Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1](/[CH:4]=[CH:5]/[C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1)([O-:3])=[O:2].[CH:16](=[O:20])[CH:17]([CH3:19])[CH3:18].CC(O)C.CCCCCC>C(Cl)(Cl)Cl>[CH3:18][C:17]([CH3:19])([C@H:5]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1)[CH2:4][N+:1]([O-:3])=[O:2])[CH:16]=[O:20]
Reactant: CC(C)C=O
Reactant: O=[N+]([O-])/C=C/c1ccc2ccccc2c1
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Solvent: CC(C)O
Product: CC(C)(C=O)[C@@H](C[N+](=O)[O-])c1ccc2ccccc2c1

Procedure:
The title compound was prepared from (E)-2-(2-nitrovinyl)naphthalene and isobutyraldehyde according to General Procedure. The enantiomeric excess was determined by HPLC with Chiralpak AS-H column at 210 nm (2-propanol:hexane=10:90), 1 mL/min, tmajor=16.2 min, tminor=18.0 min, [α]D20=+1.7 (c=1.8, CHCl3)
Reaction SMILES: [F:1][C:2]([F:34])([O:6][C:7]1[CH:33]=[CH:32][C:10]([CH:11]=[N:12][NH:13][C:14]([NH:16][N:17]=[CH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]([F:31])([F:30])[CH:27]([F:29])[F:28])=[CH:21][CH:20]=2)=[NH:15])=[CH:9][CH:8]=1)[CH:3]([F:5])[F:4].C(N(C(C)C)CC)(C)C.[CH3:44][N:45]([CH3:49])[C:46](Cl)=[O:47]>C(#N)C>[F:1][C:2]([F:34])([O:6][C:7]1[CH:33]=[CH:32][C:10]([CH:11]=[N:12][NH:13][C:14](=[NH:15])[N:16]([N:17]=[CH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]([F:31])([F:30])[CH:27]([F:29])[F:28])=[CH:21][CH:20]=2)[C:46]([N:45]([CH3:49])[CH3:44])=[O:47])=[CH:9][CH:8]=1)[CH:3]([F:4])[F:5]
Reactant: N=C(NN=Cc1ccc(OC(F)(F)C(F)F)cc1)NN=Cc1ccc(OC(F)(F)C(F)F)cc1
Reactant: CN(C)C(=O)Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)N(N=Cc1ccc(OC(F)(F)C(F)F)cc1)C(=N)NN=Cc1ccc(OC(F)(F)C(F)F)cc1
Yield: 92.9 %

Procedure:
A solution of 1,3-bis{[p-(1,1,2,2-tetrafluoroethoxy)benzylidene]amino}guanidine (29.84 g, 0.06 mol), diisopropylethylamine (15.51 g, 0.12 mol) and dimethylcarbamoyl chloride (129.2 g, 0.12 mol) in acetonitrile (200 mL) is stirred at reflux for 22 hours. The reaction mixture is cooled, and the acetonitrile is evaporated under reduced pressure. The residue is dissolved in ethyl acetate (250 mL), and the organic solution is washed with water, saturated NaCl and dried over Na2SO4. The solvent is evaporated under reduced pressure, and the residue is crystallized from benzene-hexanes to give the desired product as a yellow solid, mp 141.5°-143.5° C. in 92.9% yield.
Reaction SMILES: OC(C(F)(F)F)=O.[NH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[S:21](=[O:23])(=[O:22])[N:20]([CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:19](=[O:30])[CH2:18]2)=[C:13]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:12]=1.C(N(CC)CC)C.[CH:46]1([CH2:52][S:53](Cl)(=[O:55])=[O:54])[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1>C(Cl)Cl>[CH2:32]([O:31][C:13]1[CH:12]=[C:11]([CH2:10][CH2:9][NH:8][S:53]([CH2:52][CH:46]2[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]2)(=[O:55])=[O:54])[CH:16]=[CH:15][C:14]=1[N:17]1[CH2:18][C:19](=[O:30])[N:20]([CH2:24][CH2:25][Si:26]([CH3:27])([CH3:28])[CH3:29])[S:21]1(=[O:23])=[O:22])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(CCN)cc2OCc2ccccc2)S1(=O)=O
Reactant: O=S(=O)(Cl)CC1CCCCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: C[Si](C)(C)CCN1C(=O)CN(c2ccc(CCNS(=O)(=O)CC3CCCCC3)cc2OCc2ccccc2)S1(=O)=O
Reaction time: 1 h

Procedure:
5-[4-(2-Aminoethyl)-2-benzyloxyphenyl]-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one TFA salt (Example 67, step A) (0.49 g, 0.96 mmol) is dissolved in 5 mL of CH2Cl2 and triethylamine (0.27 mL, 1.92 mmol) is added. Cyclohexylmethyl sulfonyl chloride (0.19 g, 0.96 mmol) is then added and the reaction stirred for 1 h. The reaction mixture is concentrated and the residue is partitioned between EtOAc and 1N HCl and extracted with EtOAc. The combined organic layers are washed with sat. sodium bicarbonate and brine, dried over MgSO4 and concentrated to a yellow oil. The oil is purified by chromatography over silica (hexane/EtOAc gradient) to afford the title compound as an oil.
Reaction SMILES: [OH:1][C@H:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:3][C:4]#[N:5].[O:17]1[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18]1.O1CCCC1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CCCCCC.O>[O:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[O:1][C@H:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:3][C:4]#[N:5]
Reactant: C1=COCCC1
Reactant: CCCCCCCCCCC[C@@H](O)CC#N
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: CCCCCCCCCCC[C@H](CC#N)OC1CCCCO1
Temperature: 50 °C
Yield: 100 %

Procedure:
2.16 g of (R)-3-hydroxy-tetradecanenitrile, 1.93 ml of dihydropyran and 20 ml of tetrahydrofuran were placed in a reactor and stirred, and 266 mg of pyridinium p-toluenesulfonate was added thereto, heated to 50° C., and stirred for about 2 hours. The mixture was cooled to room temperature, 30 ml of water and 30 ml of hexane were added thereto, and stirred vigorously for 5 minutes. The resulting mixture was allowed to undergo phase separation and the aqueous layer was removed. The organic layer was dried over anhydrous magnesium sulfate and concentrated under a reduced pressure, to give 2.97 g of the title compound (yield: 100%) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6]([C:12]1[CH:13]=[CH:14][C:15]([O:19][CH3:20])=[C:16]([NH2:18])[CH:17]=1)=[CH:5]2.[Cl:21][C:22]1[CH:23]=[C:24]([S:29](Cl)(=[O:31])=[O:30])[CH:25]=[C:26]([Cl:28])[CH:27]=1.N1C=CC=CC=1>O>[Cl:28][C:26]1[CH:25]=[C:24]([S:29]([NH:18][C:16]2[CH:17]=[C:12]([C:6]3[NH:7][C:8]4[C:4]([CH:5]=3)=[CH:3][C:2]([F:1])=[C:10]([F:11])[CH:9]=4)[CH:13]=[CH:14][C:15]=2[O:19][CH3:20])(=[O:30])=[O:31])[CH:23]=[C:22]([Cl:21])[CH:27]=1
Reactant: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1N
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1NS(=O)(=O)c1cc(Cl)cc(Cl)c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
The product from Example 3, 5-(5,6-difluoro-1H-indol-2-yl)-2-methoxy-phenylamine, (0.274 g, 1.0 mmol) was mixed with 3,5-dichlorobenzenesulfonyl chloride (0.256 g, 1.0 mmol) and pyridine (3 mL) was added, and the reaction mixture was heated briefly to 50° C. and then allowed to stand overnight at room temperature. Water (7 mL) was added and the mixture allowed to stand 2 hours at room temperature. The mixture was partitioned between water (200 mL) and ethyl acetate (200 mL), and the organic layer was washed with 1N HCl (100 mL), water (100 mL), and brine (100 mL), dried (magnesium sulfate), filtered, and concentrated to a purple-tinted solid. The solid was triturated with hexanes/ethyl acetate, 1/1, v/v to give the product (0.355 g), mp 217-219° C.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[C:4]([C:17]#[N:18])[C:5](=O)[N:6]([C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=2[F:15])[CH:7]=1.[OH2:20].[NH2:21][NH2:22]>C(O)C>[NH2:18][C:17]1[C:4]2[C:5](=[O:20])[N:6]([C:8]3[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=3[F:15])[CH:7]=[C:2]([Br:1])[C:3]=2[NH:22][N:21]=1
Reactant: N#Cc1c(Cl)c(Br)cn(-c2c(F)cccc2F)c1=O
Reactant: O
Reactant: NN
Solvent: CCO
Product: Nc1n[nH]c2c(Br)cn(-c3c(F)cccc3F)c(=O)c12
Temperature: 90 °C

Procedure:
To a solution of 5-bromo-4-chloro-1-(2,6-difluorophenyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile obtained in Step F (270 mg) in ethanol (10 mL) was added hydrazine monohydrate (0.135 mL) at room temperature. The reaction mixture was heated overnight at 90° C., and cooled to room temperature. The reaction mixture was concentrated under reduced pressure, to the residue was added water, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (332 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6](C(OC)=O)=[CH:5][N:4]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].C1C[O:22][CH2:21]C1>C1COCC1>[OH:22][CH2:21][C:11]1[CH:6]=[CH:5][N:4]=[C:3]([O:2][CH3:1])[CH:12]=1
Reactant: COC(=O)c1ccc(OC)nc1
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: COc1cc(CO)ccn1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
To a 0° C. THF (70 mL) solution of methyl 6-methoxynicotinate (6.0 g, 36 mmol) was added 36 mL of 1M LAH/THF. The reaction, after stirring at 20° C. for two hours, was quenched with aq. NH4Cl, diluted with aq. HCl until all salts dissolved, and extracted with EtOAc (3×) after adjusting the pH to 5. The crude 4-hydroxymethyl-2-methoxypyridine (1.75 g), obtained after drying and concentration of the EtOAc layers, was converted to 4-methoxy-3-pyridinylcarboxaldehyde following the procedure described in step A of Example 123. The title compound was prepared from 4-methoxy-3-pyridinylcarboxaldehyde following the procedure described in step A of Example 119.
Reaction SMILES: C[Si](C)(C)[NH:3][Si](C)(C)C.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([C:18](=O)[CH2:19][CH3:20])[CH:15]=[CH:16][CH:17]=1.C(#N)[CH:23]([CH2:25][C:26]#[N:27])O>C(O)(=O)C.O>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([C:18](=[C:25]([C:23]#[N:3])[C:26]#[N:27])[CH2:19][CH3:20])[CH:15]=[CH:16][CH:17]=1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: N#CCC(O)C#N
Reactant: CCC(=O)c1cccc(OC)c1
Solvent: O
Solvent: CC(=O)O
Product: CCC(=C(C#N)C#N)c1cccc(OC)c1
Temperature: 70 °C
Reaction time: 12 h
Yield: 89.7 %

Procedure:
Hexamethyldisilazane (5.51 mL, 26.3 mmol) was added dropwise to acetic acid (11.30 mL, 197 mmol) at RT under nitrogen. The resulting solution was then added to a solution of 1-[3-(methyloxy)phenyl]-1-propanone (Description 1) (2.7 g, 16.44 mmol) and malonitrile (2.173 g, 32.9 mmol) in acetic acid (10 mL). The reaction mixture was stirred at 70° C. for 12 h. The reaction mixture was cooled to RT then diluted with water (30 mL), the aqueous layer was then extracted with DCM (3×50 mL) and the combined organic extracts were dried over a phase separating column and concentrated. Purification by chromatography on silica gel, eluting with a gradient of 0-20% ethyl acetate in cyclohexane, afforded the title compound (3.13 g). LCMS (A) m/z: 211 [M−1]−, Rt 1.40 min (basic).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](SC)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[F:14][C:15]([F:25])([F:24])[C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][NH2:19]>>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:19][CH2:18][C:17]3[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=3[C:15]([F:14])([F:24])[F:25])=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: NCc1ccccc1C(F)(F)F
Reactant: CSc1ncnc2cc(N)ncc12
Product: Nc1cc2ncnc(NCc3ccccc3C(F)(F)F)c2cn1
Temperature: 150 °C
Reaction time: 1 h
Yield: 58.9 %

Procedure:
A mixture of 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (225 mg, 1.17 mmol) and 2-(trifluoromethyl)benzylamine (0.90 mL, 6.42 mmol) is stirred under N2 at 150° C. for 1 h. The resulting product is chromatographed on silica gel (5% EtOH/EtOAc) to give 7-amino-4-(2-trifluoromethylbenzyl)aminopyrido[4,3-d]pyrimidine (0.22 g, 59%) as a white solid. 1H NMR (DMSO) δ 9.16 (1H, s), 8.88 (1H, t, J=5.7 Hz), 8.23 (1H, s), 7.75 (1H, d, J=7.7 Hz), 7.62 (1H, t, J=7.5 Hz), 7.50 (1H, d, J=7.4 Hz), 7.47 (1H, t, J=7.6 Hz), 6.51 (2H, brs), 6.39 (1H, s), 4.92 (2H, d, J=5.5 Hz).
Reaction SMILES: [CH3:1][C:2]1[C@@H:19]([O:20]C([C@H](O)[C@@H](NC(C2C=CC=CC=2)=O)C2C=CC=CC=2)=O)[CH2:18][C@:14]2([OH:41])[C:15]([CH3:17])([CH3:16])[C:3]=1[C@@H:4]([O:59]C(C)=O)[C:5]([C@@:7]1([CH3:58])[C@H:12]([C@@H:13]2[O:42][C:43]([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)=[O:44])[C@:11]2([O:53][C:54]([CH3:56])=[O:55])[CH2:51][O:52][C@@H:10]2[CH2:9][C@@H:8]1[OH:57])=[O:6].[BH4-].[Na+]>[Co](Cl)Cl.COCCOC>[CH3:1][C:2]1[C@@H:19]([OH:20])[CH2:18][C@:14]2([OH:41])[C:15]([CH3:16])([CH3:17])[C:3]=1[C@@H:4]([OH:59])[C:5]([C@@:7]1([CH3:58])[C@H:12]([C@@H:13]2[O:42][C:43]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[O:44])[C@:11]2([O:53][C:54]([CH3:56])=[O:55])[CH2:51][O:52][C@@H:10]2[CH2:9][C@@H:8]1[OH:57])=[O:6]
Reactant: CC(=O)O[C@H]1C(=O)[C@@]2(C)[C@H]([C@H](OC(=O)c3ccccc3)[C@]3(O)C[C@H](OC(=O)[C@H](O)[C@@H](NC(=O)c4ccccc4)c4ccccc4)C(C)=C1C3(C)C)[C@]1(OC(C)=O)CO[C@@H]1C[C@@H]2O
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(=O)O[C@@]12CO[C@@H]1C[C@H](O)[C@@]1(C)C(=O)[C@H](O)C3=C(C)[C@@H](O)C[C@@](O)([C@@H](OC(=O)c4ccccc4)[C@H]21)C3(C)C
Yield: 21 %

Procedure:
In the third embodiment, 7% cobalt chloride (based on the taxol in the starting material) was added to the reaction solvent, CH3OCH2CH2OCH3 (glyme) and contacted with sodium borohydride at room temperature for 144 hours. This process resulted in a 21% yield of 10-deacetylbaccatin III. A low positive yield of 10-deacetylbaccatin III was also obtained in a similar experiment using 0.1% SnCl2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[NH:6][C:5](=[O:10])[C:4]=1[CH2:11][NH:12][C:13]([C:15]1[C:23]2[C:18](=[N:19][CH:20]=[CH:21][CH:22]=2)[N:17]([CH:24]([C:26]2[CH:27]=[C:28]([CH:33]=[CH:34][CH:35]=2)[C:29]([O:31]C)=O)[CH3:25])[C:16]=1[CH3:36])=[O:14].OCC1(OC[C@@H](O)[C@@H](O)[C@H]1O)O.C(O)C.[CH3:52][NH2:53]>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[NH:6][C:5](=[O:10])[C:4]=1[CH2:11][NH:12][C:13]([C:15]1[C:23]2[C:18](=[N:19][CH:20]=[CH:21][CH:22]=2)[N:17]([CH:24]([C:26]2[CH:35]=[CH:34][CH:33]=[C:28]([C:29](=[O:31])[NH:53][CH3:52])[CH:27]=2)[CH3:25])[C:16]=1[CH3:36])=[O:14]
Reactant: CN
Reactant: COC(=O)c1cccc(C(C)n2c(C)c(C(=O)NCc3c(OC)cc(C)[nH]c3=O)c3cccnc32)c1
Agent: OCC1(O)OC[C@@H](O)[C@@H](O)[C@H]1O
Solvent: CCO
Product: CNC(=O)c1cccc(C(C)n2c(C)c(C(=O)NCc3c(OC)cc(C)[nH]c3=O)c3cccnc32)c1
Yield: 30 %

Procedure:
Methyl 3-(1-(3-(((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-1-yl)ethyl)benzoate (20 mg, 0.041 mmol) was added to 30% methylamine ethanol solution (10 mL). The mixture was stirred under 50 Psi at 100° C. for 12 hours in a 100 mL of sealed tube. The solvent was evaporated and the residue was purified by preparative-HPLC (Instrument: Gilson GX281 Column: ASB C18 150*25 mm*5 um Mobile phase A: water with 0.05% ammonia solution Mobile phase B: MeCN Column temperature: 30° C. Gradient: 17-47% B 15 min) to afford the title compound (17.4 mg, yield: 30%). LRMS (M+H+) m/z: calcd 488.22. found 488.0. 1H NMR (400 MHz, chloroform-d) δ ppm 2.01 (d, J=7.28 Hz, 3 H) 2.26 (s, 3 H) 2.50 (s, 3 H) 2.96 (d, J=4.63 Hz, 3 H) 3.91 (s, 3 H) 4.64 (d, J=5.51 Hz, 2 H) 5.95 (s, 1 H) 6.14 (br. S., 1 H) 6.55 (d, J=8.16 Hz, 1 H) 7.05-7.13 (m, 1 H) 7.33 (t, J=8.05 Hz, 1 H) 7.51-7.59 (m, 1 H) 7.60-7.64 (m, 1 H) 8.24 (d, J=5.51 Hz, 2 H).
Reaction SMILES: I[C:2]1[S:3][C:4]([CH3:8])=[C:5]([CH3:7])[N:6]=1.C(=O)(O)[O-].[Na+].[CH3:14][O:15][C:16]1[N:21]=[C:20]([O:22][CH3:23])[C:19](B(O)O)=[CH:18][N:17]=1>COCCOC.C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:7][C:5]1[N:6]=[C:2]([C:19]2[C:20]([O:22][CH3:23])=[N:21][C:16]([O:15][CH3:14])=[N:17][CH:18]=2)[S:3][C:4]=1[CH3:8]
Reactant: Cc1nc(I)sc1C
Reactant: COc1ncc(B(O)O)c(OC)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: COCCOC
Product: COc1ncc(-c2nc(C)c(C)s2)c(OC)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2-iodo-4,5-dimethyl-1,3-thiazole (prepared in a similar manner to that described in JACS 123 (6), 1017-1022, (2001), 250 mg, 1.046 mmol) was dissolved in 1,2-Dimethoxyethane (DME) (4.357 ml). Tetrakis(triphenylphosphine)palladium(0) (60.4 mg, 0.052 mmol) was added and the mixture was stirred at room temperature for 10 minutes. Sodium bicarbonate (4.183 ml, 4.18 mmol) and [2,4-bis(methyloxy)-5-pyrimidinyl]boronic acid (385 mg, 2.091 mmol) were added and the resulting mixture was stirred at 85° C. for 2 hours. The mixture was allowed to cool to rt and left standing at rt over the week end. The mixture was diluted with DCM (5 mL), the aqueous phases was separated and extracted with DCM (2×5 mL). The organics were combined and dried over sodium sulphate to give a yellow solid that was purified by silica chromatography, eluting with DCM:MeOH from 100:0 to 95:5 to afford the title compound as a pale yellow solid (143 mg).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)=[CH:17][CH:18]=3)[CH:13]=2)=[O:11])=[CH:5][CH:4]=1.[CH2:29]([N:31]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)[CH3:30].C(OCC)(=O)C>CN(C=O)C>[Cl-:1].[CH2:29]([N+:31]1([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]3[CH2:21][CH2:20][C:19]4[C:14](=[CH:15][C:16]([C:22]5[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=5)=[CH:17][CH:18]=4)[CH:13]=3)=[O:11])=[CH:5][CH:4]=2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)[CH3:30]
Reactant: CCN1CCCCCCC1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CCl)cc2)CC3)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC[N+]1(Cc2ccc(NC(=O)C3=Cc4cc(-c5ccc(C)cc5)ccc4CC3)cc2)CCCCCCC1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 14 h
Yield: 69.4 %

Procedure:
In DMF (3 ml) was dissolved N-[4—(chloromethyl)-phenyl]-7—(4-methylphenyl)-3,4-dihydronaphthalene-2-carboxamide (150 mg), and to the mixture was added 1-ethylperhydroazocine (109 mg). The mixture was stirred at room temperature for 14 hours. To the reaction mixture was added ethyl acetate (100 ml), and the resulting precipitate was filtered and recrystallized from ethyl acetate-methanol to give 1-ethyl-1-[4-[7—(4-methylphenyl)-3,4-dihydronaphthalene-2-carboxamido]benzyl]perhydroazocinium chloride (Compound 39) (142 mg) as colorless crystals.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:12][C:13]([OH:15])=O.[NH2:16][C:17]1[S:18][CH:19]=[C:20]([CH3:26])[C:21]=1[C:22]([O:24][CH3:25])=[O:23]>>[CH3:26][C:20]1[C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:17]([NH:16][C:13](=[O:15])[CH2:12][N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:10][CH2:11][C:2]2=[O:1])[S:18][CH:19]=1
Reactant: O=C(O)CN1C(=O)CCc2ccccc21
Reactant: COC(=O)c1c(C)csc1N
Product: COC(=O)c1c(C)csc1NC(=O)CN1C(=O)CCc2ccccc21

Procedure:
The title compound was prepared from 2-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetic acid (0.43 g, 2.09 mmol) and methyl 2-amino-4-methylthiophene-3-carboxylate (0.358 g, 2.09 mmol) according to protocol B. Retention time (min)=6.895, method [7], MS(ESI) 359.1 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([CH3:10])[CH:3]=1.[F:11][CH:12]([F:15])[CH2:13]I>>[F:11][CH:12]([F:15])[CH2:13][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([CH3:10])[CH:3]=1
Reactant: Cc1cc(O)ccc1C=O
Reactant: FC(F)CI
Product: Cc1cc(OCC(F)F)ccc1C=O
Yield: 67.4 %

Procedure:
The compound was synthesized as in Example 87.1, using 4-hydroxy-2-methylbenzaldehyde (54.4 mg, 0.40 mmol) in place of 4-hydroxybenzaldehyde and 2,2-difluoro-1-iodoethane (153 mg, 0.80 mmol) in place of 1-iodo-(3,3,3-trifluoro)propane to give 4-(2,2-difluoroethoxy)-2-methylbenzaldehyde (54 mg, 68%). Used without further characterization.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-])=O)=[C:6]([CH:9]=1)[NH:7][CH3:8].[Cl-].[NH4+]>CCO.O.[Fe]>[Br:1][C:2]1[CH:9]=[C:6]([NH:7][CH3:8])[C:5]([NH2:10])=[CH:4][CH:3]=1
Reactant: CNc1cc(Br)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CNc1cc(Br)ccc1N
Temperature: 60 °C
Yield: 90 %

Procedure:
To a solution of 5-bromo-N-methyl-2-nitroaniline (10 g, 43.5 mmol) in EtOH/H2O (700 mL) was added Fe (14.6 g, 261 mmol), ammonium chloride (14 g, 261 mmol) and the reaction mixture was heated at 60° C. for 4 h. The crude reaction mixture was filtered, concentrated, dissolved in ethyl acetate, washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was used in next reaction without further purification. (7.9 g, yield 90%) MS (ESI+) e/z: 202.1.
Reaction SMILES: [I-].C([N+]1C2C(=CC=CC=2)C=CC=1I)C.[CH2:15]([OH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[C:23]1([CH2:29][C:30](O)=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CCCC)CCCC)CCC>C(Cl)Cl>[C:23]1([CH2:29][C:30]([O:22][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: OCc1ccccc1
Reactant: O=C(O)Cc1ccccc1
Agent: CC[n+]1c(I)ccc2ccccc21
Agent: [I-]
Solvent: CCCCN(CCCC)CCCC
Solvent: ClCCl
Product: O=C(Cc1ccccc1)OCc1ccccc1
Yield: 95 %

Procedure:
To a suspended CH2Cl2 (2 ml) solution of 1-ethyl-2-iodoquinolinium iodide (493 mg, 1.2 mmol) was added a mixture of benzyl alcohol (108 mg, 1.0 mmol), phenylacetic acid (136 mg, 1.0 mmol) and tri-n-butylamine (444 mg, 2.4 mmol) in CH2Cl2 (2 ml), and the resulting mixture was refluxed for 3 hours. After evaporation of the solvent, the residue was separated by silica gel column chromatography, and benzyl phenylacetate was isolated in 95% yield.
Reaction SMILES: CO.C[O-].[Na+].C(O)(=O)C.[CH:10]([NH2:12])=[NH:11].S(=O)(=O)(O)O.O.[F:19][CH:20]([CH3:28])[C:21](=O)[CH2:22][C:23](OC)=[O:24]>CO>[F:19][CH:20]([C:21]1[N:12]=[CH:10][NH:11][C:23](=[O:24])[CH:22]=1)[CH3:28]
Reactant: COC(=O)CC(=O)C(C)F
Reactant: N=CN
Agent: C[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: CC(F)c1cc(=O)[nH]cn1
Temperature: 40 °C
Reaction time: 12 h
Yield: 65 %

Procedure:
To a solution in which 9.33 g of methyl 4-fluoro-3-oxopentanoate had been dissolved in 115 ml of methanol were successively added 36.5 g of a 28% sodium methoxide methanol solution and 9.84 g of formamidine acetate at room temperature, and the mixture was stirred at 40° C. for 12 hours. To the mixture was further added 0.66 g of formamidine acetate and after stirring the mixture at 50° C. for 2 hours, the mixture was cooled to 10° C. or lower. After cooling, a mixture of 9.51 g of conc. sulfuric acid and 8.5 g of water was added to the reaction mixture. After stirring the mixture at 50° C. for 30 minutes, insolubles were removed by filtration and the filtrate was quantitated by the liquid chromatography internal standard method. As a result, 7.99 g of 6-(1-fluoroethyl)-4-pyrimidone was found to be formed (yield: 89.2%). The filtrate was concentrated under reduced pressure and the concentrated solution was recrystallized from 40 ml of 2-propanol to obtain 5.82 g of 6-(1-fluoroethyl)-4-pyrimidone.
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:13]([NH2:20])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>>[CH2:13]([NH:20][C:1](=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCN
Reactant: CCCCCCC/C=C/C(=O)O
Product: CCCCCCC/C=C/C(=O)NCCCCCCC

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and heptylamine as starting materials to give the aimed compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][NH2:9])=[N:6][CH:5]=[CH:4][N:3]=1.[N:10]([O-])=O.[Na+]>C(O)(=O)C.O>[Cl:1][C:2]1[C:7]2[N:6]([N:10]=[N:9][N:8]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=N[O-]
Reactant: NNc1nccnc1Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Clc1nccn2nnnc12
Temperature: 10 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
2-Chloro-3-hydrazinylpyrazine (440 g, 3.0 mol) was suspended in acetic acid (500 mL) and cooled to 10° C. A solution of sodium nitrite (220 g, 3.2 mol) in water (200 mL) at 10° C. was added. The resulting mixture was stirred at 10° C. for 1 h, during which time a crystalline solid precipitated. The precipitate was collected by filtration, washed with ethanol (200 mL) and dried to afford the desired product as a red solid (350 g, 73% yield).