC(=O)C1=C(c2ccccc2)C=C(Cl)CC1
Reactant: CCOC(=O)C1CC=C(Cl)C=C1c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)c1ccccc1-c1ccccc1
Product: O=C(O)c1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 53.8 %
Yield: 23.7 %

Procedure:
To a stirred solution of a mixture(620 mg, 2.54 mmol) of ethyl 4-chloro-2-phenylcyclohexa-2,4-dienecarboxylate and ethyl 4-chloro-2-phenylcyclohexa-1,3-dienecarboxylate in MeOH(5 ml), NaOMe(28% in MeOH, 1.98 g, 10.1 mmol) was added. After stirring for 17 hr at room temperature, the solvent was evaporated under reduced pressure. Water was added to the residue and dil. HCl aq., and it was extracted with AcOEt. The organic layer was washed with brine and dried over MgSO4. After removal of the solvent, the residue was purified by column chromatography on silica gel with n-hexane-AcOEt to afford 136 mg of ethyl 2-phenylbenzoate(y=23.7%) and 236 mg of 2-phenylbenzoic acid(y=53.8%). 1H-NMR(ppm, 300 MHz, CDCl3) δ ester 7.82(1H, dd, J=1.4 and 7.7 Hz), 7.10-7.60(8H), 4.08(2H, d, J=7.0 Hz), 0.98(3H, t, J=7.0 Hz); acid 7.95(1H, d, J=7.9 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.O[CH:12]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:24]=[C:25]([NH:29][C:30](=[O:34])[CH:31]([CH3:33])[CH3:32])[CH:26]=[CH:27][CH:28]=2)[CH2:19][CH2:18]1>>[C:8]([C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[O:1][CH:12]([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:24]=[C:25]([NH:29][C:30](=[O:34])[CH:31]([CH3:33])[CH3:32])[CH:26]=[CH:27][CH:28]=2)[CH2:19][CH2:18]1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1cccc(O)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(O)c3ccccc3)CC2)c1
Product: CC(=O)c1cccc(OC(CCCCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccccc2)c1

Procedure:
Prepared by Procedure A and Scheme AN using 1-(3-hydroxyphenyl)ethanone and N-{3-[1-(5-hydroxy-5-phenylpentyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 526.9 (M+H)+.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[NH2:11][C:12]1[C:13]([C:30]#[C:31][C:32]2[CH:33]=[C:34]([OH:38])[CH:35]=[CH:36][CH:37]=2)=[N:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH:27]([CH3:29])[CH3:28])(=[O:26])=[O:25])=[CH:20][CH:19]=2)=[CH:16][N:17]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH:27]([S:24]([C:21]1[CH:20]=[CH:19][C:18]([C:15]2[N:14]=[C:13]([C:30]#[C:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH2:3][CH2:4][N:5]4[CH2:10][CH2:9][O:8][CH2:7][CH2:6]4)[CH:33]=3)[C:12]([NH2:11])=[N:17][CH:16]=2)=[CH:23][CH:22]=1)(=[O:25])=[O:26])([CH3:29])[CH3:28]
Reactant: ClCCN1CCOCC1
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(C#Cc3cccc(O)c3)n2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(C#Cc3cccc(OCCN4CCOCC4)c3)n2)cc1
Temperature: 65 °C
Reaction time: 0.08 h
Yield: 50 %

Procedure:
4-(2-Chloroethyl)morpholine hydrochloride (31.93 mg, 0.1716 mmol) was added to a stirred solution of 3-[2-[3-amino-6-(4-isopropylsulfonylphenyl)pyrazin-2-yl]ethynyl]phenol (45 mg, 0.1144 mmol) and K2CO3 (39.53 mg, 0.2860 mmol) in DMF (1 mL) and the reaction mixture warmed to 65° C. for 16 hours. The reaction mixture was partitioned between DCM and saturated aqueous NaHCO3 and stirred for 5 minutes. The layers were separated by filtration through a phase separation cartridge and the aqueous layer retained was washed with DCM (×2). The combined organic extracts were passed through a 5 g SCX-2 cartridge and washed with MeOH. The product was eluted by washing the cartridge with 2M NH3 in MeOH. The solvent was removed in vacuo and the material was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 μM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected and freeze-dried to give the mono-TFA salt of the title compound as a yellow solid (29 mg, 41% Yield). 1H NMR (400.0 MHz, DMSO) δ 1.09 (d, 6H), 3.22-3.25 (m, 2H), 3.41-3.74 (m, 7H), 4.01 (d, 2H), 4.43 (s, 2H), 6.98 (s, 2H), 7.14 (d, 1H), 7.41-7.48 (m, 3H), 7.92 (d, 2H), 8.23 (d, 2H), 8.78 (s, 1H) and 9.88 (s, 1H) ppm; (ES+) 507.3.
Reaction SMILES: [H-].[Na+].C1COCC1.C(OCC)(=O)CC(OCC)=O.[CH3:19][C:20]1[C:21](/[CH:34]=[CH:35]/[C:36]([O:38][C:39]2[CH:50]=[CH:49][CH:48]=[CH:47][C:40]=2[C:41]([O:43]CC=C)=[O:42])=[O:37])=[CH:22][C:23]2[C:24]([CH3:33])([CH3:32])[CH2:25][CH2:26][C:27]([CH3:31])([CH3:30])[C:28]=2[CH:29]=1>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.O>[CH3:19][C:20]1[C:21](/[CH:34]=[CH:35]/[C:36]([O:38][C:39]2[CH:50]=[CH:49][CH:48]=[CH:47][C:40]=2[C:41]([OH:43])=[O:42])=[O:37])=[CH:22][C:23]2[C:24]([CH3:33])([CH3:32])[CH2:25][CH2:26][C:27]([CH3:30])([CH3:31])[C:28]=2[CH:29]=1
Reactant: C=CCOC(=O)c1ccccc1OC(=O)/C=C/c1cc2c(cc1C)C(C)(C)CCC2(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(=O)CC(=O)OCC
Solvent: C1CCOC1
Product: Cc1cc2c(cc1/C=C/C(=O)Oc1ccccc1C(=O)O)C(C)(C)CCC2(C)C

Procedure:
117 mg (4.9 mmol) of sodium hydride (80% in oil) and 15 ml of THF are introduced into a round-bottomed flask under a stream of nitrogen. 540 μl (3.6 mmol) of diethyl malonate are then added dropwise and the mixture is stirred until the evolution of gas has ceased. This solution is introduced dropwise into a mixture of 1.4 g (3.24 mmol) of allyl (E)-2-[3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)acryloyloxy]benzoate, 20 ml of THF and 187 mg of tetrakis(triphenylphosphine)palladium(0) and stirred at room temperature for three hours. The reaction medium is poured into water and extracted with ethyl ether, and the organic phase is separated out after settling has taken place, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with a mixture of heptane and ethyl acetate (95/5). After evaporating the solvents, 800 mg (63%) of (E)-2-[3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)acryloyloxy]benzoic acid, with a melting point of 137-8° C., are collected.
Reaction SMILES: S=[C:2]1[CH2:6][S:5][C:4](=[O:7])[NH:3]1.[CH2:8]([N:10]([CH2:14][CH3:15])[CH2:11][CH2:12][NH2:13])[CH3:9]>CO>[CH2:8]([N:10]([CH2:14][CH3:15])[CH2:11][CH2:12][NH:13][C:2]1[CH2:6][S:5][C:4](=[O:7])[N:3]=1)[CH3:9]
Reactant: O=C1NC(=S)CS1
Reactant: CCN(CC)CCN
Solvent: CO
Product: CCN(CC)CCNC1=NC(=O)SC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-thioxo-1,3-thiazolidin-2-one (5.32 g) in methanol (200 mL) was added N,N-diethylethane-1,2-diamine (6.17 mL). The reaction mixture was stirred at room temperature overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (5.44 g).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[C:11]([F:29])=[C:12]([N:16]2[CH2:21][CH2:20][C:19]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)(O)[CH2:18][CH2:17]2)[CH:13]=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].ClCCl.CS(Cl)(=O)=O>CN(C1C=CN=CC=1)C.O>[Si:1]([O:8][CH2:9][C:10]1[C:11]([F:29])=[C:12]([N:16]2[CH2:17][CH:18]=[C:19]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)[CH2:20][CH2:21]2)[CH:13]=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(N2CCC(O)(c3cccnc3)CC2)c1F
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCc1cccc(N2CC=C(c3cccnc3)CC2)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.9 %

Procedure:
1-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]-4-(pyridin-3-yl)piperidin-4-ol (908 mg) was mixed with dichloromethane (15 ml), and TEA (1.1 g), DMAP (799 mg), and MsCl (749 mg) were added thereto at 0° C., followed by stirring at room temperature overnight. Water and EtAOc were added to the reaction mixture, and the organic layer was washed with water and saturated brine, and dried over anhydrous sodium carbonate. The solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (EtOAc/hexane) to obtain 1′-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]-1′,2′,3′,6′-tetrahydro-3,4′-bipyridine (477 mg).
Reaction SMILES: [NH2:1][C:2]([O:4]CC)=[O:3].[N-:7]=[C:8]=[O:9].[C:10]1([CH3:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(C(C)=O)C>>[CH2:14]([N:1]=[C:2]=[O:4])[CH2:15][CH2:10][CH2:11][CH2:12][CH2:13][N:7]=[C:8]=[O:9].[CH3:16][C:10]1[C:15](=[CH:14][C:13](=[CH:12][CH:11]=1)[N:1]=[C:2]=[O:3])[N:7]=[C:8]=[O:9]
Reactant: [N-]=C=O
Reactant: Cc1ccccc1
Reactant: CCOC(N)=O
Solvent: CCC(C)=O
Product: Cc1ccc(N=C=O)cc1N=C=O
Product: O=C=NCCCCCCN=C=O
Temperature: 80 °C

Procedure:
As the adhesive layer, a polyester-urethane adhesive was used and a composition for an adhesive layer was prepared as follows. That is, a polyester resin (80 parts by weight, VYLON RV-200) manufactured by Toyo Boseki Kabushiki Kaisha was dissolved in a mixed solvent (1940 parts by weight) of toluene/methyl ethyl ketone=80/20 (weight ratio) while heating at 80° C. After cooling, DESMODUER HL (20 parts by weight, manufactured by Sumitomo Bayer Urethane) which is isocyanulate polyhydric isocyanate obtained from hexamethylene diisocyanate and toluene diisocyanate as starting materials, was added as isocyanulate polyhydric isocyanate, and triethylene diamine (0.06 part by weight) was added as a curing catalyst, and the mixture was stirred for 10 min.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:20]=4[O:27][CH3:28])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1)=[O:32]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:14][CH2:15][CH:16]([C:19]4[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:20]=4[O:27][CH3:28])[CH2:17][CH2:18]3)=[O:12])=[CH:7][N:8]2[CH2:30][C:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)=[O:32])=[CH:4][CH:3]=1
Reactant: O=C(CCl)c1ccccn1
Reactant: COc1cccc(OC)c1C1CCN(C(=O)c2c[nH]c3cc(Cl)ccc23)CC1
Product: COc1cccc(OC)c1C1CCN(C(=O)c2cn(CC(=O)c3ccccn3)c3cc(Cl)ccc23)CC1

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2,6-dimethoxy-phenyl)-piperidin-1-yl]-methanone (preparation described herein), with commercially available 2-chloro-1-pyridin-2-yl-ethanone gave the title compound.
Reaction SMILES: C[Si](C)(C)CCOC[N:7](COCC[Si](C)(C)C)[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:29]2[CH2:35][CH:34]3[N:36]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH:31]([CH2:32][CH2:33]3)[CH2:30]2)[C:9]=1SC.O[O:57][S:58]([O-:60])=O.[K+].[C:62]([O-])(O)=O.[Na+]>CO.O>[NH2:7][C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:29]2[CH2:30][CH:31]3[N:36]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH:34]([CH2:33][CH2:32]3)[CH2:35]2)[C:9]=1[S:58]([CH3:62])(=[O:60])=[O:57]
Reactant: O=S([O-])OO
Reactant: CSc1c(C2CC3CCC(C2)N3C(=O)OC(C)(C)C)nc2c(-c3ccc(-c4ccccc4)nc3)cnn2c1N(COCC[Si](C)(C)C)COCC[Si](C)(C)C
Reactant: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1C2CCC1CC(c1nc3c(-c4ccc(-c5ccccc5)nc4)cnn3c(N)c1S(C)(=O)=O)C2
Temperature: 65 °C

Procedure:
A mixture of compound tert-butyl 3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-(methylthio)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (319 mg, 0.4 mmol), Oxone (1.2 g, 2 mmol) and NaHCO3 (336 mg, 4 mmol) in MeOH (12 mL) and Water (3 mL) was heated at 65° C. for 15 h, at which time LC/MS analysis confirmed full consumption of starting material. After cooling, it was diluted with DCM: MeOH (1:1, 100 mL) and filtered. The filtrate was concentrated to afford the crude title product which was used for the next step without further purification.