Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[Cl:9].[Cl:10]C1C=CC=CC=1>>[Cl:9][C:3]1[C:4]([Cl:10])=[C:5]([Cl:8])[CH:6]=[CH:7][CH:2]=1
Reactant: Clc1ccccc1
Reactant: Clc1ccc(Cl)c(Cl)c1
Product: Clc1cccc(Cl)c1Cl
Yield: 381.3 %

Procedure:
Example 3 was repeated replacing the benzene with 139.5 g of chlorobenzene. After 20 hours reaction, 25.7 g of 1,2,4-trichlorobenzene-insoluble polymer and 98.0 g of trichlorobenzene-soluble polymer were obtained. This indicates that while less reactive than benzene, chlorobenzene is also a suitable aromatic reactant.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C@@H:12]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].Cl[C:29]1[N:34]=[C:33]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:32]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[CH:31][N:30]=1>CN(C)C=O>[C:24]([O:23][C:21]([NH:20][C@H:12]([CH2:11][CH2:10][CH2:9][CH2:8][NH:7][C:29]1[N:34]=[C:33]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:32]([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)=[CH:31][N:30]=1)[CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:22])([CH3:26])([CH3:25])[CH3:27]
Reactant: CCOC(=O)CC[C@@H](CCCCN)NC(=O)OC(C)(C)C
Reactant: Clc1ncc(-c2ccccc2)c(-c2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC[C@@H](CCCCNc1ncc(-c2ccccc2)c(-c2ccccc2)n1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 5.7 %

Procedure:
481 mg (1.48 mmol) of cesium carbonate were added to a solution of 135 mg (0.49 mmol) of ethyl (R)-8-amino-4-tert-butoxycarbonylaminooctanoate in 3.5 ml of dimethylformamide, and the mixture was stirred at room temperature. After 60 minutes, a solution of 87 mg (0.33 mmol) of 2-chloro-4,5-diphenylpyrimidine in 2.5 ml of dimethylformamide was added, and the mixture was stirred at 90° C. for 6 hours. The solvent was concentrated and the residue was partitioned between ethyl acetate and water. The organic phase was dried and concentrated under high vacuum. The residue was purified by a preparative HPLC (Purosphere, gradient acetonitrile/(water+0.5% TFA), gradient 20% acetonitrile to 100% in 30 minutes). 10 mg of ethyl (R)-4-tert-butoxycarbonylamino-8-(4,5-diphenylpyrimidin-2-ylamino)octanoate were obtained. The product obtained in this way was stirred with 50% trifluoroacetic acid for 2 hours, mixed with water and freeze dried. 12 mg (4%) of the desired product were obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:16][CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[N:4][C:5]([C:8]2[C:13]([Cl:14])=[CH:12][N:11]=[C:10](F)[CH:9]=2)=[CH:6][N:7]=1.[NH2:24][C@H:25]1[CH2:30][CH2:29][C@H:28]([OH:31])[CH2:27][CH2:26]1>CS(C)=O>[Cl:14][C:13]1[C:8]([C:5]2[CH:6]=[N:7][C:2]([Cl:1])=[C:3]([NH:16][CH2:17][CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[N:4]=2)=[CH:9][C:10]([NH:24][C@H:25]2[CH2:30][CH2:29][C@H:28]([OH:31])[CH2:27][CH2:26]2)=[N:11][CH:12]=1
Reactant: Fc1cc(-c2cnc(Cl)c(NCC3CCOCC3)n2)c(Cl)cn1
Reactant: N[C@H]1CC[C@H](O)CC1
Solvent: CS(C)=O
Product: O[C@H]1CC[C@H](Nc2cc(-c3cnc(Cl)c(NCC4CCOCC4)n3)c(Cl)cn2)CC1
Temperature: 120 °C

Procedure:
To a scintillation vial containing 3-chloro-6-(5-chloro-2-fluoropyridin-4-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrazin-2-amine (20 mg, 0.056 mmol) was added DMSO (1 ml) and trans-4-aminocyclohexanol (32.2 mg, 0.280 mmol). The reaction mixture was capped and heated to 120° C. in an oil bath for 3 hr. The reaction product was purified by reverse phase preparative HPLC to yield trans-4-(5-chloro-4-(5-chloro-6-((tetrahydro-2H-pyran-4-yl)methyl)aminopyrazin-2-yl)pyridin-2-yl-amino)cyclohexanol (2.2 mg, 4.86 μmol, 8.69% yield), LCMS (m/z): 452.1 (MH+), retention time=0.76 min as a TFA salt after lypholyzing. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.17-1.26 (m, 4H) 1.27-1.39 (m, 2H) 1.58 (dd, J=13.11, 1.76 Hz, 2H) 1.84-2.02 (m, 5H) 3.30 (d, J=7.04 Hz, 4H) 3.43-3.61 (m, 2H) 3.84 (dd, J=11.35, 3.13 Hz, 2H) 6.58 (s, 1H) 7.66 (s, 1H) 7.90 (s, 1H).
Reaction SMILES: C1(C[O:5][C:6]2[C:7]([O:26][CH3:27])=[CH:8][CH:9]=[C:10]3[C:15]=2[O:14][C:13](=[O:16])[CH:12]=[C:11]3[NH:17][C:18]2[C:23]([Cl:24])=[CH:22][N:21]=[CH:20][C:19]=2[Cl:25])CC1.Cl>O>[Cl:25][C:19]1[CH:20]=[N:21][CH:22]=[C:23]([Cl:24])[C:18]=1[NH:17][C:11]1[C:10]2[C:15](=[C:6]([OH:5])[C:7]([O:26][CH3:27])=[CH:8][CH:9]=2)[O:14][C:13](=[O:16])[CH:12]=1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCC1CC1
Agent: Cl
Solvent: O
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
8-(Cyclopropylmethoxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2H-chromen-2-one (5.4 g, 13.3 mmol, Example 5) was added in one portion to conc. HCl (90 mL). After 1 h of vigorous stirring, the mixture was diluted with water (50 mL, 0° C.) and cooled to 0° C. The white precipitate was filtered, washed with water (100 mL, 0° C.), and then resuspended in water (100 mL, 0° C.). After 30 min of vigorous stirring, the white solid was filtered, washed with water (100 mL, 0° C.), and dried to give 4-(3,5-dichloropyridin-4-ylamino)-8-hydroxy-7-methoxy-2H-chromen-2-one: 1H NMR (400 MHz, DMSO-d6): δ 9.53 (br, 2H), 8.79 (s, 2H), 7.66 (d, 1H), 7.12 (d, 1H), 4.60 (s, 1H), 3.90 (s, 3H); MS (ESI): 352.9.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=[C:10]([C:20](O)=[O:21])[CH:9]=2)=[CH:4][CH:3]=1.[CH2:23]([N:26]1[CH:30]=[CH:29][C:28]([CH2:31][NH2:32])=[N:27]1)[CH2:24][CH3:25]>>[CH2:23]([N:26]1[CH:30]=[CH:29][C:28]([CH2:31][NH:32][C:20]([C:10]2[CH:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[C:13]([O:14][CH2:15][C:16]([F:19])([F:17])[F:18])=[CH:12][N:11]=2)=[O:21])=[N:27]1)[CH2:24][CH3:25]
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)cn1
Reactant: CCCn1ccc(CN)n1
Product: CCCn1ccc(CNC(=O)c2cc(-c3ccc(Cl)cc3)c(OCC(F)(F)F)cn2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 4-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (example D) and 1-propyl-1H-pyrazole-3-methanamine (CAS Registry No. 1006333-47-6) as starting materials; LC-MS (UV peak area/ESI) 100%, 453.1306 (M+H)+.
Reaction SMILES: C[O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH:19]=[C:18]([CH2:20][C:21]4[CH:25]=[CH:24][S:23][C:22]=4[C:26]([NH2:28])=[O:27])[N:17]=[CH:16]3)=[CH:11][CH:10]=2)=[CH:7][CH:6]=[CH:5][N:4]=1.[Na+].[I-].C[Si](Cl)(C)C>C(C#N)(C)=O>[O:2]=[C:3]1[C:8]([C:9]2[CH:10]=[CH:11][C:12]([N:15]3[CH:19]=[C:18]([CH2:20][C:21]4[CH:25]=[CH:24][S:23][C:22]=4[C:26]([NH2:28])=[O:27])[N:17]=[CH:16]3)=[CH:13][CH:14]=2)=[CH:7][CH:6]=[CH:5][NH:4]1
Reactant: COc1ncccc1-c1ccc(-n2cnc(Cc3ccsc3C(N)=O)c2)cc1
Agent: CC(=O)C#N
Agent: C[Si](C)(C)Cl
Agent: [I-]
Product: NC(=O)c1sccc1Cc1cn(-c2ccc(-c3ccc[nH]c3=O)cc2)cn1
Temperature: 80 °C

Procedure:
To a solution of 5-chloro-N-((1-(4-(2-methoxypyridin-3-yl)phenyl-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide (0.01 g, 0.024 mmol) in AcCN (1 mL) was added NaI (0.011 g, 0.072 mmol) and TMSCl (0.045 mL, 0.36 mmol). After heating at 80° C. for 90 min, the reaction mixture was cooled to room temperature, and purified by preparative HPLC to yield 5-chloro-N-((1-(4-(2-oxo-1,2-dihydropyridin-3-yl)phenyl-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide (MS 411.0, 413.0 (M+H) Cl pattern).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]1[N:25]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23]2[CH:32]=[CH:33][CH:34]=[CH:35][C:22]=2[N:21]([CH2:36][CH3:37])[C:20]1=[O:38]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][CH:19]2[N:25]=[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:23]3[CH:32]=[CH:33][CH:34]=[CH:35][C:22]=3[N:21]([CH2:36][CH3:37])[C:20]2=[O:38])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: CCN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Product: CCN1C(=O)C(NC(=O)[C@H](C)NC(=O)Cc2cc(F)cc(F)c2)N=C(c2ccccc2)c2ccccc21

Procedure:
Following General Procedure A above using N-(3,5-difluorophenylacetyl)-L-alanine (Example B) and 3-amino-2,3-dihydro-1-ethyl-5-phenyl-1H-1,4-benzodiazepin-2-one (prepared as described in Example 8-X using ethyl iodide), the title compound was prepared as a solid having a melting point of 155-158° C. The reaction was monitored by tlc on silica gel (Rf=0.48 in 10% methanol/dichloromethane) and purification was by silica gel chromatography using 10% methanol/dichloromethane as the eluant, followed by recrystallization from diethyl ether.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]([C:29]4[N:30]=[N:31][N:32]([CH2:34][C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[CH:33]=4)O)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].C([SiH](CC)CC)C.FC(F)(F)S(O)(=O)=O>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][C:29]4[N:30]=[N:31][N:32]([CH2:34][C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[CH:33]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)c4cn(Cc5ccccc5)nn4)cc3)cc2)CC1
Agent: CC[SiH](CC)CC
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Cc4cn(Cc5ccccc5)nn4)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-(4′-{4-[(1-Benzyl-1H-[1,2,3]triazol-4-yl)-hydroxy-methyl]-3-methyl-isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid ethyl ester (0.123 g, 0.230 mmol) and triethylsilane (0.044 mL, 0.276 mmol) were dissolved in CH2Cl2 (0.5 mL) then trifluoromethanesulfonic acid (0.5 mL) was slowly added. After stirring for 1 hour at room temperature, an additional portion of triethylsilane (0.050 mL) was added and the reaction was heated to 50° C. for 3.5 hours. An additional portion of triethylsilane (1 mL) was added and the reaction continued to stir at 50° C. for 1 hour. The reaction mixture was concentrated, dissolved in CH2Cl2, and filtered through a plug of silica gel. The crude material was then purified via preparatory HPLC to afford the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.Br[CH2:31][C:32]1[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:33]=1[F:39]>>[F:38][C:37]1[CH:36]=[CH:35][CH:34]=[C:33]([F:39])[C:32]=1[CH2:31][O:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:19])[F:20])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cccc(F)c1CBr
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1
Product: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(OCc2c(F)cccc2F)c1

Procedure:
The title compound was prepared from [4-(3-hydroxyphenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and 2-Bromomethyl-1,3-difluorobenzene following the procedure of Example 478: MS (ESI) m/z 520.
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH:18]=[C:17]3[C@@H:7]([CH2:8][CH2:9][C:10]4[C@:15]3([CH3:16])[CH:14]=[CH:13][C:12](=[O:20])[CH:11]=4)[C@@H:6]1[CH2:5][CH2:4][C:3]2=[O:21].C[O-].[Na+].[C:25](O)(=O)C.C=O>C1COCC1.CO.O.C(N(CC)CC)C>[CH2:25]=[C:4]1[CH2:5][C@H:6]2[C@H:7]3[C:17](=[CH:18][CH2:19][C@:2]2([CH3:1])[C:3]1=[O:21])[C@:15]1([CH3:16])[C:10](=[CH:11][C:12](=[O:20])[CH:13]=[CH:14]1)[CH2:9][CH2:8]3
Reactant: CC(=O)O
Reactant: C[C@]12C=CC(=O)C=C1CC[C@@H]1C2=CC[C@]2(C)C(=O)CC[C@@H]12
Agent: C=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=C1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@]2(C)C1=O
Reaction time: 0.5 h

Procedure:
Androsta-1,4,9(11)-triene-3,17-dione (I, 0.7 g) in THF (8 ml) and dimethyloxylate (0.44 g) were combined and cooled to 3° in an ice bath. Sodium methoxide in methanol (25%, 0.685 ml) was added dropwise with no temperature rise. TLC after about 1/2 hr showed the reaction was nearly completed. Acetic acid (0.05 ml), triethylamine (0.26 ml) and methanol (1 ml) were added. Formaldehyde (37%, 0.28 ml) was added and the reaction mixture stirred at 20°-25°. TLC, after approximately 11/2 hrs. showed the reaction was complete. The reaction mixture was added to water and extracted with ethyl acetate. The layers were separated, the aqueous layer was extracted with ethyl acetate and combined with the organic extract. The combined organic extract was washed with water and separated from the organic layer. Methylene chloride was added and the mixture dried over sodium sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure to an oil. Acetone was added and the title compound was obtained upon crystallization.
Reaction SMILES: [NH2:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:53])[N:15]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])[C:16](=[O:34])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:4].[C:54]([O:58][C:59]([NH:61][C@H:62]([C:67]([O:69]C(C)(C)C)=O)[CH2:63][C:64]([OH:66])=[O:65])=[O:60])([CH3:57])([CH3:56])[CH3:55]>ClCCl>[C:54]([O:58][C:59]([NH:61][C@H:62]([C:67]([NH:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:53])[N:15]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])[C:16](=[O:34])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:4])=[O:69])[CH2:63][C:64](=[O:65])[O:66][C:5]([CH3:10])([CH3:6])[CH3:3])=[O:60])([CH3:55])([CH3:56])[CH3:57]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)N(CCCCCCCCCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CN
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)C(=O)OC(C)(C)C
Solvent: ClCCl
Product: CCCCCCCC/C=C\CCCCCCCC(=O)N(CCCCCCCCCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CNC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Yield: 88 %

Procedure:
from N-(2-glycyl-amino-2-deoxy-β-D-glucopyranosyl)-N-octadecyl-oleamide and N-tert-butyloxycarbonyl-O-tert-butyl-L-aspartic acid. Yield 88%. [α]D =+13.8° (c=0.93, dichloromethane).
Reaction SMILES: [CH:1]([CH:3]([CH2:9][C:10]([CH3:12])=[O:11])[C:4]([O:6][CH2:7][CH3:8])=[O:5])=O.O>C1C=CC=CC=1>[CH3:12][C:10]1[O:11][CH:1]=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH:9]=1
Reactant: CCOC(=O)C(C=O)CC(C)=O
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)c1coc(C)c1

Procedure:
The abovementioned mixture of ethyl 2-formyllevulinate and its diethyl ketal was dissolved in benzene, the catalyst was added, and the resulting solution was refluxed with a Dean-Stark trap for 3-3.5 h until the water was completely removed. The reaction mixture was then distilled under reduced pressure, resulting in 15 g (97 mmol) of ethyl 5-methylfuran-3-carboxylate, boiling point 97° C./15 mm Hg.
Reaction SMILES: [Li].C(NC(C)C)(C)C.[Li]CCCC.[C:14]([C@@H:18]1[O:22][C:21](=[O:23])[C@H:20]([CH3:24])[O:19]1)([CH3:17])([CH3:16])[CH3:15].[F:25][C:26]([F:30])([F:29])[CH2:27]I.[NH4+].[Cl-]>C1COCC1>[C:14]([C@@H:18]1[O:22][C:21](=[O:23])[C@@:20]([CH3:24])([CH2:27][C:26]([F:30])([F:29])[F:25])[O:19]1)([CH3:17])([CH3:15])[CH3:16]
Reactant: FC(F)(F)CI
Reactant: C[C@@H]1O[C@H](C(C)(C)C)OC1=O
Agent: [Cl-]
Agent: [Li]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)[C@@H]1OC(=O)[C@@](C)(CC(F)(F)F)O1
Temperature: -45 °C
Reaction time: 0.75 h
Yield: 38.2 %

Procedure:
To a solution of lithium diiospropylamide (prepared from 13 ml of diisopropylamine and 54 ml of 1.6 M n-BuLi in hexanes in 200 ml of anhydrous THF at 0° C.) at -72° C. was added slowly 2-(s)-t-butyl-5-(s)-methyl-1,3-dioxolan-4-one (12.95 g, 81.9 mmol, Tetrahedron, 1984, 40, 1313) at such a rate as to maintain the internal temperature below -60° C. and the mixture was aged at -72° C. for an hour. 1,1,1-Trifluoro-2-iodoethane (25 g, 119 mmol) was added quickly, the reaction temperature increased to -45° C. and the mixture was aged at -72° C. for 45 min. and then allowed to warm up to -20° C. over 20 min. Saturated aq. NH4Cl was then added and the product was extracted in i-PrOAc, dried over Na2SO4, concentrated and distilled under reduced pressure to afford 7.51 g of a brown oil BP 90° C./20 mm Hg.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Cl.[NH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+].CC(C)([O-])C.[K+]>O.CN1CCCC1=O>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][C:8]([F:10])=[CH:7][CH:6]=2)[NH:12][C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: N#Cc1ccc(F)cc1F
Reactant: CCOC(=O)CN
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1[nH]c2cc(F)ccc2c1N
Temperature: 40 °C
Reaction time: 2 h
Yield: 7.5 %

Procedure:
Under nitrogen, stir and heat a mixture of 2,4-difluorobenzonitrile (1.14 g, 8.2 mmol), ethyl glycinate hydrochloride (1.5 mg, 10.7 mmol), potassium carbonate (3.4 g, 24.6 mmol) and 1-methyl-2-pyrrolidinone (20 mL). After 2 h allow the reaction to cool to 40° C. and add potassium tert-butoxide (300 mg, 2.7 mmol). Allow the reaction to stir and for 1 h and then add additional potassium tert-butoxide (500 mg, 4.4 mmol). Cool to room temperature overnight, pour the reaction mixture onto ice. Add water to dissolve the solids in the reaction flask and add to the reaction quench. Filter off the precipitated brown solid and extract the filtrate with ethyl acetate. Wash the extract with water (2×'s), brine and dry over magnesium sulfate. Filter and concentrate under vacuum to give a residue, which is triturated with dichloromethane to afford a solid. Collect the solid, concentrate the filtrate and chromatograph the solid on silica gel (10 g, Sepack cartridge) with dichloromethane as the eluent. Collect the appropriate fractions and concentrate to obtain a solid. Combine with the previously collected solid to provide 136.7 mg (7.5%) of the title compound: MS 223(M+H).
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:14][OH:15]>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH:14]=[O:15]
Reactant: OCc1ccc2oc3c(c2c1)CCCC3
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: O=Cc1ccc2oc3c(c2c1)CCCC3
Temperature: 25 °C
Reaction time: 72 h

Procedure:
40.4 g (0.2 mol) of 6,7,8,9-tetrahydro-2-dibenzofuranmethanol are dissolved in 800 ml of toluene and 176 g (2 mols) of manganese dioxide are added. The dark suspension is stirred at room temperature for 72 hours and then filtered over diatomaceous earth and the resulting filtrate is evaporated to dryness under a waterpump vacuum. 6,7,8,9-Tetrahydro-2-dibenzofurancarboxaldehyde is thus obtained as a dark yellow oily product which, according to the thin layer chromatogram (toluene/ethyl acetate 1:1) is a single compound and can be used for further reactions without additional purification.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[CH:2]([CH2:4][C:5]([OH:7])=[O:6])[OH:3].C(=O)([O-])[O-].[K+:14].[K+]>O>[OH2:3].[C:1]([O-:9])(=[O:8])[CH:2]([CH2:4][C:5]([OH:7])=[O:6])[OH:3].[K+:14]
Reactant: O=C(O)CC(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C(O)CC(O)C(=O)[O-]
Temperature: 10 °C
Reaction time: 4 h
Yield: 138.8 %

Procedure:
26.8 g (0.2 mole) of DL-malic acid and 13.8 g (0.1 mole) of potassium carbonate are dissolved in 200 ml of water. The solution (pH 4.1) is concentrated under reduced pressure to make the total weight thereof 60 g. The concentrated solution is cooled to 10° C., and the mixture obtained (i.e., the mixture of the concentrated solution and crystals precipitated) is stirred at the same temperature for 4 hours. After stirring, the mixture had a pH of 4.1. The crystalline precipitates are collected by filtration, washed with an aqueous 80% methanol solution, and dried at 35° C. for 16 hours. 26.4 g of monopotassium DL-malate monohydrate are obtained as crystals. The amounts of DL-malic acid, potassium and water contained in the product are shown in Table 6. The results of this table indicate that the product obtained is the pure crystals of monopotassium DL-malate monohydrate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[CH:6][NH:5][C:4]=1/[CH:8]=[C:9]1\[C:10](=[O:24])[NH:11][C:12]2[C:17]\1=[C:16]([C:18]#[C:19][Si](C)(C)C)[CH:15]=[CH:14][CH:13]=2.[C-]#N.[K+]>CCO.O.[N+]([O-])([O-])=O.[Ag+]>[C:18]([C:16]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:17]=1/[C:9](=[CH:8]/[C:4]1[NH:5][CH:6]=[CH:7][C:3]=1[O:2][CH3:1])/[C:10](=[O:24])[NH:11]2)#[CH:19]
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#C[Si](C)(C)C)c21
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [C-]#N
Solvent: O
Solvent: CCO
Product: C#Cc1cccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2

Procedure:
Using Method K above, a solution of (Z)-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-4-(2-trimethylsilyl-ethynyl)-2H-indol-2-one (1.3 g, 3.86 mmol) (from Step 1 above) in EtOH (80 mL) was treated with AgNO3 (1.46 g, 8.59 mmol) in ethanol (5 mL) and water (15 mL) at room temperature for 1 h followed by KCN (2.71 g, 41.6 mmol) in water (10 mL) to give (Z)-1,3-dihydro-4-ethynyl-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 1.02 g, 100%).
Reaction SMILES: [I:1][C:2]1[C:3]([CH3:12])=[C:4]([N+:9]([O-:11])=[O:10])[C:5](=[O:8])[NH:6][CH:7]=1.[H-].[Na+].[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Cl)=[CH:19][CH:18]=1>O>[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][N:6]2[CH:7]=[C:2]([I:1])[C:3]([CH3:12])=[C:4]([N+:9]([O-:11])=[O:10])[C:5]2=[O:8])=[CH:19][CH:18]=1
Reactant: COc1ccc(CCl)cc1
Reactant: Cc1c(I)c[nH]c(=O)c1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COc1ccc(Cn2cc(I)c(C)c([N+](=O)[O-])c2=O)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 75 %

Procedure:
A mixture of 5-iodo-4-methyl-3-nitro-2-pyridone (2.90 g, 10.4 mmol) and sodium hydride (60% in oil, 0.44 g, 11 mmol) was stirred at rt for 2.5 hours. 4-Methoxybenzyl chloride (1.50 mL) was added, and the mixture was stirred at rt for 18 h. Water was added, and the mixture and extracted with ethyl acetate. The organic phase was washed, dried and evaporated. Chromatography of the residue over silica gel (35% ethyl acetate/petroleum ether) followed by crystallization from water gave 1-(4-methoxybenzyl)-5-iodo-4-methyl-3-nitro-2-pyridone (3.11 g, 75%).
Reaction SMILES: C[N:2]1[CH2:7][CH:6]=[C:5]([C:8](=[O:10])[CH3:9])[CH2:4][CH2:3]1.ClC(OC(Cl)=O)C>ClCCl>[NH:2]1[CH2:3][CH:4]=[C:5]([C:8](=[O:10])[CH3:9])[CH2:6][CH2:7]1
Reactant: CC(=O)C1=CCN(C)CC1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Product: CC(=O)C1=CCNCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 1-(1,2,3,6-tetrahydro-1-methyl-4pyridinyl)ethanone, O-methyloxime (3 g, 17.8 mmol) in 20 ml dry dichloromethane was cooled to 0° C., treated dropwise with 1-chloroethylchloroformate (2.55 g, 17.8 mmol), and stirred 18 hours at room temperature. The reaction mixture was then concentrated in vacuo to an oil which was heated under reflux one hour in 50 ml of methanol. The methanol was distilled off and the residue was chromatographed over silica gel eluting with 5% methanol in ethyl acetate. The desired fractions were combined, concentrated in vacuo, and treated with methanolic hydrogen chloride to give 1.75 g of 1-(1,2,3,6-tetrahydro-4-pyridinyl)ethanone, O-methyloxime hydrochloride, mp 185°-186° C.