Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH:21]([C:24]1[N:25]([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:26](=[O:34])[C:27]2[C:32]([CH3:33])=[N:31][O:30][C:28]=2[N:29]=1)[CH2:22][CH3:23])[C:12](=[O:20])[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)(C)(C)C.[SiH](CC)(CC)CC.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH:21]([C:24]1[N:25]([CH2:35][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:26](=[O:34])[C:27]2[C:32]([CH3:33])=[N:31][O:30][C:28]=2[N:29]=1)[CH2:22][CH3:23])[C:12](=[O:20])[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1
Reactant: CCC(c1nc2onc(C)c2c(=O)n1Cc1ccccc1)N(CCCNC(=O)OC(C)(C)C)C(=O)c1ccc(C)cc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(c1nc2onc(C)c2c(=O)n1Cc1ccccc1)N(CCCN)C(=O)c1ccc(C)cc1
Reaction time: 0.5 h

Procedure:
A solution of the compound from Example 1 Step 6 (60 mg, 0.10 mmol) in CH2Cl2 (2.5 mL) at room temperature was treated with Et3SiH (150 mL) followed by TFA (1.0 mL). The reaction mixture was stirred for 0.5 h then concentrated under vacuum to the desired product as a colorless film (32 mg, 65%); 1H NMR (DMSO-d6) δ 7.62 (s, 1H), 7.25 (m, 7H), 7.22 (s, 1H), 5.77 (d, J=16.5 Hz, 1H), 5.39 (s, 1H), 4.90 (d, J=15.9 Hz, 1H), 3.40 (t, J=7.0 Hz, 2H), 2.92 (s, 3H), 2.54 (s, 3H), 2.09 (m, 1H), 1.92 (m, 1H), 1.91 (m, 1H), 1.89 (t, J=7.0 Hz, 3H), 0.68 (m, 1H); LC/MS (ESI): 474 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1.S(O[CH2:19][CH:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH2:22][CH2:21]1)(=O)(=O)C>O>[CH2:29]([O:28][C:26]([N:23]1[CH2:24][CH2:25][CH:20]([CH2:19][NH:13][S:10]([C:7]2[CH:6]=[CH:5][C:4]([CH3:3])=[CH:9][CH:8]=2)(=[O:12])=[O:11])[CH2:21][CH2:22]1)=[O:27])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CS(=O)(=O)OCC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(S(=O)(=O)NCC2CCN(C(=O)OCc3ccccc3)CC2)cc1
Temperature: 25 °C

Procedure:
Sodium hydride (300 mg of a 60% suspension) was added to a stirred solution of 4-methylphenylsulphonamide and the mixture stirred at room temperature until effervescence had ceased. N-benzyloxycarbonylpiperidine-4-methanol mesylate (1.09 g) was added and the mixture heated at 100° C. for 7 hours. After cooling to room temperature it was diluted with water (200 ml) and extracted with ether (4×40 ml); the extracts were combined, washed with water (2×) and brine, dried (MgSO4) and evaporated to yield N-(1-benzyloxycarbonylpiperidin-4-ylmethyl)-4-methylphenylsulphonamide NMR (d6DMSO): δ0.8-1.1 (2H,m); 1.5-1.7 (3H,m); 2.35 (3H,s); 2.6 (2H,t); 2.7-2.9 (2H,m); 4.0 (2H,d); 5.0 (2H,s); 7.2-7.5 (7H,m); 7.55 (1H,t); 7.7 (2H,d); m/e 403 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[CH:11][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>ClCCl.CO>[Cl:1][C:2]1[CH:14]=[C:13]([NH2:15])[CH:12]=[CH:11][C:3]=1[CH2:4][N:5]1[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: O=[N+]([O-])c1ccc(CN2CCCCC2)c(Cl)c1
Solvent: ClCCl
Solvent: CO
Product: Nc1ccc(CN2CCCCC2)c(Cl)c1

Procedure:
Prepared analogously to Example 3.1.b. from 1-(2-chloro-4-nitrobenzyl)piperidine. Yield: 1.88 g (90% of theory); C12H17ClN2 (M=224.73); calc.: molecular ion peak (M+H)+: 225/227 (Cl); found: molecular ion peak (M+H)+: 225/227 (Cl); Rf value: 0.2 (silica gel, dichloromethane/methanol (9:1)).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]#[N:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.N.[H][H]>C1COCC1.CO.[Ni]>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][NH2:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: N#Cc1ccc2[nH]ncc2c1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CO
Solvent: C1CCOC1
Product: NCc1ccc2[nH]ncc2c1
Reaction time: 8 h

Procedure:
To a suspension of 1H-indazole-5-carbonitrile (0.235 g, 1.64 mmol) in THF (6 mL) was added 2 mL of 2 N ammonia in methanol and the flask was charged with 0.05 g Raney® 2800 nickel. A hydrogen balloon was attached to the flask and the system was purged 3 times with hydrogen. After stirring vigorously overnight the reaction mixture was diluted with methanol and filtered through a pad of celite. The solvent was evaporated in vacuo to provide 1-(1H-indazole-5-yl)methanamine.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:13](=[O:14])[CH:12]3[CH2:15][C:10]([C:16]4[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=4)([CH2:11]3)[C:9]2=[O:25])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCOCC>COCCO.[Pd]>[NH2:22][C:19]1[CH:18]=[CH:17][C:16]([C:10]23[CH2:11][CH:12]([CH2:15]2)[C:13](=[O:14])[N:8]([CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:9]3=[O:25])=[CH:21][CH:20]=1
Reactant: O=C1C2CC(c3ccc([N+](=O)[O-])cc3)(C2)C(=O)N1CC1CCCCC1
Agent: [Pd]
Solvent: CCOCC
Solvent: COCCO
Product: Nc1ccc(C23CC(C2)C(=O)N(CC2CCCCC2)C3=O)cc1

Procedure:
In a manner analogous to that described in Example 1a, 6.0 g of 3-cyclohexylmethyl-1-(4-nitrophenyl)-3-azabicyclo[3.1.1]heptane-2,4-dione are dissolved in 120 ml of 2-methoxyethanol, hydrogenated in the presence of 0.6 g of 5% palladium-on-carbon and worked up. Melting point 140°-146° (from ether) Rf (ether)=0.25.
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH:46][C:47]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][N:50]=3)=[O:48])[CH:43]=[CH:44][CH:45]=2)=[N:8]1>Cl.O1CCOCC1>[NH:18]1[CH:19]=[N:20][C:16]([C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[NH:7][N:8]=[C:9]3[C:40]2[CH:41]=[C:42]([NH:46][C:47]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][N:50]=3)=[O:48])[CH:43]=[CH:44][CH:45]=2)=[N:17]1
Reactant: O=C(Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1)c1ccccn1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(Nc1cccc(-c2n[nH]c3ccc(-c4nc[nH]n4)cc23)c1)c1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
[N-(3-{1-Perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)](1H-indazol-3-yl)}phenyl)-2-pyridylcarboxamide was dissolved in 4 mL of 4.0 N HCl in 1,4-dioxane and the reaction was stirred at room temperature overnight. After neutralization with aqueous NaHCO3, the crude product was extracted with ethyl acetate and purified by preparative HPLC. (0.037 g, 39% yield over 2 steps): 1H NMR (CD3OD) δ 8.81 (s, 1H), 8.76 (dt, 1H), 8.55 (t, 1H), 8.45 (br s, 1H), 8.25 (dt, 1H), 8.12 (dd, 1H), 8.09 (td, 1H), 8.00 (dt, 1H), 7.85 (dt, 2H), 7.73 (d, 1H), 7.65 (ddd, 1H), 7.59 (t, 1H); ES-MS (m/z) 382 [M+H]+.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1([CH3:17])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.[CH3:18]N(P(N(C)C)(N(C)C)=O)C.CI>C1COCC1>[CH3:18][O:3][C:4]1([CH3:17])[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9]1
Reactant: CC1(O)CCN(C(=O)OC(C)(C)C)CC1
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: COC1(C)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 55 °C

Procedure:
A suspension of 60% NaH in mineral oil (160 mg, 4 mmol) in THF (5 mL) at room temperature was treated with a solution of Example 494A (430 mg, 2.00 mmol) in THF (5 mL), heated to 55° C. for 2 hours, cooled to room temperature, treated with HMPA (2.5 mL) and methyl iodide (0.50 mL), heated to 55° C. for 16 hours, cooled to room temperature, quenched with 10% aqueous citric acid, and extracted twice with diethyl ether. The combined extracts were washed sequentially with water, saturated NaHCO3, and brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 10%-20% ethyl acetate/heptane to provide the desired product.
Reaction SMILES: [OH:1][C:2]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:11].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>CC(=O)CC>[CH2:24]([N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]([OH:1])([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:3]1=[O:11])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCc1ccccc1
Reactant: O=C1Nc2ccccc2C1(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCC(C)=O
Product: O=C1N(Cc2ccccc2)c2ccccc2C1(O)c1ccccc1
Yield: 64.7 %

Procedure:
Combine 3-hydroxy-3-phenyl-1,3-dihydro-indol-2-one (225 mg, 1 mmol) and cesium carbonate (977 mg, 3 mmol) in 2-butanone (5 mL). Add benzyl bromide (0.13 mL, 1 mmol) and heat at 60° C. for 3 h. with vigorous stirring. Dilute the reaction with water and wash with ethyl acetate (2×). Wash combined organic portions with brine and then dry (MgSO4), filter and concentrate in vacuo to give an oil. Purify with radial chromatography (gradient of 10% EtOAc/hexanes to 25% EtOAc/hexanes) to give 204 mg (65%) of the title compound as a white solid. MS (ES): m/z=298 (M+1−H2O); 1H NMR(DMSO-d6); δ7.37-7.27 (m, 11H), 7.18 (m, 1H), 7.05 (m, 1H), 6.98 (m, 1H), 6.87 (s, 1H), 4.92 (s, 2H).
Reaction SMILES: O.[C:2]1([CH3:19])[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:18][CH2:17][CH2:16][C@H:12]2[C:13]([OH:15])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.C[O:22][C:23](=[O:27])[C@H:24]([CH3:26])[NH2:25].[Li+].[OH-]>C1COCC1.O>[C:2]1([CH3:19])[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH2:18][CH2:17][CH2:16][C@H:12]2[C:13]([NH:25][C@H:24]([C:23]([OH:27])=[O:22])[CH3:26])=[O:15])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H](C)N
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)O)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)N[C@@H](C)C(=O)O)cc1

Procedure:
N-(Toluene-4-sulfonyl)-L-proline hydrate was coupled to L-alanine methyl ester hydrochloride using the procedure described in Method 3. The resulting methyl ester was deesterified via hydrolysis using LiOH in THF/water to provide the title compound as a solid, mp=160.5-162.5° C.
Reaction SMILES: O[CH:2]([CH2:7][CH2:8][S:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1)[CH2:3][C:4](=[O:6])[CH3:5].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:18][C:16]([F:17])([F:19])[C:13]1[CH:14]=[CH:15][C:10]([S:9][CH2:8][CH2:7][CH:2]=[CH:3][C:4](=[O:6])[CH3:5])=[CH:11][CH:12]=1
Reactant: CC(=O)CC(O)CCSc1ccc(C(F)(F)F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(=O)C=CCCSc1ccc(C(F)(F)F)cc1

Procedure:
1.96 Grams of 4-hydroxy-6-(4-trifluoromethylphenylthio)-2-hexanone were dissolved in 30 ml of toluene, and 0.04 g of p-toluenesulfonic acid was added thereto. The resulting mixture was refluxed for 2.5 hours with stirring, allowed to cool and then treated in the same manner as in Production example 34. Thus, 6-(4-trifluoromethylphenylthio)-3-hexen-2-one was obtained (purity: 95.1%).
Reaction SMILES: CS([O:5][CH2:6][C@@H:7]([NH:12][C:13]1[C:18]([F:19])=[CH:17][N:16]=[C:15]([C:20]2[C:28]3[C:23](=[N:24][CH:25]=[C:26]([F:29])[CH:27]=3)[N:22]([S:30]([C:33]3[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=3)(=[O:32])=[O:31])[CH:21]=2)[CH:14]=1)[C:8]([CH3:11])([CH3:10])[CH3:9])(=O)=O.[C:40]([O-])(=[S:42])[CH3:41].[K+].O>CN(C=O)C>[C:40](=[S:42])([O:5][CH2:6][C@@H:7]([NH:12][C:13]1[C:18]([F:19])=[CH:17][N:16]=[C:15]([C:20]2[C:28]3[C:23](=[N:24][CH:25]=[C:26]([F:29])[CH:27]=3)[N:22]([S:30]([C:33]3[CH:34]=[CH:35][C:36]([CH3:37])=[CH:38][CH:39]=3)(=[O:31])=[O:32])[CH:21]=2)[CH:14]=1)[C:8]([CH3:10])([CH3:9])[CH3:11])[CH3:41]
Reactant: CC([O-])=S
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cc(N[C@H](COS(C)(=O)=O)C(C)(C)C)c(F)cn3)c3cc(F)cnc32)cc1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=S)OC[C@@H](Nc1cc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncc(F)cc23)ncc1F)C(C)(C)C
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-2-(5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-4-ylamino)-3,3-dimethylbutyl methanesulfonate, 55a, (10.5 g, 18.11 mmol) in dry DMF (200 mL) was added potassium thioacetate (3.1 g, 27.1 mmol). The brown solution was heated with stirring at 80° C. for 1 hour. The thick brown suspension was poured into water and extracted with EtOAc (3×100 mL). The combined organic phases were dried (MgSO4), filtered and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0-30% EtOAc/Hexanes gradient) to afford 6.8 g of the desired product, 56a, as a pale brown solid: 1H NMR (400 MHz, CDCl3) δ 8.41 (m, 2H), 8.23 (s, 1H), 8.01 (m, 3H), 7.23-7.16 (m, 2H), 4.99 (d, J=10.1 Hz, 1H), 4.37 (m, 1H), 3.21 (dd, J=13.8, 2.3 Hz, 1H), 3.09-2.95 (m, 1H), 2.31 (s, 3H), 2.16 (s, 3H), 1.02 (s, 9H); LC/MS (10-90% ACN/water 5 min with 0.9% FA) m/z 560.99 (M+H) RT=4.14 minutes.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH:11]([OH:15])[CH2:12][CH:13]=[CH2:14])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[H-].[Na+].[CH2:18](Br)[CH:19]=[CH2:20]>>[CH2:20]([O:15][CH:11]([CH:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1)[CH2:12][CH:13]=[CH2:14])[CH:19]=[CH2:18]
Reactant: C=CCBr
Reactant: C=CCC(O)C1CCC2(CC1)OCCO2
Agent: [H-]
Agent: [Na+]
Product: C=CCOC(CC=C)C1CCC2(CC1)OCCO2
Reaction time: 1 h

Procedure:
A solution of 1-(1,4-dioxaspiro[4.5]decan-8-yl)but-3-en-1-ol (436 mg, 2.05 mmol), prepared in the previous step, was added to a suspension of sodium hydride (104 mg, 4.12 mmol, 95%) dropwise at 0° C. under argon. After the complete addition, the reaction mixture was allowed to reach room temperature and stirred 1 hour. Allyl bromide (0.35 mL, 4.05 mmol) was added dropwise and the mixture stirred overnight at room temperature. It was poured onto ice cooled saturated NaHCO3 solution. After extraction with ether, the organic layer was concentrated in vacuo and the residue purified by flash chromatography (silica gel, DCM) to afford the product.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.Br[CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[O:26]([CH2:25][CH2:24][CH2:23][N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: BrCCCOc1ccccc1
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(CCCOc3ccccc3)CC1)O2

Procedure:
Compound 144 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, bromo-3-phenoxypropane and conditions outlined in procedure W. M.p.=127-129° C.; 400 MHz 1H NMR (DMSO-d6) δ: 7.89 (d, J=7.6 Hz, 1H), 7.81-7.78 (m, 2H), 7.57 (dddd, J=2.4, 2.6, 5.2, 5.6 Hz, 2H), 7.28 (dd, J=6.8, 7.6 Hz, 2H), 6.94-6.86 (m, 4H), 4.01 (t, J=6.4 Hz, 2H), 3.08 (s, 2H), 2.77 (d, J=12.0 Hz, 2H), 2.55-2.47 (m, 2H), 2.34 (t, J=10.4 Hz, 2H), 2.00 (d, J=12.6 Hz, 2H), 1.903 (d, J=6.8 Hz, 2H), 1.81 (dt, J=4.0, 12.2 Hz, 2H); LCMS: 436 [M+H].
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[OH-].[K+].C1(C)C=CC(S(O[CH2:21][CH:22]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH3:23])(=O)=O)=CC=1.Cl>O.C(O)C>[CH2:25]([O:24][CH:22]([CH3:23])[CH2:21][O:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: Oc1ccc(O)cc1
Reactant: CCCCCOC(C)COS(=O)(=O)c1ccc(C)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCOC(C)COc1ccc(O)cc1
Reaction time: 13 h

Procedure:
16.7 g of hydroquinone, 8.6 g of 85% KOH, 14 g of water and 200 ml of ethanol were added into a four-necked flask, and the reaction was carried out for 13 hours. After elevated in temperature to 50° C., the reaction was further carried out for 3 hours and 30 g of (2'-pentyloxypropyl) p-toluenesulfonate was added dropwise to the reaction mixture and at the temperature elevated to 70° C., the reaction was carried out for 1 hour and then for 3 hours by heating under reflux, and the mixture was left standing at room temperature for 22 hours. After 500 ml of water and a small amount of hydrochloric acid were added to the residue after evaporation of ethanol, the mixture was extracted with 500 ml of hexane. The product after washing twice with water was dried over Na2SO4, recrystallization was effected with hexane.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10]([OH:12])=[O:11])[CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)O.[CH3:18]O>>[Br:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:18])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)/C=C/c1cccc(Br)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)/C=C/c1cccc(Br)c1
Yield: 47 %

Procedure:
A solution of trans-3-(3-bromophenyl)-2-propenoic acid (0.405 mol) in methanol (300 ml) was treated with conc. sulfuric acid (6.0 ml) and heated under reflux for 10 h. The cooled mixture was filtered to afford the title compound (46.14 g, 47%) as brilliant white crystals, m.p. 53-55° C. (Found: C, 50.10; H, 3.58; Br; 33.21. C10H9BrO2 requires C, 49.82; H, 3.76; Br, 33.14%); Vmax (nujol)/cm-1 1730.5, 1715.0, 1644; δH (270 MHz) 3.81 (3H, s, OCH3); 6.43 (1H, d, 2-H, 3J2,3 =16.2 Hz); 7.25 (1H, t, 5'-H, Jo =7.8 Hz); 7.43 (1H, dt, 4'-H, Jo =7.9, Jm =1.0 Hz); 7.50 (1H, dt, 6'-H, Jo =7.9, Jm =1.0 Hz); 7.60 (1H, d, 3-H, 3J3,2 =16.2 Hz); 7.66 (1H, t, 2'-H, Jm =1.7 Hz). δC (67.8 MHz) 51.8 (OCH3); 123.0 (3'-C); 133.0 (4'-C); 136.4 (1'-C); 143.1 (3-C); 166.9 (CO2Me). Remaining signals lie in the range 119.3-130.7 ppm; m/z 242.0, 240.0 (46.67, 47.64, M+), 211.0, 209.0 (72.69, 74.00), 182.9, 180.9 (15.67, 1683), 161.0 (4.19), 130.0 (9.44), 102.1 (100).
Reaction SMILES: [S:1](=[O:5])(=O)([OH:3])[OH:2].[CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1>>[CH:14]1[C:15]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:12][C:13]=1[S:1]([OH:3])(=[O:5])=[O:2]
Reactant: c1ccc2ccccc2c1
Reactant: O=S(=O)(O)O
Product: O=S(=O)(O)c1ccc2ccccc2c1
Reaction time: 2 h

Procedure:
1,050 g of sulfuric acid was added to 1,280 g of naphthalene, and the reaction was carried out at 160° C. for 2 hours. Unreacted materials were separated and discharged outside the container under a reduced pressure. Then, 857 g of 35% by weight concentration formalin was added and reacted at 105° C. for 5 hours to obtain a condensation product formed by methylene type bonding of β-naphthalene sulfonic acid. After being neutralized with ammonium water, the condensation product was filtrated to yield a filtrate liquid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15]([OH:17])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:27]>O.C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15]([O:17][CH2:25][C:26](=[O:27])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(CBr)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCCCC1CC(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCCCC1CC(=O)OCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.2 %

Procedure:
2-Carboxymethyl-piperidine-1-carboxylic acid tert butyl ester (2.86 g) and sodium carbonate (0.62 g) were dissolved in water (30 ml) using gentle warming. A solution of 2-bromoacetophenone (2.33 g) in ethanol (60 ml) was then added and the mixture boiled for 2 h. the mixture was cooled to room temperature and stood for 16 h. The mixture was again boiled for 2 h. solvent removed at reduced pressure and the residue partitioned between water and ethyl acetate. The organic phase was dried (MgSO4) and solvent removed at reduced pressure. The residue was column chromatographed (silica gel, 1:1 ethyl acetate:pentane) to give the title compound (3.14 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[O:7][CH2:6][C:5](CO)([N+:8]([O-:10])=[O:9])[CH2:4][O:3]1.[OH-].[Na+]>C(O)(=O)C>[CH3:1][C:2]1([CH3:13])[O:3][CH2:4][CH:5]([N+:8]([O-:10])=[O:9])[CH2:6][O:7]1
Reactant: CC1(C)OCC(CO)([N+](=O)[O-])CO1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC1(C)OCC([N+](=O)[O-])CO1
Temperature: 60 °C
Yield: 107.6 %

Procedure:
Into a 250 ml round bottom flask equipped with a stir bar, thermometer and reflux condensor topped with a nitrogen inlet was added 5.73 g (0.03 mole) of 2,2-dimethyl-5-hydroxymethyl-5-nitro-1,3-dioxane and 70 ml 10% sodium hydroxide which was heated to 60° C. for one hour. The solution was cooled to 5° C. and at this temperature acidified to pH 5 with concentrated acetic acid. The precipitated solid was filtered off and dried to give 5.2 g (92%) of 2,2-dimethyl-5-nitro-1,3-dioxane m.p. 60°-61° C. 1H NMR in CD3OD also confirmed the structure.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=3[CH3:25])[CH2:14][CH2:13]2)=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[C:26]([N:29]1[CH2:33][CH2:32][NH:31][C:30]1=[O:34])(=[O:28])[CH3:27]>>[C:26]([N:29]1[CH2:33][CH2:32][N:31]([C:2]2[CH:3]=[CH:4][C:5]([C:10]([N:12]3[CH2:17][CH2:16][N:15]([C:18]4[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=4[CH3:25])[CH2:14][CH2:13]3)=[O:11])=[C:6]([CH:9]=2)[C:7]#[N:8])[C:30]1=[O:34])(=[O:28])[CH3:27]
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3C#N)CC2)c(C)c1
Reactant: CC(=O)N1CCNC1=O
Product: CC(=O)N1CCN(c2ccc(C(=O)N3CCN(c4ccc(C)cc4C)CC3)c(C#N)c2)C1=O
Yield: 60.9 %

Procedure:
Using 5-bromo-2-[4-(2,4-dimethylphenyl)piperazine-1-carbonyl]benzonitrile (996 mg) described in Preparation Example 188 and 1-acetylimidazolidin-2-one (384 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (679 mg) was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:15])=[C:6]([NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])[CH:7]=1.[CH3:16][Si:17]([C:20]#[CH:21])([CH3:19])[CH3:18].C(N(CC)CC)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.C1COCC1>[F:11][C:10]([F:13])([F:12])[C:9]([NH:8][C:6]1[CH:7]=[C:2]([C:21]#[C:20][Si:17]([CH3:19])([CH3:18])[CH3:16])[CH:3]=[CH:4][C:5]=1[F:15])=[O:14]
Reactant: C#C[Si](C)(C)C
Reactant: O=C(Nc1cc(Br)ccc1F)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1ccc(F)c(NC(=O)C(F)(F)F)c1
Temperature: 60 °C
Yield: 84.3 %

Procedure:
To an oven-dried flask under N2 was added N-(5-bromo-2-fluorophenyl)-2,2,2-trifluoroacetamide (750 mg, 2.62 mmol), anhydrous degassed THF (100 mL), dichlorobis(triphenylphosphine)palladium(II) (230 mg, 0.33 mmol), copper(I) iodide (38 mg, 0.20 mmol), and trimethylsilylacetylene (640 mg, 6.53 mmol). Next, triethylamine (2.64 g, 26 mmol) was added dropwise and the resulting mixture was heated at 60° C. overnight. The crude reaction mixture was adsorbed to silica gel and purified by column chromatography (0-10% EtOAc in hexanes) to afford the desired product (0.67 g, 84%) as an off white solid. ESIMS (M−H)−=302.