Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]#[N:8])=[CH:4][CH:3]=1.[Br:9]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)(Cl)Cl>[Br:9][CH2:1][C:2]1[S:6][C:5]([C:7]#[N:8])=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C#N)s1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(CBr)s1
Temperature: 25 °C
Yield: 22.7 %

Procedure:
5-Methylthiophene-2-carbonitrile (500 mg, 4.06 mmol) in carbon tetrachloride (10 mL) was stirred with N-bromosuccinimide (867 mg, 4.87 mmol) and 2,2′-azobis(isobutyronitrile) (133 mg, 0.810 mmol) at 60° C. for 4.5 hours and allowed to cool to room temperature. After addition of saturated aqueous sodium thiosulfate, the reaction mixture was extracted with chloroform, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1␣1/1 (v/v)) to give the title compound as a yellow oil (186 mg, yield 23%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([OH:19])[CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:5]=[CH:6][CH:7]=1.[C:20]([CH:22]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)#[CH:21]>>[CH:22]1([C:20]#[C:21][C:2]2[CH:3]=[C:4]([CH:8]([OH:19])[CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:5]=[CH:6][CH:7]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CC(C)(C)OC(=O)NCCC(O)c1cccc(Br)c1
Reactant: C#CC1CCCCCCC1
Product: CC(C)(C)OC(=O)NCCC(O)c1cccc(C#CC2CCCCCCC2)c1

Procedure:
Sonogashira reaction of 39 with ethynyl cyclooctane yielded tert-butyl 3-(3-(2-cyclooctylethynyl)phenyl)-3-hydroxypropylcarbamate as light yellow oil. Yield (470 mg, 91%): 1H NMR (400 MHz, CDCl3) δ 7.39 (s, 1H), 7.22-7.29 (m, 3H), 4.86 (bs, 1H), 4.72 (m, 1H), 3.23 (bs, 1H), 3.11-3.19 (m, 1H), 2.76-2.79 (m, 2H), 1.92-1.96 (m, 2H), 1.74-1.81 (m, 6H), 1.53-1.60 (m, 6H), 1.45 (s, 9H), 1.27 (an, 2H).
Reaction SMILES: [CH2:1]([S:8]([CH2:11][C:12](O)=O)(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1C=O>>[CH2:1]([S:8](/[CH:11]=[CH:12]/[C:17]1[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=1[Cl:15])(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1Cl
Reactant: O=C(O)CS(=O)(=O)Cc1ccccc1
Product: O=S(=O)(/C=C/c1ccccc1Cl)Cc1ccccc1
Yield: 72 %

Procedure:
A solution of benzyl sulfonylacetic acid (0.01 mol) and 2-chlorobenzaldehyde (0.01 mol) was subjected to Procedure 1, Part B. The title compound was obtained in 72% yield.
Reaction SMILES: [CH:1]([Cl:4])(Cl)Cl.[CH2:5]=[C:6]1[C@H:12]([CH3:13])[O:11]C(O)[CH2:8][C@@H:7]1[NH:14][C:15](=[O:20])[C:16]([F:19])([F:18])[F:17].FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[CH2:5]=[C:6]1[C@H:12]([CH3:13])[O:11][CH:1]([Cl:4])[CH2:8][C@@H:7]1[NH:14][C:15](=[O:20])[C:16]([F:18])([F:19])[F:17]
Reactant: ClC(Cl)Cl
Reactant: C=C1[C@@H](NC(=O)C(F)(F)F)CC(O)O[C@H]1C
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: C=C1[C@@H](NC(=O)C(F)(F)F)CC(Cl)O[C@H]1C
Reaction time: 8 h
Yield: 90 %

Procedure:
A solution of 0.51 g (2 mmol) of the intermediate VIII in 10 ml of acetic acid and 40 ml of water was heated at 100° C. for two hours, then evaporated to dryness to give 2,3,4,6-tetradeoxy-4-C-methylene-3-trifluoroacetamido-L-threo-hexopyranose (IX, 0.47 g, 99%) as a white solid: m.p. 168°-170° C., [α]D20° -160° (c=0.5, CHCl3). Treatment of IX (0.36 g, 1.5 mmol) in 25 ml of dry methylene dichloride with 4 ml of trifluoroacetic anhydride for 2 hours at 0° C. and 1 hour at 20° C. gave, after evaporation, the 1-0-trifluoroacetate (X), which was directly used for the preparation of the corresponding 1-chloro-derivative by treatment with dry hydrogen chloride in anhydrous diethyl ether at 0° C. After standing at 0° C. overnight, the reaction mixture was evaporated to dryness to give 2,3,4,6-tetradeoxy-4-C-methylene-3-trifluoroacetamido-L-threo-hexopyranosyl chloride (III-A, 0.35 g, 90%), suitable for the subsequent coupling reaction without further purification.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:9].Cl[C:11]1[C:20]([C:21]#[N:22])=[C:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([Cl:29])[CH:17]=2)[N:12]=1>C1(C)C=CC=CC=1.O>[Cl:29][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([N:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:9])[C:20]([C:21]#[N:22])=[C:19]2[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: N#Cc1c(Cl)nc2ccc(Cl)cc2c1-c1ccccc1
Reactant: O=C1CCCCN1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: N#Cc1c(N2CCCCC2=O)nc2ccc(Cl)cc2c1-c1ccccc1
Temperature: 100 °C
Yield: 64.9 %

Procedure:
To a suspension of sodium hydride (31.5 mg, 55% in mineral oil, 0.723 mmol) in toluene (4 ml) was added piperidin-2-one (133 mg, 1.34 mmol) followed by 2,6-dichloro-4-phenyl-quinoline-3-carbonitrile (prepared as described in example 27 step B) (200 mg, 0.669 mmol) and the mixture was heated to 100° C. for 6 h. The reaction mixture was cooled to room temperature, diluted with water and extracted twice with DCM and twice with EtOAc. The combined extracts were washed with brine, dried with Na2SO4 and evaporated. The remaining residue was triturated with cold diethyl ether to afford the title compound (157 mg, 62%) as light yellow solid. MS (ESI): 362.3 (M+H)+.
Reaction SMILES: C([N:4]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11](S(C)=O)=[C:12]3[C:17](=[O:18])[CH2:16][C:15]([CH3:20])([CH3:19])[CH2:14][C:13]=23)=[N:5]1)(=O)C.[CH3:24][C:25]([S-:28])([CH3:27])[CH3:26].[Na+]>C1COCC1>[CH3:19][C:15]1([CH3:20])[CH2:14][C:13]2=[C:9]([C:6]3[CH:7]=[CH:8][NH:4][N:5]=3)[S:10][C:11]([S:28][C:25]([CH3:27])([CH3:26])[CH3:24])=[C:12]2[C:17](=[O:18])[CH2:16]1
Reactant: CC(C)(C)[S-]
Reactant: CC(=O)n1ccc(-c2sc(S(C)=O)c3c2CC(C)(C)CC3=O)n1
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)CC(=O)c2c(SC(C)(C)C)sc(-c3cc[nH]n3)c2C1
Yield: 48.4 %

Procedure:
To a stirred solution of 1-(1-acetylpyrazol-3-yl)-6,6-dimethyl-3-methanesulphinyl-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one (73 mg, 0.21 mmol) in THF (7 mL) was added sodium 2-methyl-2-propanethiolate (47 mg, 0.42 mmol). After 90 min more sodium 2-methyl-2-propanethiolate (15 mg, 0.14 mmol) was added, and after a further 30 min the mixture was partitioned between EtOAc (15 mL) and water (10 mL). The organic layer was separated, dried (Na2SO4) and evaporated. The residue was chromatographed on silica gel, eluting with petrol:EtOAc (1:1), to give the title compound (34 mg, 48%) as a yellow solid. mp 220-222° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH:16][C:17]2[CH:32]=[CH:31][C:30](I)=[CH:29][C:18]=2[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][N:23]=2)=[O:20])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:34](#[N:37])[CH:35]=[CH2:36]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH:16][C:17]2[CH:32]=[CH:31][C:30](/[CH:36]=[CH:35]\[C:34]#[N:37])=[CH:29][C:18]=2[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][N:23]=2)=[O:20])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CC#N
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccc(I)cc2C(=O)Nc2ccc(Cl)cn2)CC1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccc(/C=C\C#N)cc2C(=O)Nc2ccc(Cl)cn2)CC1
Yield: 19 %

Procedure:
Using methods substantially equivalent to those described in Example 259-A, 2-[(1-tert-butoxycarbonylpiperidin-4-ylcarbonyl)amino]-N-(5-chloropyridin-2-y)-5-iodobenzamide was condensed with acrylonitrile. From the reaction mixture was isolated (Z)-2-[(1-tert-butoxycarbonylpiperidin-4-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)-5-(2-cyanovinyl)benzamide (0.19 g, 19%), as well as the (E)-isomer (see prior example).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:18]2[N:23]=[C:22]([C:24]3[CH:50]=[CH:49][CH:48]=[CH:47][C:25]=3[O:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]4[CH2:35][CH2:36][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:38][CH:39]=4)=[CH:30][CH:29]=3)[CH:21]=[CH:20][CH:19]=2)[C:10]=1[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])=[O:5])[CH3:2].[H][H]>CCOC(C)=O.[Pt](=O)=O>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:18]2[N:23]=[C:22]([C:24]3[CH:50]=[CH:49][CH:48]=[CH:47][C:25]=3[O:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([CH:34]4[CH2:35][CH2:36][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:44])[CH3:45])=[O:41])[CH2:38][CH2:39]4)=[CH:30][CH:29]=3)[CH:21]=[CH:20][CH:19]=2)[C:10]=1[C:11]([F:16])([F:17])[C:12]([F:13])([F:14])[F:15])=[O:5])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)c1cnn(-c2cccc(-c3ccccc3OCc3ccc(C4=CCN(C(=O)OC(C)(C)C)CC4)cc3)n2)c1C(F)(F)C(F)(F)F
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnn(-c2cccc(-c3ccccc3OCc3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc3)n2)c1C(F)(F)C(F)(F)F
Reaction time: 0.33 h

Procedure:
To a degassed solution of the title compound from Example 8 Step E (549 mg, 0.79 mmol) in EtOAc (15 mL) was added platinum(IV) oxide (200 mg). The reaction flask was fitted with a hydrogen balloon attached to a 3-way adapter. The reaction mixture was then evacuated and back-filled with hydrogen. After this process was repeated three times, the reaction mixture was placed under a hydrogen atmosphere, and was stirred vigorously. After 20 min, the reaction mixture was filtered though Celite, rinsing with EtOAc. The filtrate was then concentrated in vacuo. Purification by chromatography on silica gel (0 to 40% EtOAc in hexanes, then 40 to 100% EtOAc in hexanes) provided the title compound: LCMS m/z 700.8 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 8.21 (s, 1H), 8.13 (d, J=8.0 Hz, 1H), 7.86-7.82 (m, 2H), 7.38-7.35 (m, 2H), 7.30 (d, J=8.0 Hz, 2H), 7.19 (d, J=8.0 Hz, 2H), 7.09-7.06 (m, 2H), 5.12 (s, 2H), 4.37 (q, J=7.0 Hz, 2H), 4.29-4.20 (br m, 2H), 2.83-2.76 (br m, 2H), 2.68-2.63 (m, 1H), 1.84-1.81 (m, 2H), 1.49 (s, 9H), 1.38 (t, J=7.0 Hz, 3H).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.Cl.[CH2:14](O)[CH3:15]>>[Br:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([O:12][CH2:14][CH3:15])=[O:11])=[CH:7][CH:8]=1
Reactant: CCO
Reactant: O=C(O)Cc1ccc(CBr)cc1
Agent: Cl
Product: CCOC(=O)Cc1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.00 g of 2-[4-(bromomethyl)phenyl]acetic acid was suspended in 5 mL of a 4M solution of hydrogen chloride in ethanol, and this suspension was stirred for 2 hours at room temperature. The reaction mixture was concentrated under reduced pressure to yield 0.954 g of ethyl 2-[4-(bromomethyl)phenyl]acetate as light brown oil.
Reaction SMILES: [C:1]([CH:9]=[CH:10][C:11]([OH:13])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14]([OH:17])(=[S:16])[CH3:15]>C(OCC)C>[C:14]([S:16][CH:10]([CH2:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:11]([OH:13])=[O:12])(=[O:17])[CH3:15]
Reactant: CC(O)=S
Reactant: O=C(O)C=CC(=O)c1ccccc1
Solvent: CCOCC
Product: CC(=O)SC(CC(=O)c1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 1.76 g of 3-benzoylacrylic acid in 30 ml of diethyl ether was added 0.8 ml of thioacetic acid, and the resulting mixture was stirred at room temperature for 5 hours. The diethyl ether was removed from the reaction mixture by evaporation under reduced pressure, and the residue was purified by silica gel column chromatography using a mixture of hexane and dichloromethane as an eluent and recrystallized from a mixture of hexane and diethyl ether to give 2.09 g of 2-acetylthio-3-benzoylpropionic acid.
Reaction SMILES: [CH2:1]([NH:5][C:6](=O)[CH2:7][CH2:8][N:9]([CH2:20][CH2:21][C:22](=O)[NH:23][CH2:24][CH2:25][CH2:26][CH3:27])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11])[CH2:2][CH2:3][CH3:4].B.C(Cl)Cl>O1CCCC1>[CH2:24]([NH:23][CH2:22][CH2:21][CH2:20][N:9]([CH2:8][CH2:7][CH2:6][NH:5][CH2:1][CH2:2][CH2:3][CH3:4])[S:10]([C:13]1[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=1)(=[O:12])=[O:11])[CH2:25][CH2:26][CH3:27]
Reactant: CCCCNC(=O)CCN(CCC(=O)NCCCC)S(=O)(=O)c1ccc(C)cc1
Agent: B
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCCNCCCN(CCCNCCCC)S(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C

Procedure:
Dissolve N-butyl-3-[(2-butylcarbamoyl-ethyl)-(toluene-4-sulfonyl)-amino]-propionamide (10 mmol) prepared in example 9, Scheme VI, step C in tetrahydrofuran (50 mL). Cool the solution to 0° C. and add borane (20 mmol, 1M solution in tetrahydrofuran. Heat the reaction to reflux for 18 hours. After cooling, dilute the reaction with methylene chloride (200 mL), rinse with water (100 mL), brine (100 mL), dry over anhydrous sodium sulfate, filter and concentrate under vacuum. Purify the residue by flash chromatography (silica gel, methanol/methylene chloride) to provide N,N-bis-(3-butylamino-propyl)-4-methyl-benzenesulfonamide.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][CH:8]=1>>[F:6][C:7]1[CH:12]=[C:11]([S:2]([Cl:1])(=[O:5])=[O:3])[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][CH:8]=1
Reactant: O=S(=O)(O)Cl
Reactant: Fc1ccc(-c2ccccc2)cc1
Product: O=S(=O)(Cl)c1cc(F)ccc1-c1ccccc1
Reaction time: 0.5 h

Procedure:
Chlorosulfonic acid (8.7 mL, 0.13 mole) was added dropwise to 4-fluorobiphenyl (10.2 grams, 59 mmol) while stirring in an ice bath. Stirring was continued with ice cooling for 0.5 hours and then the reaction mixture was poured onto ice. The resulting white precipitate was collected by filtration and dissolved in chloroform. The chloroform solution was washed with water and brine, dried over magnesium sulfate and concentrated to afford a white solid. The desired product, 4-fluorobiphenylsulfonyl chloride (4.3 grams, 27%), was separated from 4-fluorobiphenylsulfonic acid (an unwanted side product) by crystallization of the latter from ethyl acetate and crystallization of the remaining material from hexane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:18]2[C:13](=[C:14]([C:21]3[CH:26]=[CH:25][C:24](F)=[CH:23][C:22]=3F)[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=2)[CH2:12][CH2:11][C:10]1=[O:29].[ClH:30]>C(Cl)Cl.O1CCOCC1>[Cl:30][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:14]1[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[C:18]2[C:13]=1[CH2:12][CH2:11][C:10](=[O:29])[N:9]2[C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[Cl:8].[ClH:1]
Reactant: COc1cc(-c2ccc(F)cc2F)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)CC2
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1cc(-c2ccccc2Cl)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)CC2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Compound 1 (0.95 g, 1.68 mmol), 1a (0.76 g, 2.19 mmol), Pd(PPh3)4 (0.19 g, 0.17 mmol) and LiCl (0.28 g, 6.72 mmol) in 30 mL of dioxane were purged with nitrogen for 3 times and the solution was heated at 108° C. for 20 h. Solvent was removed by vacuum and the residue was dissolved in EtOAc. The organic layer was washed with aqueous NaHCO3, dried with Na2SO4 and was purified by flash chromatography EtOAc/hexane=1:3 to give compound 2. Step B: Compound 2 (1.00 g, 1.68 mmol) in 10 mL of CH2Cl2 was added solution of HCl in dioxane (6.7 mL as 4M solution) and the resulting solution was stirred at rt for 24 h. Volatiles were removed by vacuum to give compound 6 as HCl salt. Mass spectrum (ESI), 499 (M+1).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20](=O)([O:24]CC)[O:21][CH2:22][CH3:23].[Na]>>[O:1]([C:8]1[CH:9]=[C:10]([CH:14]([C:20]([O:21][CH2:22][CH3:23])=[O:24])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)OCC
Reactant: CCOC(=O)Cc1cccc(Oc2ccccc2)c1
Agent: [Na]
Product: CCOC(=O)C(C(=O)OCC)c1cccc(Oc2ccccc2)c1

Procedure:
The method which comprises brominating m-methyldiphenyl ether with N-bromosuccinimide to form m-(bromomethyl)diphenyl ether, reacting it with sodium cyanide in dimethylsulfoxide to form m-(cyanomethyl)diphenyl ether, hydrolyzing and esterifying it to form ethyl α-(m-phenoxyphenyl)acetate, reacting the resulting ester with diethyl carbonate in the presence of metallic sodium to form diethyl 2-(m-phenoxyphenyl)malonate, reacting the product with methyl iodide to form diethyl 2-methyl-2-(m-phenoxyphenyl)-malonate, hydrolyzing the product to form 2-methyl-2-(m-phenoxyphenyl)malonic acid, and decarboxylating the product under heat to form α-(m-phenoxyphenyl)propionic acid (Japanese Patent Publication No. 45586/76).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]1(=[O:15])[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1.Cl>>[OH:7][C:1]1[CH:6]=[CH:5][C:4]([C:1]2([C:11]3[CH:10]=[CH:9][C:8]([OH:15])=[CH:13][CH:12]=3)[CH2:6][CH2:5][C:4]([C:11]3[CH:12]=[CH:13][C:8]([OH:15])=[CH:9][CH:10]=3)([C:4]3[CH:5]=[CH:6][C:1]([OH:7])=[CH:2][CH:3]=3)[CH2:3][CH2:2]2)=[CH:3][CH:2]=1
Reactant: O=C1CCC(=O)CC1
Reactant: Oc1ccccc1
Agent: Cl
Product: Oc1ccc(C2(c3ccc(O)cc3)CCC(c3ccc(O)cc3)(c3ccc(O)cc3)CC2)cc1

Procedure:
Into a molten mixture of 300 g (3.2 mole) of phenol and 22.4 g (0.2 mole) of 1,4-cyclohexanedione (m.p. 78° C.) was introduced hydrochloric acid gas at a temperature of 50° C. to saturation.
Reaction SMILES: [C:1](#[N:3])[CH3:2].[P:4]([OH:7])([OH:6])[OH:5]>O>[NH2:3][C:1]([P:4]([OH:7])([OH:6])=[O:5])([P:4]([OH:7])([OH:6])=[O:5])[CH3:2]
Reactant: CC#N
Reactant: OP(O)O
Solvent: O
Product: CC(N)(P(=O)(O)O)P(=O)(O)O
Temperature: 80 °C
Yield: 71 %

Procedure:
A mixture of acetonitrile (8.2 g, 0.2 mole), phosphorous acid (32.8 g, 0.4 mole), ISOPAR-M (20 g), and the above wetting agents (0.5 g each) was reacted for 3 hours at 150° C. The mixture was cooled to 80° C and water (50 g) was added. The colorless emulsion broke to give colorless granular 1-amino-1,1-diphosphono ethane, 29 g (71% yield), m.p. 270°-271° C (decomposition).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]([CH3:32])[C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:20]([CH3:31])[CH2:19]3)=[CH:13][CH:12]=2)=[O:9])=[CH:4][CH:3]=1.[F:33][C:34]1[CH:35]=[C:36]([OH:40])[CH:37]=[CH:38][CH:39]=1>>[F:33][C:34]1[CH:35]=[C:36]([O:40][C:2]2[N:7]=[CH:6][C:5]([C:8]([N:10]([CH3:32])[C:11]3[CH:16]=[CH:15][C:14]([CH2:17][N:18]4[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:20]([CH3:31])[CH2:19]4)=[CH:13][CH:12]=3)=[O:9])=[CH:4][CH:3]=2)[CH:37]=[CH:38][CH:39]=1
Reactant: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3ccc(Cl)nc3)cc2)CCN1C(=O)OC(C)(C)C
Reactant: Oc1cccc(F)c1
Product: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3ccc(Oc4cccc(F)c4)nc3)cc2)CCN1C(=O)OC(C)(C)C

Procedure:
The title compound was prepared from 1,1-dimethylethyl (2S)-4-({4-[[(6-chloro-3-pyridinyl)carbonyl](methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate (D54) and 3-fluorophenol in a similar manner to that described for D55 in Description 55, yielding the title compound as a pale yellow oil (0.057 g). MS (ES): MH+ 535.3.
Reaction SMILES: [N+](C1C=CC(O[C:9]([NH:11][C@H:12]([C@@H:20]([O:43][Si](C)(C)C)[CH2:21][C@@H:22]([NH:30][C:31]([O:33]C2C=CC([N+]([O-])=O)=CC=2)=O)[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:10])=CC=1)([O-])=O.[NH2:50][CH2:51][C:52]1[CH:53]=[N:54][CH:55]=[CH:56][CH:57]=1>CN(C=O)C>[N:54]1[CH:55]=[CH:56][CH:57]=[C:52]([CH2:51][NH:50][C:9]([NH:11][C@H:12]([C@@H:20]([OH:43])[CH2:21][C@@H:22]([NH:30][C:31]([NH:50][CH2:51][C:52]2[CH:53]=[N:54][CH:55]=[CH:56][CH:57]=2)=[O:33])[CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:10])[CH:53]=1
Reactant: C[Si](C)(C)O[C@@H](C[C@H](Cc1ccccc1)NC(=O)Oc1ccc([N+](=O)[O-])cc1)[C@H](Cc1ccccc1)NC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: NCc1cccnc1
Solvent: CN(C)C=O
Product: O=C(NCc1cccnc1)N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)NCc1cccnc1
Reaction time: 18 h

Procedure:
To a solution of 87 mg of the resultant compound from Example 218 in 1 ml of DMF was added 0.028 ml of 3-aminomethylpyridine. After 18 hours, the solvent was removed in vacuo and the residue was dissolved in 1 ml of methanol and 0.05 ml of chlorotrimethylsilane was added. After 0.5 hour, the solvent was removed in vacuo, neutralized with sodium bicarbonate solution and extraction with ethyl acetate (2×25 ml). The organic solution was dried and concentrated. Purification by silica gel column chromotography provided 35 mg of desired product. 1H NMR (CD3OD): δ 1.60 (t, 2H), 2.60-2.80 (m, 4H), 3.70 (m, 1H), 4.00 (m, 1H), 4.10 (m, 1H), 4.25-4.35 (m, 4H), 7.10-7.25 (m, 10H), 7.35 (m, 2H), 7.60 (m, 2H), 8.40 (m, 4H). Mass spectrum: (M+H)+ =553.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19](Cl)[N:18]=[C:17]([N:31]3[CH2:36][CH2:35][N:34]([CH:37]=[O:38])[CH2:33][CH2:32]3)[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:39]([OH:43])[CH2:40][CH2:41][OH:42]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:42][CH2:41][CH2:40][CH2:39][OH:43])[N:18]=[C:17]([N:31]3[CH2:36][CH2:35][N:34]([CH:37]=[O:38])[CH2:33][CH2:32]3)[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccccc1Oc1c(Cl)nc(N2CCN(C=O)CC2)nc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Reactant: OCCCO
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(N2CCN(C=O)CC2)nc1OCCCO

Procedure:
The procedure described in Synthesis Example 3 was repeated by use of 4-t-butyl-N-[6-chloro-2-(4-formylpiperazinyl)-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide and 1,3-propanediol, to thereby obtain the title compound as a pale yellow solid.
Reaction SMILES: [CH:1]1[C:6]2([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][C:3](=[O:12])[CH:2]=1.[H][H]>O1CCCC1.[C].[Pd]>[CH2:5]1[C:6]2([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:1][CH2:2][C:3](=[O:12])[CH2:4]1
Reactant: O=C1C=CC2(CCCCC2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: O=C1CCC2(CCCCC2)CC1
Yield: 103.2 %

Procedure:
To a solution of spiro[5.5]undec-1-en-3-one (8.9 g) obtained in Step 1 in tetrahydrofuran (360 mL) was added 5% palladium carbon (0.89 g), followed by stirring the reaction mixture at room temperature in an atmosphere of hydrogen under normal pressure for 2 hours. Then, the reaction mixture was filtered through Celite and the filtrate was concentrated to obtain spiro[5.5]undecan-3-one (9.3 g).
Reaction SMILES: [OH:1][CH:2]1[CH:6]2[CH2:7][CH2:8][CH:3]1[C:4]1[C:12]([C:13](=[O:35])[NH:14][CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([CH2:28][CH3:29])([CH3:27])[CH3:26])=[CH:21][C:20]=3[C:30]([CH2:33][CH3:34])([CH3:32])[CH3:31])=[CH:11][C:10]([OH:36])=[CH:9][C:5]=12.[Cl:37]N1C(=O)CCC1=O>O1CCCC1>[O:1]=[C:2]1[CH:6]2[CH2:7][CH2:8][CH:3]1[C:4]1[C:12]([C:13](=[O:35])[NH:14][CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([CH2:28][CH3:29])([CH3:27])[CH3:26])=[CH:21][C:20]=3[C:30]([CH2:33][CH3:34])([CH3:32])[CH3:31])=[C:11]([Cl:37])[C:10](=[O:36])[CH2:9][C:5]=12
Reactant: CCC(C)(C)c1ccc(OCCCNC(=O)c2cc(O)cc3c2C2CCC3C2O)c(C(C)(C)CC)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Product: CCC(C)(C)c1ccc(OCCCNC(=O)C2=C(Cl)C(=O)CC3=C2C2CCC3C2=O)c(C(C)(C)CC)c1

Procedure:
The above (4.9 g) synthesized in (3) above was dissolved in tetrahydrofuran (60 ml), and N-chlorosuccinimide (2.9 g) was added thereto, followed by reacting the reaction for 6 hours. Thereafter, the solvent was distilled off, and the residue was purified by silica gel chromatography to obtain 3,6-dioxo-4-[3-(2,4-di-t-pentylphenoxy)propylcarbamoyl]-5-chlorobenzonorbornene. (Yield: 5.0 g (95.7 %).