Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]2[C:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:17]=[C:18]([Cl:19])[C:4]=2[N:3]=1.[NH2:25][C:26]1[C:34]2[O:33][C:32]([F:36])([F:35])[O:31][C:30]=2[CH:29]=[CH:28][CH:27]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C1(C)C(C)=CC=CC=1>[Cl:19][C:18]1[C:4]2[N:3]=[C:2]([NH:25][C:26]3[C:34]4[O:33][C:32]([F:36])([F:35])[O:31][C:30]=4[CH:29]=[CH:28][CH:27]=3)[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]=2[C:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:17]=1
Reactant: CCOC(=O)CCCn1c(Cl)nc2c(Cl)ccc(C(CC)CC)c21
Reactant: Nc1cccc2c1OC(F)(F)O2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1C
Product: CCOC(=O)CCCn1c(Nc2cccc3c2OC(F)(F)O3)nc2c(Cl)ccc(C(CC)CC)c21
Temperature: 150 °C
Reaction time: 2 h
Yield: 80.8 %

Procedure:
A mixture of ethyl 4-[2,4-dichloro-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]butanoate (Reference Example 33; 815 mg, 2.19 mmol), 4-amino-2,2-difluoro-1,3-benzodioxole (950 mg, 5.49 mmol), p-toluenesulfonic acid monohydrate (416 mg, 2.19 mmol) and xylene (3.0 mL) was stirred at 150° C. for 2 hr. The mixture was neutralized with aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 0-20% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was washed with n-hexane to give the title compound as a colorless powder (900 mg, 1.77 mmol, 81%).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25]([CH2:33][CH2:34][O:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[C:26]([C:28]([O:30]CC)=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12].[OH-].[Na+]>C1COCC1.CO>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25]([CH2:33][CH2:34][O:35][CH2:36][C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)=[C:26]([C:28]([OH:30])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: CCOC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)sc1CCOCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Nc1nc2ccccc2s1)c1cccc2c1CN(c1nc(C(=O)O)c(CCOCc3ccccc3)s1)CC2

Procedure:
To compound 55A (138 mg, 0.230 mmol) in THF (3 ml) and MeOH (3 ml) was treated with 10% sodium hydroxide (0.46 ml, 1.152 mmol) for 1 day. The reaction mixture was concentrated and acidified by conc. HCl. The precipitate was collected by filtration and dried to provide the title compound: 1H NMR (500 MHz, DMSO-D6) δ ppm 12.89 (2H, s), 8.03 (1H, d), 7.80 (1H, d), 7.67 (1H, d), 7.42-7.51 (2H, m), 7.33-7.42 (2H, m), 7.25-7.31 (4H, m), 7.17-7.21 (1H, m), 4.82 (2H, s), 4.46 (2H, s), 3.74 (2H, t), 3.60 (2H, t), 3.28-3.35 (2H, m), 3.03 (2H, t); LCMS (APCI) m/e 571.
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=[O:4].[CH2:8]([C:12]1[N:16]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[C:25]([C:30]([OH:32])=[O:31])=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:20][CH:19]=2)[C:15]2[C:33](O)=[CH:34][CH:35]=[C:36]([CH3:37])[C:14]=2[N:13]=1)[CH2:9][CH2:10][CH3:11].C(Cl)(=O)C>N1C=CC=CC=1>[C:3]([O:5][C:33]1[C:15]2[N:16]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[C:25]([C:30]([OH:32])=[O:31])=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:20][CH:19]=3)[C:12]([CH2:8][CH2:9][CH2:10][CH3:11])=[N:13][C:14]=2[C:36]([CH3:37])=[CH:35][CH:34]=1)(=[O:4])[CH3:2]
Reactant: CCCCc1nc2c(C)ccc(O)c2n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Reactant: O=C(O)C(F)(F)F
Solvent: CC(=O)Cl
Solvent: c1ccncc1
Product: CCCCc1nc2c(C)ccc(OC(C)=O)c2n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Reaction time: 2 h

Procedure:
0.55 g (1 mmol) of 4'-[(2-n-butyl-7-hydroxy-4-methyl-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylic acid trifluoroacetate is dissolved in 20 ml of pyridine. 0.5 ml (7 mmol) of acetyl chloride is added dropwise to the mixture at 5° C. with stirring. The mixture is stirred for 1 hour at 5° C. and then for 2 hours at ambient temperature. The pyridine is distilled off in vacuum on a rotary evaporator. The residue is mixed with water and filtered under suction. After washing with water, it is dried at 50° C. in vacuum.
Reaction SMILES: [H-].[Na+].F[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[OH:21]>CN(C)C=O.O.Cl[Cu]>[F:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[O:21][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Oc1cc(F)ccc1F
Agent: Cl[Cu]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2cc(F)ccc2F)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 80.5 %

Procedure:
Into a 500 mL 3-necked round-bottom flask, was placed a solution of sodium hydride (3.9 g, 162.50 mmol, 1.7 equiv) in N,N-dimethylformamide (200 mL). This was followed by the addition of a solution of 1-fluoro-4-nitrobenzene (13.6 g, 96.39 mmol, 1.00 equiv) in N,N-dimethylformamide (50 mL) dropwise with stirring at 0° C. over 20 min. The reaction mixture was stirred for 2 hr at 25° C. and then CuCl (9.6 g, 96.97 mmol, 1.0 equiv) was added, followed by addition of a solution of 2,5-difluorophenol (15.5 g, 119.15 mmol, 1.2 equiv) in N,N-dimethylformamide (50 mL) dropwise with stirring at 25° C. over 10 min. The resulting solution was stirred for 12 h at 100° C. in an oil bath and then diluted with water and washed with ether, water and brine. The reaction mixture was dried over anhydrous sodium sulfate and concentrated. The residue was loaded onto a silica gel column and eluted with ethyl acetate/petroleum ether (1/8) to give 19.5 g (81%) of 1,4-difluoro-2-(4-nitrophenoxy)benzene as a brown solid,
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15]>>[CH3:8][C:6]1[CH:7]=[C:2]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15])[CH:3]=[C:4]([CH3:9])[CH:5]=1
Reactant: NCCCCO
Reactant: Cc1cc(C)cc(Br)c1
Product: Cc1cc(C)cc(NCCCCO)c1
Yield: 90 %

Procedure:
Using the general procedure, 5-bromo-m-xylene (136 μL, 1.0 mmol) was coupled with 4-aminobutanol (138 μL, 1.5 mmol). Purification of the crude product by column chromatography on silica gel using hexane/ethyl acetate (2:1) as eluent afforded the desired product as a colorless oil (174 mg, 90% yield). Rf=0.4 (hexane/ethyl acetate=1:1).
Reaction SMILES: C([SiH](CC)CC)C.[NH:8]([C:15]1[C:20]([CH:21](O)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:19][N:18]=[C:17]([Cl:29])[N:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O.C(=O)([O-])[O-].[Na+].[Na+]>FC(F)(F)C(O)=O>[NH:8]([C:15]1[C:20]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:19][N:18]=[C:17]([Cl:29])[N:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OC(c1ccccc1)c1cnc(Cl)nc1Nc1ccccc1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Clc1ncc(Cc2ccccc2)c(Nc2ccccc2)n1
Reaction time: 64 h
Yield: 25.8 %

Procedure:
Triethylsilane (0.14 ml, 1.10 mmol) was added to a solution of 4-anilino-2-chloro-5-[1-hydroxy-1-phenylmethyl]pyrimidine (Method 58; 170 mg, 0.55 mmol) in trifluoroacetic acid (1.5 ml), and the mixture was stirred for 64 hours. Water (20 ml) was added and the mixture was neutralised with sodium carbonate powder and extracted with DCM (3×20 ml). The extracts were combined, washed with water (30 ml), dried, concentrated to a volume of 5 ml, and loaded on a Varian Mega Bond Elut column. Elution with DCM and concentration of the appropriate fractions gave the product as a yellow crystalline solid (42 mg, 26%). NMR (CDCl3): 3.93 (s, 2H), 6.45 (br s, 1H), 7.08 (m, 1H), 7.2-7.4 (m, 9H), 8.09 (s, 1H); MS (MH+): 296.2, 298.2.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:12][C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=1[NH:20][C:21]([C:23]1[CH:33]=[CH:32][C:26]([O:27][CH2:28][C:29](Cl)=[O:30])=[CH:25][CH:24]=1)=[O:22]>O1CCOCC1>[CH:1]([NH:4][C:29](=[O:30])[CH2:28][O:27][C:26]1[CH:32]=[CH:33][C:23]([C:21](=[O:22])[NH:20][C:14]2[CH:15]=[CH:16][CH:17]=[C:18]([Cl:19])[C:13]=2[Cl:12])=[CH:24][CH:25]=1)([CH3:3])[CH3:2]
Reactant: O=C(Cl)COc1ccc(C(=O)Nc2cccc(Cl)c2Cl)cc1
Reactant: CC(C)N
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)NC(=O)COc1ccc(C(=O)Nc2cccc(Cl)c2Cl)cc1
Reaction time: 5 h

Procedure:
0.71 g of isopropylamine and 3.0 g of triethylamine were dissolved in 20 ml of dioxane. To this solution, a solution prepared by dissolving 4-(2,3-dichlorophenyl-carbamoyl)-phenoxyacetyl chloride prepared in the same manner as in Example 3 in 5 ml of dioxane, was dropwise added over a period of about 5 minutes at room temperature under stirring. After completion of the dropwise addition, the stirring was continued at room temperature for further 5 hours. After completion of the reaction, the reaction solution was treated in the same manner as in Example 3 to obtain 3.8 g of desired N-isopropyl-4-(2,3-dichlorophenyl-carbamoyl)-phenoxyacetamide.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[N:18]=[CH:17][C:16]2[N:15]([CH3:19])[C:14](=[O:20])[C@@H:13]([CH2:21][CH3:22])[N:12]([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[C:11]=2[N:10]=1.[C:28](O)([C:30](F)(F)F)=[O:29]>C(O)(=O)C>[CH:23]1([N:12]2[C:11]3[N:10]=[C:9]([C:8]4[CH:7]=[CH:6][N:5]=[CH:4][C:3]=4[CH2:2][NH:1][C:28](=[O:29])[CH3:30])[N:18]=[CH:17][C:16]=3[N:15]([CH3:19])[C:14](=[O:20])[C@H:13]2[CH2:21][CH3:22])[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(-c3ccncc3CN)nc2N1C1CCCC1
Reactant: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: CC[C@@H]1C(=O)N(C)c2cnc(-c3ccncc3CNC(C)=O)nc2N1C1CCCC1

Procedure:
The title compound was prepared similarly to the methods described in Example 102, with (R)-2-(3-(aminomethyl)pyridin-4-yl)-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropteridin-6(5H)-one (Example 105) instead of (R)-2-(3-aminopyridin-4-yl)-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropteridin-6(5H)-one (Example 91), and with acetic acid instead of benzoic acid. LCMS (0.05% TFA): 409.2 m/z (M+H)+; 1H-NMR (CDCl3, 500 MHz): δ: 8.98 (bs, 1H), 8.82 (d, 1H, J=5.0 Hz), 8.39 (d, 1H, J=5.0 Hz), 8.05 (s, 1H), 7.31 (bs, 1H), 4.84 (s, 2H), 4.46 (m, 1H), 4.37 (m, 1H), 3.44 (s, 3H), 2.03 (m, 1H), 1.95 (s, 3H), 1.94˜1.68 (m, 9H), 0.91 (t, 3H, J=7.5 Hz).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:26][CH3:27])[CH2:4][O:5][C:6]1[C:15]([CH3:16])=[C:14]2[C:9]([C:10](O)=[CH:11][C:12]([C:17]3[S:18][CH:19]=[C:20]([CH:22]([CH3:24])[CH3:23])[N:21]=3)=[N:13]2)=[CH:8][CH:7]=1.O=P(Cl)(Cl)[Cl:30].CO.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[Cl:30][C:10]1[C:9]2[C:14](=[C:15]([CH3:16])[C:6]([O:5][CH2:4][CH:3]([O:26][CH3:27])[O:2][CH3:1])=[CH:7][CH:8]=2)[N:13]=[C:12]([C:17]2[S:18][CH:19]=[C:20]([CH:22]([CH3:24])[CH3:23])[N:21]=2)[CH:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(COc1ccc2c(O)cc(-c3nc(C(C)C)cs3)nc2c1C)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CO
Product: COC(COc1ccc2c(Cl)cc(-c3nc(C(C)C)cs3)nc2c1C)OC
Temperature: 80 °C

Procedure:
7-(2,2-Dimethoxy-ethoxy)-2-(4-isopropyl-thiazol-2-yl)-8-methyl-quinolin-4-ol (875 mg, 2.3 mmol) was dissolved in pyridine (20 mL). POCl3 (4.2 ml, 46.0 mmol) was added slowly. The reaction was heated at 80° C. for 4 hours. The reaction was cooled to 0° C. and methanol (5 mL) was added. The reaction was neutralized with a saturated aqueous sodium bicarbonate solution. The product was extracted with ethyl acetate (3×20 mL). The combined organics were dried with sodium sulfate, filtered and was concentrated. 4-Chloro-7-(2,2-dimethoxy-ethoxy)-2-(4-isopropyl-thiazol-2-yl)-8-methyl-quinoline (410 mg, 44%) was purified by silica gel chromatography.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([OH:10])=O.C(N(CC)CC)C.ClC(OCCCC)=O.[CH3:26][C:27]1([CH3:37])[NH:31][CH2:30][C:29](=[O:32])[N:28]1[CH2:33][C:34]([NH2:36])=[O:35]>CN(C)C=O>[CH3:26][C:27]1([CH3:37])[N:31]([C:8](=[O:10])[CH2:7][N:3]2[CH2:4][CH2:5][CH2:6][C:2]2=[O:1])[CH2:30][C:29](=[O:32])[N:28]1[CH2:33][C:34]([NH2:36])=[O:35]
Reactant: O=C(O)CN1CCCC1=O
Reactant: CC1(C)NCC(=O)N1CC(N)=O
Agent: CCCCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1(C)N(CC(N)=O)C(=O)CN1C(=O)CN1CCCC1=O
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
An ice cold solution of 2-oxo-1-pyrrolidineacetic acid (1.45 g) and triethylamine (1.45 ml) in dimethylformamide (7 ml) was treated dropwise while stirring with butyl chloroformate (1.3 ml). After stirring at 0° C. for 45 minutes, 2,2-dimethyl-5-oxo-1-imidazolidineacetamide (1.75 g) was added at once and stirring was prolonged at room temperature overnight. After evaporation under reduced pressure, the residue was chromatographed on a silica gel column, eluting with dichloromethane/methanol 1:1. The selected fractions were collected and evaporated, the residue was taken up with ethyl acetate and the resulting solid was crystallized from ethanol, to give the title compound as a white powder, m.p. 225°-227° C., (decomp.).
Reaction SMILES: [CH:1]12[CH:12]=[CH:11][CH:7]([CH:8]3[CH:10]1[CH2:9]3)[CH:6]1[CH:2]2[C:3](=[O:14])[O:4][C:5]1=[O:13].[CH3:15][OH:16]>>[CH3:15][O:16][C:3]([CH:2]1[CH:1]2[CH:12]=[CH:11][CH:7]([CH:8]3[CH:10]2[CH2:9]3)[CH:6]1[C:5]([OH:4])=[O:13])=[O:14]
Reactant: O=C1OC(=O)C2C3C=CC(C4CC34)C12
Reactant: CO
Product: COC(=O)C1C2C=CC(C3CC23)C1C(=O)O
Temperature: 25 °C
Reaction time: 72 h
Yield: 94 %

Procedure:
rac-(1R,2S,6R,7S,8S,10R)-4-Oxatetracyclo[5.3.2.02,6.08,10]dodec-11-ene-3,5-dione (prepared as described in Example 51a, 0.86 g, 4.50 mmol) was dissolved in methanol (20 mL). The reaction was stirred at 25° C. for 72 h. The mixture was concentrated to afford a clear oil. Purification by flash column chromatography (Teledyne Isco RediSep column; 0 to 60% ethyl acetate in hexanes) afforded the desired product, rac-(1S,2S,4R,5R,6S,7R)-7-(Methoxycarbonyl)tricyclo [3.2.2.02,4]non-8-ene-6-carboxylic acid (0.94 g, 4.23 mmol, 94%) as a white solid. 1H NMR (400 MHz, CDCl3) δ: 0.06-0.17 (2H, m), 1.26-1.38 (2H, m), 2.74-2.85 (2H, m), 3.15-3.19 (2H, m), 3.67 (3H, s), 5.85-5.86 (2H, m). LC-MS (ESI) calcd for C12H14O4 222.24, found 223.5 [M+H+].
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[N:7][C:8]([Cl:12])=[CH:9][C:10]=1Cl)=[O:4].[CH3:13][N:14]1[CH:18]=[CH:17][C:16]([NH2:19])=[N:15]1>CN1CCCC1=O>[CH3:1][O:2][C:3]([C:5]1[N:6]=[N:7][C:8]([Cl:12])=[CH:9][C:10]=1[NH:19][C:16]1[CH:17]=[CH:18][N:14]([CH3:13])[N:15]=1)=[O:4]
Reactant: COC(=O)c1nnc(Cl)cc1Cl
Reactant: Cn1ccc(N)n1
Solvent: CN1CCCC1=O
Product: COC(=O)c1nnc(Cl)cc1Nc1ccn(C)n1
Temperature: 110 °C
Yield: 32.2 %

Procedure:
4,6-Dichloro-pyridazine-3-carboxylic acid methyl ester (165 mg, 0.8 mmol) and 1-methyl-1H-pyrazol-3-amine (81 mg, 0.837 mmol) were dissolved in of N-methylpyrrolidinone (3.2 mL). The reaction was heated at 110° C. for 2 h, then cooled and concentrated in vacuo. The residue was diluted with water and then extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (sodium sulfate), filtered and concentrated in vacuo. Purification by chromatography (silica, 10 to 70% ethyl acetate in hexanes) gave 6-chloro-4-(1-methyl-1H-pyrazol-3-ylamino)-pyridazine-3-carboxylic acid methyl ester (69 mg, 32%) as a light brown solid. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 10.09 (br. s., 1H) 8.24 (s, 1H) 7.34 (d, J=2.3 Hz, 1H) 6.02 (d, J=2.3 Hz, 1H) 4.08 (s, 3H) 3.91 (s, 3H); LCMS (EI/CI) m/z: 268 [M+H].
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[Cl:7][GeH:8]([Cl:10])[Cl:9]>>[CH3:3][CH:2]([CH2:4][Ge:8]([Cl:10])([Cl:9])[Cl:7])[C:1]([OH:6])=[O:5]
Reactant: Cl[GeH](Cl)Cl
Reactant: C=C(C)C(=O)O
Product: CC(C[Ge](Cl)(Cl)Cl)C(=O)O
Temperature: 5 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
84.7 ml (0.1 mol) of methacrylic acid was added dropwise over 5 minutes to 18 g (0.1 mol) of crude trichlorogermane which had been cooled to 5° C. in an ice bath. The mixture was stirred at the same temperature for one hour and then at room temperature for 1.5 hour. The precipitated crystal was filtered by suction, washed with 10 ml of n-hexane which had been dried over potassium chloride for four times, dried by suction and kept in a desiccator containing phosphorus pentoxide at 65° C. for one hour with reducing the pressure by a vacuum pump which uses potassium hydroxide containing trap to obtain 17.03 g of crystalline 2-methyl-3-(trichlorogermyl) propionic acid:
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:5]2[C:13]([CH3:20])=[C:14]([NH2:19])[C:15]([CH3:18])=[C:16]([CH3:17])[C:4]=2[O:3]1.[CH3:22][O:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:22][O:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([NH:19][C:14]2[C:15]([CH3:18])=[C:16]([CH3:17])[C:4]3[O:3][C:2]([CH3:21])([CH3:1])[CH:6]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)[C:5]=3[C:13]=2[CH3:20])=[O:29])=[CH:26][CH:25]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: Cc1c(C)c2c(c(C)c1N)C(c1ccccc1)C(C)(C)O2
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)Nc2c(C)c(C)c3c(c2C)C(c2ccccc2)C(C)(C)O3)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.9 %

Procedure:
To a solution of 2,2,4,6,7-pentamethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-amine (1.60 g, 5.69 mmol) and 4-methoxybenzoyl chloride (1.16 g, 6.82 mmol) in chloroform (20 ml) was added triethylamine (0.87 ml, 6.26 mmol) and the mixture was stirred at room temperature for 30 minutes. The solvent was removed under reduced pressure. Water (30 ml) was added into the residue and the product was extracted twice with ethyl acetate. The combined organic layers were washed with 1N hydrochloric acid and an aqueous, saturated solution of sodium hydrogen carbonate, dried on magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue was crystallized from methanol to obtain 1.70 g (72% yield) of the title compound. Melting point: 190-192° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.CS(O[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]2[N:26]=[C:27](/[CH:30]=[CH:31]/[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[O:28][CH:29]=2)=[CH:19][CH:18]=1)(=O)=O>>[N:1]1([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[N:26]=[C:27](/[CH:30]=[CH:31]/[C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[O:28][CH:29]=3)=[CH:19][CH:18]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: CS(=O)(=O)OCCCCCCc1ccc(OCc2coc(/C=C/c3ccccc3)n2)cc1
Product: C(=C/c1nc(COc2ccc(CCCCCCn3ccnc3)cc2)co1)\c1ccccc1
Yield: 66 %

Procedure:
In substantially the same manner as in Working Example 8, imidazole was allowed to react with 6-[4-[2-[(E) -2-phenylethenyl]-4-oxazolylmethoxy]phenyl]hexyl methanesulfonate to give 4-[4-[6-(1-imidazolyl)hexyl]phenoxymethyl]-2-[(E)-2-phenylethenyl]oxazole. The yield was 66%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 108-109° C.
Reaction SMILES: [CH3:1][C:2]([CH2:8][CH:9]([CH3:11])[CH3:10])=[C:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1.[CH3:12][Li].O>CCOCC>[CH3:1][C:2]([C:3]1[CH2:7][CH:6]=[CH:5][CH:4]=1)([CH3:12])[CH2:8][CH:9]([CH3:11])[CH3:10]
Reactant: [Li]C
Reactant: CC(CC(C)C)=C1C=CC=C1
Solvent: CCOCC
Solvent: O
Product: CC(C)CC(C)(C)C1=CC=CC1
Temperature: 25 °C
Reaction time: 96 h
Yield: 80 %

Procedure:
To a solution of 8.00 g (54.0 mmol) of 6-methyl-6-isobutylfulvene in 30 ml of ether, 54.0 ml (61.6 mmol) of an ether solution of methyllithium was dropwise added in a nitrogen atmosphere with ice cooling, followed by stirring at room temperature for 4 days. Then, 30 ml of water was added. The separated organic phase was washed with water and a saturated saline solution, then dried over magnesium sulfate and filtered. From the filtrate, the solvent was removed under reduced pressure to obtain a liquid. The liquid was subjected to vacuum distillation (120° C./25 mmHg) to obtain 7.10 g (43.2 mmol) of a light yellow liquid (yield: 80%)
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH:12]1(O)[CH2:16][CH2:15][CH2:14][CH2:13]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH:12]1([O:1][C:2]2[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: COc1ccc(C#N)c(O)c1
Reactant: OC1CCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(C#N)c(OC2CCCC2)c1
Temperature: 25 °C
Yield: 95.9 %

Procedure:
To a solution of 2-hydroxy-4-methoxy-benzonitrile (90 mg, 0.60 mmol, example 9), cyclopentanol (55 mg, 0.64 mmol) and triphenylphosphine (167 mg, 0.64 mmol) in THF (3 mL) at −78° C. was added diethyl azodicarboxalate (0.16 mL, 0.860 mmol, 85%). The cooling bath was removed and the reaction was allowed to warm up to room temperature over 1.5 h. The reaction mixture was concentrated in vacuo, and purification of the residue by flash chromatography (Biotage system, KP-Sil™ 32-63 μm, 60 Å silica gel) eluting with 0-8% diethyl ether in hexanes yielded 2-cyclopentyloxy-4-methoxy-benzonitrile as a clear liquid (125 mg, 90%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7](=[O:35])[N:8]([CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:29])[F:28])=[C:22]([O:30][CH2:31][CH:32]3[CH2:34][CH2:33]3)[CH:21]=1)[CH2:16][C:17](O)=[O:18])[C:9]2=[O:14])(=[O:3])[CH3:2].[C:36](N1C=CN=C1)([N:38]1C=CN=[CH:39]1)=O.CNC.O>O1CCCC1>[C:1]([NH:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7](=[O:35])[N:8]([CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:28])[F:29])=[C:22]([O:30][CH2:31][CH:32]3[CH2:34][CH2:33]3)[CH:21]=1)[CH2:16][C:17]([N:38]([CH3:39])[CH3:36])=[O:18])[C:9]2=[O:14])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc2c1C(=O)N(C(CC(=O)O)c1ccc(OC(F)F)c(OCC3CC3)c1)C2=O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)Nc1cccc2c1C(=O)N(C(CC(=O)N(C)C)c1ccc(OC(F)F)c(OCC3CC3)c1)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.8 %

Procedure:
To a solution of 3-(4-acetylamino-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-propionic acid (470 mg, 1.04 mmol) in tetrahydrofurane (10 ml) was added carbonyldiimidazole (250 mg, 1.56 mmol) at room temperature. The solution was stirred at room temperature for 2 hours. To the mixture was added dimethylamine (2.0N in THF, 1.0 ml, 2.0 mmol). The resulted mixture was stirred at room temperature for 3 hours. Water (20 ml) was added to the reaction mixture. The solvent was removed in vacuo. The resulted mixture was dissolved in ethyl acetate (30 ml) and extracted with water (20 ml). The organic layer was washed with saturated sodium bicarbonate solution (3×20 ml), water (20 ml), brine (20 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The resulted oil was stirred with ether overnight. The suspension was filtered to give a yellowish solid. The solid was purified by HPLC(CH3CN: Water=45:55) to give 3-(4-acetylamino-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-N,N-dimethyl-propionamide as a white solid (160 mg, 30%): mp 80-82° C.; 1H NMR: δ (CDCl3): δ 0.33-0.39 (m, 2H), 0.60-0.68 (m, 2H), 1.21-1.30 (m, 1H), 2.25 (s, 3H), 2.90 (s, 3H), 2.97 (dd, J=5 Hz, the other doublet is buried, 1H), 3.05 (s, 3H), 3.87 (d, J=7.5 Hz, 2H), 3.94 (dd, J=10 Hz, the other doublet is buried, 1H), 5.83 (dd, J=5, 10 Hz, 1H), 6.69 (t, JH-F=75 Hz, 1H), 7.12-7.15 (m, 3H), 7.45 (d, J=7.5 Hz, 1H), 7.62 (t, J=7.5 Hz, 1H), 8.73 (d, J=8.5 Hz, 1H), 9.53 (s, 1H). 13C NMR (CDCl3): δ 3.8, 3.9, 10.8, 25.6, 35.4, 36.1, 37.7, 51.9, 74.5, 112.6, 116.7, 120.8, 114.9, 116.0, 118.5, 120.9, 123.4, 125.3, 131.9, 136.4, 138.0, 138.6, 140.7, 151.2, 168.7, 169.8, 169.9, 170.6; Anal. Calcd. for C26H27F2N3O6: C, 60.58; H, 5.28; N, 8.15. Found: C, 60.23; H, 5.26; N, 8.02.