Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20](Cl)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:35][C:36]1[CH:46]=[CH:45][C:39](/[CH:40]=[CH:41]/B(O)O)=[CH:38][CH:37]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.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>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20](/[CH:41]=[CH:40]/[C:39]3[CH:45]=[CH:46][C:36]([Cl:35])=[CH:37][CH:38]=3)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Reactant: OB(O)/C=C/c1ccc(Cl)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(/C=C/c2ccc(Cl)cc2)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Temperature: 85 °C

Procedure:
In a 30 mL sealed cap glass vial, tert-butyl 6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (150 mg, 0.299 mmol), (E)-4-chlorostyrylboronic acid (54.6 mg, 0.299 mmol) and PdCl2(PPh3)2 (42.0 mg, 0.060 mmol) were dissolved in dioxane (5 mL). To the reaction mixture was added 2N aqueous sodium carbonate solution (2 mL). The cap was sealed and the reaction mixture was heated at 85° C. for 2 hours. The reaction mixture was subsequently diluted with water (5 mL) and extracted with EtOAc (2×30 mL). The combined organic phase was dried over sodium sulfate and evaporated to give the intermediate, tert-butyl 6-(((3R,4R)-3-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-4-yl)amino)-4-((E)-4-chlorostyryl)-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate. The intermediate was diluted with dichloromethane (3.0 mL) and treated with TFA (3 mL) for 1.5 hours to remove the protecting groups. The volatiles were subsequently evaporated from the reaction mixture, and the residual material was dissolved in DMSO (8 mL) and purified by preparative HPLC, eluting with 20-60% ACN (0.035% TFA) and water (0.05% TFA). The pure product fractions were combined, evaporated to a minimal volume, and lyophilized to give a TFA salt of the title compound as a pale yellow solid (42 mg, 35%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.77 (d, J=15.66 Hz, 1H), 1.98-2.22 (m, 1H), 3.50-3.73 (m, 2H), 3.79-4.08 (m, 3H), 4.32-4.51 (m, 2H), 4.55 (br s, 1H), 7.17 (d, J=5.05 Hz, 1H), 7.50 (d, J=8.59 Hz, 2H), 7.55-7.73 (m, 2H), 7.92 (d, J=4.55 Hz, 3H), 8.22 (d, J=16.17 Hz, 1H), 8.53 (s, 1H). ESI-MS m/z [M+H]+ calc'd for C20H20ClFN4O2, 403. found, 403.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:32][C:33]1[C:38]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[CH:37][CH:36]=[C:35]([C:48]2[CH:53]=[CH:52][C:51]([OH:54])=[CH:50][CH:49]=2)[N:34]=1.[CH2:55]([C@@H:60]1[O:62][C@H:61]1[CH2:63]O)[CH2:56][CH2:57][CH2:58][CH3:59]>O1CCCC1>[F:32][C:33]1[C:38]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[CH:37][CH:36]=[C:35]([C:48]2[CH:49]=[CH:50][C:51]([O:54][CH2:63][C@H:61]3[C@H:60]([CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])[O:62]3)=[CH:52][CH:53]=2)[N:34]=1
Reactant: CCCCCCCCOc1ccc(-c2ccc(O)cc2)nc1F
Reactant: CCCCC[C@@H]1O[C@H]1CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCCOc1ccc(-c2ccc(OC[C@@H]3O[C@H]3CCCCC)cc2)nc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 54.7 %

Procedure:
0.91 g (5.25 mmol) of diethyl azodicarboxylate is added dropwise at 0° C. to 1.37 g (5.25 mmol) of triphenylphosphine in 20 ml of tetrahydrofuran, and the mixture is stirred at 0° C. for 30 minutes. 1.11 g (3.50 mmol) of 2-fluoro-6-(4-hydroxyphenyl)-3-octyloxypyridine (prepared as described in EXAMPLE 21) and 0.75 g (5.25 mmol) of (2S,3S)-3-pentyl-2-oxiranylmethanol are then added. After a reaction time of 18 hours at room temperature, the solvent is distilled off, and the residue is purified by chromatography (silica gel, 8:2 hexane/ethyl acetate). Recrystallization from hexane gives 0.85 g of (2S,3S)-3-pentyloxiran-2-ylmethyl 4-(2-fluoro-3-octyloxypyridin-6-yl)phenyl ether having an [α]D20 (2.6% in CH2Cl2) of -18.01°. ##STR71##
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:30])[CH2:7][CH:8]1[C:17]2[C:12](=[C:13]([CH3:22])[C:14]([C:18]([NH:20][OH:21])=[NH:19])=[CH:15][CH:16]=2)[CH2:11][CH2:10][N:9]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[C:38]([C:40]1[CH:41]=[C:42]([CH:46]=[CH:47][C:48]=1[O:49][CH:50]([CH3:52])[CH3:51])[C:43](Cl)=O)#[N:39]>O1CCOCC1>[CH2:1]([O:5][C:6](=[O:30])[CH2:7][CH:8]1[C:17]2[C:12](=[C:13]([CH3:22])[C:14]([C:18]3[N:19]=[C:43]([C:42]4[CH:46]=[CH:47][C:48]([O:49][CH:50]([CH3:52])[CH3:51])=[C:40]([C:38]#[N:39])[CH:41]=4)[O:21][N:20]=3)=[CH:15][CH:16]=2)[CH2:11][CH2:10][N:9]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)Oc1ccc(C(=O)Cl)cc1C#N
Reactant: CCCCOC(=O)CC1c2ccc(C(=N)NO)c(C)c2CCN1C(=O)OC(C)(C)C
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCCCOC(=O)CC1c2ccc(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)c(C)c2CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 11.1 %

Procedure:
To a solution of 1,1-dimethylethyl 1-[2-(butyloxy)-2-oxoethyl]-6-[(hydroxyamino)(imino)methyl]-5-methyl-3,4-dihydro-2(1H)-isoquinolinecarboxylate (Preparation 19; 264 mg, 0.629 mmol) in dioxane (4 ml) was added triethylamine (0.263 ml, 1.89 mmol) followed by dropwise addition of 3-cyano-4-[(1-methylethyl)oxy]benzoyl chloride (preparation described in WO 2008128951; 169 mg, 0.755 mmol) in dioxane (2 ml). The resulting mixture was stirred at room temperature for 90 min, then heated at 100° C. for 24 h. The mixture was cooled to room temperature and most of the solvent removed in vacuo. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate. The layers were separated, and the aqueous layer further extracted with ethyl acetate. The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification by flash chromatography, eluting with 5-25% ethyl acetate in cyclohexane, gave the title compound as a pale yellow oil (41 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][N:6]=[C:5]([CH2:10][OH:11])[C:4]=1[CH3:12]>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][N:6]=[C:5]([CH:10]=[O:11])[C:4]=1[CH3:12]
Reactant: COc1c(C)cnc(CO)c1C
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: COc1c(C)cnc(C=O)c1C
Reaction time: 3 h
Yield: 100.2 %

Procedure:
(4-methoxy-3,5-dimethyl-pyridin-2-yl)methanol (Tokyo Kasei Kogyo Co., Ltd.) (300 mg) was dissolved in chloroform (15 ml) and added with manganese dioxide (chemically processed product) (3.00 g), followed by stirring for 3 hours. After completion of the reaction, the solution was filtrated through Celite and the solvent was then distilled off, thereby obtaining the subject compound (297 mg) as a white solid.
Reaction SMILES: [C:1]([CH2:4][N:5]([S:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=[O:29])=[O:28])[C:6]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:7]=1[O:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=1)([OH:3])=[O:2].C1(S(NC2C=CC(C(F)(F)F)=C[C:47]=2[O:48][CH2:49]C2C=CC(C(OC)=O)=CC=2)(=O)=O)C=CC=CC=1.COCCl.C(N(CC)CC)C>CN(C=O)C.O>[CH3:47][O:48][CH2:49][O:2][C:1]([CH2:4][N:5]([S:27]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)(=[O:28])=[O:29])[C:6]1[CH:22]=[CH:21][C:20]([C:23]([F:25])([F:24])[F:26])=[CH:19][C:7]=1[O:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([OH:16])=[O:15])=[CH:17][CH:18]=1)=[O:3]
Reactant: O=C(O)CN(c1ccc(C(F)(F)F)cc1OCc1ccc(C(=O)O)cc1)S(=O)(=O)c1ccccc1
Reactant: COC(=O)c1ccc(COc2cc(C(F)(F)F)ccc2NS(=O)(=O)c2ccccc2)cc1
Agent: COCCl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: COCOC(=O)CN(c1ccc(C(F)(F)F)cc1OCc1ccc(C(=O)O)cc1)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-[2-(N-carboxymethyl-phenylsulfonylamino)-5-trifluoromethyl-phenoxymethyl]benzoic acid (446 mg) prepared by the same procedure as Example 17→Example 2 by using methyl 4-(2-phenylsulfonylamino-5-trifluoromethylphenoxymethyl)benzoate (prepared in Example 15) was dissolved in DMF (5 ml). To the solution, methoxymethyl chloride (160 μl) and triethylamine (300 μl) were added dropwise. The mixture was stirred for 2 hours at room temperature. Water was added thereto. The mixture was extracted with ethyl acetate, washed, dried over, filtered and concentrated to give the title compound (476 mg) having the following physical data.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[N:26]=[CH:27][NH:28][C:29]=1[C:30]([NH2:32])=[O:31])(=O)C.C[O-].[Na+].C(O)(=O)C>CO>[C@@H:6]1([O:24][C:25]2[N:26]=[CH:27][NH:28][C:29]=2[C:30]([NH2:32])=[O:31])[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2nc[nH]c2C(N)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: NC(=O)c1[nH]cnc1O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 90 %

Procedure:
To a solution of 457 mg of 4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)oxy-1H-imidazole-5-carboxamide in 30 ml of dry methanol was added 270 mg of 95% sodium methoxide. The reaction mixture was stirred for 20 minutes at room temperature and 0.33 ml of acetic acid was added. Chromatographical purification on LH-20 (product of Pharmacia A/S) in methanol of the residue which was obtained after evaporation of the reaction mixture under reduced pressure, gave 260 mg of 4-β-D-glucopyranosyloxy-1H-imidazole-5-carboxamide which was crystallized with acetone. m.p. 167° C. (dec.)
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[BH4-].[Na+].C(OCC)(=O)C>CO>[OH:12][CH:10]([C:7]1[CH:8]=[CH:9][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][CH:6]=1)[CH3:11]
Reactant: CC(=O)c1ccc(C(C)=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(=O)c1ccc(C(C)O)cc1

Procedure:
To a solution of 1-(4-acetylphenyl)-ethanone (1.0 g, 6.2 mmol) in dry methanol (30 mL) at 0° C. was slowly added NaBH4 (0.07 g, 1.9 mmol). The reaction mixture was allowed to stir at 0° C. for 4 h, at which time silica gel TLC in hexanes and ethyl acetate (1:1 v/v, rf=0.5 desired product) showed a mixture of starting material, desired product, and the double-reduction side product. The reaction mixture was treated slowly with 1 N HCl solution (1 mL) at 0° C. until bubbling was no longer observed. Methanol was removed in vacuo to provide an orange residue, which was then partitioned between ethyl acetate (100 mL) and 1 N HCl (100 mL). The organic layer was washed with the 1 N HCl followed by a saturated NaCl solution (100 mL), dried over MgSO4, filtered and concentrated in vacuo to afford an orange oil. The crude product was purified by flash chromatography through a silica gel column with hexanes and ethyl acetate (65:35 v/v) to provide the desired compound (0.55 g, 54%) as a clear oil. 1H NMR (300 MHz, CDCl3) δ ppm 7.97 (d, 2H), 7.50 (d, 2H), 5.00 (dt, 1H), 2.61 (s, 3H), 1.52 (d, 3H).
Reaction SMILES: [CH3:1][CH:2]([CH2:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH2:3][PH:4](=[O:6])[OH:5].[CH2:12]([OH:23])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]=[CH2:22]>C(OOC(CC)(C)C)(CC)(C)C>[OH:23][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][P:4]([CH2:3][CH:2]([CH3:1])[CH2:7][C:8]([CH3:10])([CH3:9])[CH3:11])(=[O:5])[OH:6]
Reactant: CC(C[PH](=O)O)CC(C)(C)C
Reactant: C=CCCCCCCCCCO
Agent: CCC(C)(C)OOC(C)(C)CC
Product: CC(CC(C)(C)C)CP(=O)(O)CCCCCCCCCCCO
Temperature: 140 °C
Yield: 100.4 %

Procedure:
5 g (0.028 moles) of 2,4,4-trimethylpentyl phosphinic acid, 4.78 g (0.28 moles) of 10-undecen-1-ol and 0.3 mL (0.0014 moles) of di-tert-amylperoxide is mixed in a 50 mL single neck flask. The mixture is purged with argon to remove oxygen and is heated under argon for 5 hours at 140° C. Tert-amyl alcohol is removed by distillation and 9.8 g (quantitative yield) of (11-hydroxy-undecyl)-(2,4,4-trimethylpentyl)-phosphinic acid is obtained as a viscous oil.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([C:27]2[O:31][C:30]([CH3:32])=[N:29][C:28]=2[C:33](O)=[O:34])[CH:24]=[CH:25][CH:26]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:33]([C:28]3[N:29]=[C:30]([CH3:32])[O:31][C:27]=3[C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([O:20][CH3:19])[CH:22]=3)=[O:34])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ncc(N)n3)o2)OCCO1
Reactant: COc1cccc(-c2oc(C)nc2C(=O)O)c1
Product: COc1cccc(-c2oc(C)nc2C(=O)Nc2cnn(Cc3ccc(C(C)=O)o3)n2)c1

Procedure:
Following general procedure A followed by either B or C, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(3-methoxy-phenyl)-2-methyl-oxazole-4-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([NH:11]C(=O)/C=C\C(O)=O)=[O:10])[CH:6]=[CH:5][N:4]=1.O=P(Cl)(Cl)Cl.[NH2:24][NH:25][C:26](=[N:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[Cl:44])[C:27]1[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=1>C1(C)C=CC=CC=1>[Cl:44][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=1[N:37]1[C:26]([C:27]2[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:34])=[O:35])=[CH:29][CH:28]=2)=[N:25][N:24]=[C:6]1/[CH:7]=[CH:8]/[C:3]1[O:10][C:9]([C:7]2[CH:6]=[CH:5][N:4]=[C:3]([O:2][CH3:1])[CH:8]=2)=[N:11][N:4]=1
Reactant: CS(=O)(=O)c1ccc(C(=Nc2ccccc2Cl)NN)cc1
Reactant: COc1cc(C(=O)NC(=O)/C=C\C(=O)O)ccn1
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(-c2nnc(/C=C/c3nnc(-c4ccc(S(C)(=O)=O)cc4)n3-c3ccccc3Cl)o2)ccn1

Procedure:
To a suspension of (Z)-4-(2-methoxypyridine-4-carboamido)-4-oxobut-2-enoic acid 9 (180 mg, 0.68 mmol) in 20 mL of PhMe was added 0.2 mL of POCl3. The mixture was stirred at reflux for 2 hours. After removal of solvent, the residue was dissolved in 20 mL of THF and 220 mg (0.68 mmol) of N-amino-N′-(2-chlorophenyl)-4-methylsulfonyl-benzamidine 5 added. The mixture was stirred at ambient temperature for 18 hours. After removal of solvent, the residue was purified by column (0-5% of methanol in dichloromethane) to give 4-(5-((E)-2-(4-(2-chlorophenyl)-5-(4-(methylsulfonyl)phenyl)-4H-1,2,4-triazol-3-yl)vinyl)-1,3,4-oxadiazol-2-yl)-2-methoxypyridine as a solid. Yield: 30 mg, 8.3%.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.C(C1NC=CN=1)(C1NC=CN=1)=O.[Mg+2].[Cl-].[Cl-].[K+].[C:26]([O:32][CH2:33][CH3:34])(=[O:31])[CH2:27]C([O-])=O.[N-]1C=CN=C1>O1CCCC1>[O:9]=[C:1]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)[CH2:27][C:26]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: O=C(O)c1cccnc1
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.6 %

Procedure:
To a suspension of nicotinic acid 5.00 g (40.6 mmol) in tetrahydrofuran 50 mL was added carbonyl diimidazole 9.76 g (60.9 mmol) at 5° C. and stirred at room temperature for 1 hour. In a separate flask, a suspension of MgCl2 4.64 g (48.7 mmol) and ethyl malonate potassium salt 10.37 g (60.92 mmol) in tetrahydrofuran 50 mL was stirred at 50° C. for 4 hours. To this suspension was added the aforementioned imidazolide solution at room temperature and stirred for 12 hours. The reaction was quenched by the addition of water and extracted into ethyl acetate. The organic layer was washed by brine, dried over MgSO4, filtrated and the solvent was evaporated. Silica gel chromatography (n-hexane/AcOEt=2/1) afforded the title compound 3.89 g as pale yellow oil. Yield 49.5%.
Reaction SMILES: [CH2:1]([O:3]CC)C.Br[C:7]1[CH:8]=[CH:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[N:11][CH:12]=1.C([Li])CCC.CN(C)C=O>O>[F:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[O:13][C:10]1[N:11]=[CH:12][C:7]([CH:1]=[O:3])=[CH:8][CH:9]=1
Reactant: CCOCC
Reactant: Fc1cccc(Oc2ccc(Br)cn2)c1
Agent: [Li]CCCC
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(Oc2cccc(F)c2)nc1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 52 %

Procedure:
To a diethyl ether (100 mL) solution of 5-bromo-2-(3-fluorophenoxy)-pyridine (5.81 g, 21.7 mmol) described in Manufacturing Example 71-1-1 was added n-butyl lithium (13.8 mL, 1.57 M n-hexane solution, 21.7 mmol) under nitrogen atmosphere at −78° C., which was stirred for 40 minutes at −78° C. N,N-Dimethylformamide (2.02 mL, 26.0 mmol) was then added to the mixture at −78° C., and stirred for 25 minutes as the temperature was gradually raised to 0° C. Water was added to the reaction solution at 0° C., which was then extracted with ethyl acetate. The organic layer was separated, washed with 1 N aqueous sodium hydroxide solution and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=5:1) to obtain the tile compound (2.47 g, 52%).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)([OH:8])[CH2:6][CH3:7])[CH3:3].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH2:26][CH2:27][C:28](Cl)=[O:29])[CH:19]=[C:20]([O:24][CH3:25])[C:21]=1[O:22][CH3:23]>>[CH3:25][O:24][C:20]1[CH:19]=[C:18]([CH2:26][CH2:27][C:28]([O:8][C:5]([CH2:4][N:2]([CH3:3])[CH3:1])([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[CH2:6][CH3:7])=[O:29])[CH:17]=[C:16]([O:15][CH3:14])[C:21]=1[O:22][CH3:23]
Reactant: CCC(O)(CN(C)C)c1cccs1
Reactant: COc1cc(CCC(=O)Cl)cc(OC)c1OC
Product: CCC(CN(C)C)(OC(=O)CCc1cc(OC)c(OC)c(OC)c1)c1cccs1
Yield: 51.9 %

Procedure:
1-Dimethylaminomethyl-1-(2-thienyl)-1-propanol (1.12 g) and 3-(3,4,5-trimethoxyphenyl)propionyl chloride (1.61 g) are treated in the same manner as described in Example 1-(2), whereby 1-dimethylaminomethyl-1-(2-thienyl)propyl 3-(3,4,5-trimethoxyphenyl)propionate (1.23 g) is obtained as colorless oil.
Reaction SMILES: I[C:2]1[C:3]([CH3:18])=[N:4][N:5]([C@H:7]2[CH2:12][CH2:11][C@H:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:9][CH2:8]2)[CH:6]=1.C1COCC1.C([Mg]Cl)(C)C.CO[B:31]1[O:35][C:34]([CH3:37])([CH3:36])[C:33]([CH3:39])([CH3:38])[O:32]1>>[CH3:18][C:3]1[C:2]([B:31]2[O:35][C:34]([CH3:37])([CH3:36])[C:33]([CH3:39])([CH3:38])[O:32]2)=[CH:6][N:5]([C@H:7]2[CH2:12][CH2:11][C@H:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:9][CH2:8]2)[N:4]=1
Reactant: COB1OC(C)(C)C(C)(C)O1
Reactant: CCOC(=O)[C@H]1CC[C@H](n2cc(I)c(C)n2)CC1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCOC(=O)[C@H]1CC[C@H](n2cc(B3OC(C)(C)C(C)(C)O3)c(C)n2)CC1
Reaction time: 0.5 h

Procedure:
To a solution of ethyl trans-4-(4-iodo-3-methyl-1H-pyrazol-1-yl)cyclohexanecarboxylate (120.0 mg, 0.3313 mmol) in THF (6 mL, 80 mmol) was added 2 M isopropylmagnesium chloride in THF (0.66 mL, 1.3 mmol) at rt, and the mixture was stirred for 30 min. 2-Methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.27 mL, 1.7 mmol) was added, and the mixture stirred at rt for 2 h. The reaction was quenched with sat. NH4Cl, and the organic solvent was removed in vacuo. The material was extracted with DCM and water, and the organic layer was concentrated in vacuo to afford the title compound as a clear oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[NH:5][C:6]1[C:11](I)=[CH:10][CH:9]=[C:8]([F:13])[N:7]=1)[CH3:2].[C:15]([Si:17]([CH3:20])([CH3:19])[CH3:18])#[CH:16].C(N(CC)CC)C.C(OCC)(=O)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.O>[CH2:1]([O:3][C:4](=[O:14])[NH:5][C:6]1[C:11]([C:16]#[C:15][Si:17]([CH3:20])([CH3:19])[CH3:18])=[CH:10][CH:9]=[C:8]([F:13])[N:7]=1)[CH3:2]
Reactant: CCOC(=O)Nc1nc(F)ccc1I
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)Nc1nc(F)ccc1C#C[Si](C)(C)C
Yield: 41.5 %

Procedure:
A mixture of compound 57 (4 g, 12.9 mmol), 3.3 ml (23.4 mmol) TMSA (ethynyl-trimethyl-silane), 246 mg (1.29 mmol) Cu(I)iodide, 454 mg (0.65 mmol) PdCl2(PPh3)2 (454 mg, 0.64 mmol) and triethylamine (6.3 ml) was stirred and degassed (N2). The resulting reaction mixture was stirred for 10 hours at 100° C. (closed vessel), cooled and poured into ethyl acetate and H2O. The organic layer was washed with H2O, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (diethyl ether/PE (1/3)) to afford (6-fluoro-3-trimethylsilanylethynyl-pyridin-2yl)-carbamic acid ethyl ester (58) (oil, 1.5 g, 42%). 1H-NMR (200 MHz, CDCl3) δ 7.76 (bt, J=8 Hz, 1H), 7.68-7.60 (bs, 1H), 6.56 (dd, J=8 Hz, 3 Hz, 1H), 4.29 (q, J=8 Hz, 2H), 1.34 (t, J=8 Hz, 3H), 0.3 (s, 9H). (TLC diethyl ether/PE 1/1 Rf 0.39).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].C1(=O)O[CH2:20][CH2:19][O:18]1>CN(C=O)C>[NH:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([O:1][CH2:20][CH2:19][OH:18])[CH:10]=2)[CH:6]=[CH:7]1
Reactant: O=C1OCCO1
Reactant: Oc1ccc2cc[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCOc1ccc2cc[nH]c2c1
Temperature: 125 °C

Procedure:
A mixture of 6-hydroxyindole (2.66 g, 20 mmol) and K2CO3 (3.04 g, 22 mmol) was stirred in DMF (10 mL) at 80° C. for 10 min. A solution of ethylene carbonate (1.94 g, 22 mmol) in DMF (4 mL) was added and the mixture was heated at 125° C. for 3 h. The mixture was concentrated, diluted with water, and extracted with toluene. The organic phase was washed with 1 M aqueous Na2CO3 and brine. The organic layer was dried (Na2SO4) and concentrated. The residue was purified by flash chromatography on silica using EtOAc/toluene (1:4→36:65) as eluent. Yield 1.02 g (29%); mp 74-77° C.; HRMS m/z calcd for C10H11NO2(M)+177.0790, found 177.0784. Anal. (C10H11NO2) C, H, N.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10]Cl)=[CH:6][N:5]=1.[OH:12][C:13]1[CH:14]=[C:15]([CH:21]=[CH:22][CH:23]=1)[C:16]([O:18]CC)=[O:17].[I-].[K+].[OH-].[Na+]>CN(C=O)C.O>[Cl:3][C:4]1[N:5]=[CH:6][C:7]([CH2:10][O:12][C:13]2[CH:14]=[C:15]([CH:21]=[CH:22][CH:23]=2)[C:16]([OH:18])=[O:17])=[CH:8][CH:9]=1
Reactant: CCOC(=O)c1cccc(O)c1
Reactant: ClCc1ccc(Cl)nc1
Agent: [H-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1cccc(OCc2ccc(Cl)nc2)c1
Temperature: 20 °C
Reaction time: 48 h
Yield: 16 %

Procedure:
NaH (55% suspension in mineral oil, 1.2 g, 28 mmol) was slowly added to a suspension of 2-chloro-5-chloromethylpyridine (3.0 g, 19 mmol), ethyl 3-hydroxybenzoate (3.1 g, 19 mmol), and potassium iodide (600 mg, 3.7 mmol) in DMF (20 ml). After stirring for 2 days at 20° C., water (10 ml) and NaOH (32.5%, 2 ml) was added. The dark mixture was stirred at 80° C. overnight, whereupon it was concentrated in vacuo. The residue was purified by preparative LC-MS to give 0.80 g of the title compound. LC-MS (m/z): 264 (M+1).