Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=C(OC)C=C(OC)C=1C[S:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=1.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C.C(Cl)Cl>O>[SH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=1
Reactant: COc1cc(OC)c(CSc2ccccc2-c2cccc(O)c2)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Oc1cccc(-c2ccccc2S)c1
Yield: 66.9 %

Procedure:
2′-(2,4,6-trimethoxybenzylthio)biphenyl-3-ol (0.948 g, 2.48 mmol) was treated with TFA:triethylsilane:DCM (8 ml:3 ml:80 ml). The solution was stirred 30 min. before 40 ml water was added and the mixture was extracted with DCM (2×80 ml). The organic was washed with water, brine, dried over magnesium sulfate and concentrated. The residue was purified by silica flash chromatography (hexane:ethyl acetate 80:20) to afford 0.335 g product (1.66 mmol, 67% yield).
Reaction SMILES: [CH3:1][I:2].[N+]1([O-])C=CNC=1.C(N1C[N:20]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:19][N:18]([CH2:29][C:30]2[CH:35]=CC=CC=2)C1)C1C=CC=CC=1.CC(=NO)[C:38](=[O:40])C>C(Cl)(Cl)Cl>[I-:2].[CH2:22]([N:20]1[C:30]([CH3:35])=[C:29]([CH3:1])[N+:18]([O:40][CH3:38])=[CH:19]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(=O)C(C)=NO
Reactant: CI
Reactant: c1ccc(CN2CN(Cc3ccccc3)CN(Cc3ccccc3)C2)cc1
Agent: [O-][n+]1cc[nH]c1
Solvent: ClC(Cl)Cl
Product: CO[n+]1cn(Cc2ccccc2)c(C)c1C
Product: [I-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl iodide (0.5 mL, 7.8 mmol) was added via syringe to a solution of imidazole-N-oxide 1 (1.0 g, 4.9 mmol) in ca. 20 mL of CHCl3 (compound 1 was prepared from 1,3,5-tribenzyl-[1,3,5]triazinane and butane-2,3-dione monooxime using the procedure of Arduengo et al. (1992), supra.) The resulting mixture was stirred at room temperature overnight. Removal of the volatiles in vacuo afforded a thick yellow oil of suitable purity in an undetermined yield. 1H-NMR (δ, CDCl3): 10.32 (s, 1H, N—CH—N); 7.39 (m, 5H, C6H5); 5.56 (s, 2H, NCH2); 4.38 (s, 3H, OCH3); 2.27 (s, 3H, CH3); 2.20 (s, 3H, CH3).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:13]([O:15][CH3:16])=[O:14])[C:7]([CH3:17])=[CH:6]2.C(N(CC)CC)C.ClCCl>O>[CH:2]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:13]([O:15][CH3:16])=[O:14])[C:7]([CH3:17])=[CH:6]2)=[O:1]
Reactant: COC(=O)c1nc2ccc(CO)cc2cc1C
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1nc2ccc(C=O)cc2cc1C
Reaction time: 2 h
Yield: 77.9 %

Procedure:
To a mixture of methyl 6-hydroxymethyl-3-methylquinoline-2-carboxylate (193 mg), triethylamine (422 mg) dimethyl sulfoxide (2 ml) and dichloromethane (2 ml) was added portionwise sulfur trioxide pyridine complex (266 mg) in water bath and the mixture was stirred for 2 hours at the same temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin-layer chromatography (n-hexane:ethyl acetate=1:1, V/V) to give methyl 6-formyl-3-methylquinoline-2-carboxylate (149 mg).
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1([CH2:16][CH:17]=C)[S:13](=[O:15])(=[O:14])[C:9]2[S:10][CH:11]=[CH:12][C:8]=2[CH2:7]1)=[O:5])[CH3:2].C[OH:20].C(Cl)(Cl)Cl>>[CH2:1]([NH:3][C:4]([C:6]1([CH2:16][CH:17]=[O:20])[S:13](=[O:15])(=[O:14])[C:9]2[S:10][CH:11]=[CH:12][C:8]=2[CH2:7]1)=[O:5])[CH3:2]
Reactant: CO
Reactant: C=CCC1(C(=O)NCC)Cc2ccsc2S1(=O)=O
Solvent: ClC(Cl)Cl
Product: CCNC(=O)C1(CC=O)Cc2ccsc2S1(=O)=O
Temperature: 25 °C

Procedure:
N-Ethyl-2-allyl-2,3-dihydrothieno[2,3-b]thiophene-2-carboxamide-1,1-dioxide (7.2 g, 0.025 mol) in 1:1 methanol-chloroform (300 mL) was cooled to -78° C. Ozone was bubbled into the reaction mixture until a pale blue color persisted. The reaction was sparged with nitrogen for 10 minutes and dimethyl sulfide (7 mL) was added. The solution was warmed to room temperature and the solvents removed in vacuo. The residue was partitioned between water and ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. The solution was filtered, and the solvent evaporated to give the title compound as an oil (5.3 g).
Reaction SMILES: [S:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1.C([Li])CCC.[B:15](OC(C)C)([O:20]C(C)C)[O:16]C(C)C.P(=O)(O)(O)O>O.CCOCC>[S:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[C:2]1[B:15]([OH:20])[OH:16]
Reactant: c1cc2sccc2cn1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: O=P(O)(O)O
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: OB(O)c1cc2cnccc2s1
Temperature: -44 °C
Reaction time: 1 h

Procedure:
A three neck flask fitted with an internal thermometer containing thieno[3,2-c]pyridine (5.0 g, 37 mmol, 1 equivalent) was evacuated and then filled with a nitrogen gas atmosphere. THF (60 mL) was added and the solution was cooled to −44° C. (CH3CN/dry ice). n-Butyllithium (1.6M/hexane, 25 mL, 41 mmol, 1.1 equivalents) was added over 10 minutes, while maintaining the internal temperature at or below −33° C. The reaction was stirred at −33 to −45° C. for 60 minutes. Triisopropyl borate (10.2 mL, 44 mmol, 1.2 equivalents) was added and the cooling bath removed. The reaction was allowed to proceed for 105 minutes. Then 3.0 mL phosphoric acid (85% aqueous, 3.0 mL, 44 mmol, 1.2 equivalents) was added. A yellow solid formed, which was diluted with water and Et2O (about 150 mL each). A yellow solid was collected by filtration and was dried by suction overnight (5.05 g). Analytical Data: 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.95 (1H, s), 8.09 (1H, d, J=5.9 Hz), 8.34 (1H, d, J=6.1 Hz), 9.09 (1H, s). MS (APCI, M+1) 180.1. Microanalysis for C7H6BNSO2.H3PO4: calculated C, 30.35; H, 3.27; N, 5.06; P, 11.18. Found: C, 41.12; H, 3.19; N, 6.53; P, 0.68%.
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([NH:24][CH:25]2[CH2:30][CH2:29][CH:28]([C:31]([O-])=[O:32])[CH2:27][CH2:26]2)[N:19]=1)(=[O:4])=[O:3].[Na+].[CH2:35]([O:37][C:38]([C@@H:40]1[CH2:45][CH2:44][CH2:43][NH:42][CH2:41]1)=[O:39])[CH3:36].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>O.CN(C=O)C>[CH2:35]([O:37][C:38]([C@@H:40]1[CH2:45][CH2:44][CH2:43][N:42]([C:31]([CH:28]2[CH2:27][CH2:26][CH:25]([NH:24][C:20]3[N:19]=[C:18]([N:13]4[C:14]5[C:10](=[C:9]([O:8][CH2:7][CH2:6][CH2:5][S:2]([CH3:1])(=[O:3])=[O:4])[CH:17]=[CH:16][CH:15]=5)[CH:11]=[CH:12]4)[CH:23]=[CH:22][N:21]=3)[CH2:30][CH2:29]2)=[O:32])[CH2:41]1)=[O:39])[CH3:36]
Reactant: CCOC(=O)[C@@H]1CCCNC1
Reactant: CS(=O)(=O)CCCOc1cccc2c1ccn2-c1ccnc(NC2CCC(C(=O)[O-])CC2)n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOC(=O)[C@@H]1CCCN(C(=O)C2CCC(Nc3nccc(-n4ccc5c(OCCCS(C)(=O)=O)cccc54)n3)CC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 8 %

Procedure:
Sodium 4-{4-[4-(3-methanesulfonyl-propoxy)-indol-1-yl]-pyrimidin-2-ylamino}-cyclohexanecarboxylate (0.4 g), (R)-piperidine-3-carboxylic acid ethyl ester (0.165 g), BOP (0.537 g) and DIPEA (0.56 mL) were added to DMF (3 mL), and the mixture was stirred at room temperature overnight. The mixture was diluted with water and the resulting precipitate was collected by filtration, washed with water, dried under reduced pressure, and purified by flash chromatography (DCM/MeOH) to give 39.6 mg of (R)-1-(4-{4-[4-(3-methanesulfonyl-propoxy)-indol-1-yl]-pyrimidin-2-ylamino}-cyclohexanecarbonyl)-piperidine-3-carboxylic acid ethyl ester, MP=175.0-177.0° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([S:33]([C:36]2[CH:41]=[CH:40][C:39]([CH:42]([CH2:46][CH:47]3[CH2:51][CH2:50][CH2:49][CH2:48]3)[C:43](O)=[O:44])=[CH:38][CH:37]=2)(=[O:35])=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:52][C:53]1[S:54][CH:55]=[CH:56][N:57]=1.N1C=CC=CC=1>C(Cl)Cl.O>[CH:28]1([S:33]([C:36]2[CH:37]=[CH:38][C:39]([CH:42]([CH2:46][CH:47]3[CH2:51][CH2:50][CH2:49][CH2:48]3)[C:43]([NH:52][C:53]3[S:54][CH:55]=[CH:56][N:57]=3)=[O:44])=[CH:40][CH:41]=2)(=[O:35])=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: Nc1nccs1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(S(=O)(=O)C2CCCC2)cc1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1nccs1)C(CC1CCCC1)c1ccc(S(=O)(=O)C2CCCC2)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 71.9 %

Procedure:
A solution of triphenylphosphine (106 mg, 0.40 mmol) and N-bromosuccinimide (82 mg, 0.45 mmol) in methylene chloride (1.35 mL) was cooled to 0° C. and then treated with a solution of 2-(4-cyclopentanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (94.8 mg, 0.27 mmol) in methylene chloride. The reaction mixture was stirred at 25° C. for 45 min. At this time, the reaction was treated with 2-aminothiazole (35 mg, 0.35 mmol) and pyridine (0.03 ml, 0.40 mmol). The reaction was stirred at 25° C. for 18 h. The reaction was then diluted with water (100 mL) and extracted with chloroform (3×50 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded 2-(4-cyclopentanesulfonyl-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide (84 mg, 71.8%) as a light-orange solid: mp 180-182° C.; EI-HRMS m/e calcd for C22H28N2O3S2 (M+) 432.1541 found 432.1543.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([CH2:18][O:19][C:20]2[C:32](Cl)=[CH:31][C:23]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[C:22]([F:34])[CH:21]=2)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:35]1(B(O)O)[CH2:37][CH2:36]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O>[CH:1]([N:14]1[CH2:17][CH:16]([CH2:18][O:19][C:20]2[C:32]([CH:35]3[CH2:37][CH2:36]3)=[CH:31][C:23]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[C:22]([F:34])[CH:21]=2)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)C1CC1
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(OCC2CN(C(c3ccccc3)c3ccccc3)C2)cc1F
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1cc(C2CC2)c(OCC2CN(C(c3ccccc3)c3ccccc3)C2)cc1F
Temperature: 90 °C
Yield: 54.6 %

Procedure:
A mixture of tert-butyl 4-((1-benzhydrylazetidin-3-yl)methoxy)-5-chloro-2-fluorobenzoate (500 mg), cyclopropylboronic acid (188 mg), potassium phosphate (1.12 g) in toluene (6.2 mL) and water (0.31 mL) was purge with nitrogen. Tricyclohexylphosphine tetrafluoroborate (79 mg) and palladium acetate (24 mg) were added. The mixture was heated at 90° C. for 16 hours. The mixture was diluted with EtOAc and filtered. The filtrate was concentrated. The residue was purified with flash chromatography (0-30% EtOAc/heptane) to give the product (276 mg).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([Br:12])=[N:4][N:3]=1.CN1CCCC1=O.C(=O)([O-])[O-].[K+].[K+].[C:26]([O:30][C:31](=[O:40])[N:32]([CH3:39])[CH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)([CH3:29])([CH3:28])[CH3:27]>O>[Br:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([N:36]2[CH2:35][CH2:34][CH:33]([N:32]([CH3:39])[C:31](=[O:40])[O:30][C:26]([CH3:27])([CH3:28])[CH3:29])[CH2:38][CH2:37]2)=[N:3][N:4]=1
Reactant: Brc1nnc(Br)c2ccccc12
Reactant: CN(C(=O)OC(C)(C)C)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CN(C(=O)OC(C)(C)C)C1CCN(c2nnc(Br)c3ccccc23)CC1
Temperature: 80 °C
Yield: 95.7 %

Procedure:
Combine 1,4-dibromophthalazine (0.70 g, 2.38 mmol), N-methylpyrrolidone (7.0 mL), potassium carbonate (395 mg, 2.86 mmol), and methyl-piperidin-4-yl-carbamic acid tert-butyl ester (532 mg, 2.38 mmol). Heat at 80° C. overnight. Cool and pour into water. Collect the solid and dry in a vacuum oven at ambient temperature overnight to obtain the final product (0.96 g, 95%). ES/MS m/z (81Br) 421.0 (M+1).
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[CH2:2][CH2:3][C:4]([CH3:6])=O.C(OCC)(=O)CC(C)=O.[CH3:20][N:21]([CH3:31])[N:22]=C(C)CC(OCC)=O>>[CH3:20][N:21]([CH3:31])[N:22]=[C:4]([CH3:6])[CH2:3][CH2:2][C:1]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)CC(C)=NN(C)C
Reactant: CCOC(=O)CCC(C)=O
Solvent: CCOC(=O)CC(C)=O
Product: CCOC(=O)CCC(C)=NN(C)C

Procedure:
In the same manner but replacing ethyl levulinate with an equivalent amount of ethyl acetoacetate, ethyl acetoacetate dimethyl hydrazone, b.p. 88°-92° C/ 19-20 mm, νmaxCHCl3 3245, 3180 and 1728 cm -1, is obtained.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:5][CH:6]=1.CCN(C(C)C)C(C)C.Cl[C:23]([O:25][C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1)=[O:24]>C(Cl)Cl>[C:4]1([N:7]2[CH2:8][CH2:9][N:10]([C:23]([O:25][C:26]3[CH:27]=[CH:28][C:29]([N+:32]([O-:34])=[O:33])=[CH:30][CH:31]=3)=[O:24])[CH2:11][CH2:12]2)[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCN(c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 102.4 %

Procedure:
To a solution of phenylpiperazine (12.0 g, 74.0 mmol) and DIPEA (13.5 mL, 81.6 mmol) in DCM (70 mL) at 0° C. add 4-nitrophenyl chloroformate (16.5 g, 81.71 mmol). The reaction mixture was stirred for 30 minutes at 0° C. and then washed with saturated sodium hydrogen carbonate solution (3×200 mL), dried (MgSO4) and concentrated in vacuo to give a 4-nitrophenyl 4-phenylpiperazine-1-carboxylate (24.8 g, 102%) as a yellow solid which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([OH:12])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[Cl:19][C:20]1[CH:25]=[C:24](Cl)[CH:23]=[CH:22][N:21]=1>CC(N(C)C)=O>[Cl:19][C:20]1[CH:25]=[C:24]([O:12][C:5]2[CH:4]=[CH:3][C:2]([NH2:1])=[N:7][C:6]=2[C:8]([F:11])([F:9])[F:10])[CH:23]=[CH:22][N:21]=1
Reactant: Nc1ccc(O)c(C(F)(F)F)n1
Reactant: Clc1ccnc(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Nc1ccc(Oc2ccnc(Cl)c2)c(C(F)(F)F)n1
Temperature: 95 °C
Reaction time: 0.02 h
Yield: 41.4 %

Procedure:
A solution of 6-amino-2-(trifluoromethyl)pyridin-3-ol (0.092 g, 0.517 mmol) in DMA (5 mL) was sparged with Ar, treated with potassium t-butoxide (0.087 g, 0.775 mmol), stirred for 1 minute, treated with 2,4-dichloropyridine (0.092 g, 0.620 mmol), flushed with Ar and heated at 95° C. overnight. The mixture was cooled to RT, treated with EtOAc, washed with satd. NaHCO3 (2×), dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex) to afford 5-((2-chloropyridin-4-yl)oxy)-6-(trifluoromethyl)pyridin-2-amine (62 mg, 41%). 1H NMR (400 MHz, DMSO-d6): δ 8.27-8.24 (m, 1H), 7.52-7.49 (m, 1H), 7.04 (s, 1H), 6.94-6.91 (m, 1H), 6.76 (d, J=9.1 Hz, 1H), 6.66 (s, 2H); MS (ESI) m/z: 290.1 (M+H+).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[Br:31]NC(=O)CCC(N)=O>C1COCC1.C(OCC)(=O)C>[Br:31][CH2:14][C:13]([C:10]1[CH:11]=[CH:12][C:7]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:8][CH:9]=1)=[O:15]
Reactant: NC(=O)CCC(=O)NBr
Reactant: CC(=O)c1ccc(N2CCCCC2)cc1
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(CBr)c1ccc(N2CCCCC2)cc1
Reaction time: 0.5 h

Procedure:
4′-Piperidinoacetophenone (203 mg, 1.00 mmol) was dissolved in THF (5 mL) and treated with lithium bis(trimethylsilyl)amide (1.10 mL, 1.0 M in THF, 1.10 mmol). The solution was stirred for 30 minutes prior to the addition of chlorotrimethylsilane (140 μL, 1.10 mmol). After stirring for an additional 30 minutes N-bromosuccinamide (300 mg, 1.73 mmol) was added and the mixture was refluxed from 4 hours. Standard aqueous/ethyl acetate workup provided a yellow solid which was further purified by silica gel chromatography, eluting with 3:1 hexane/ethyl acetate, to provide 2-bromo-4′-piperidinoacetophenone as an off white solid (209 mg, 74%). 1H NMR (200 MHz, CDCl3) δ 8.75 (d, 2H), 6.84 (d, 2H), 4.61 (s, 2H), 3.40 (m, 4H), 1.68 (m, 6H).
Reaction SMILES: [OH:1]O.[CH3:3][CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]([OH:26])/[CH:9]=[CH:10]/[C@@H:11]1[C@@H:16]([CH2:17]/[CH:18]=[CH:19]\[CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[C:14](=[O:15])[CH:13]=[CH:12]1.[OH-].[Na+].Cl>CO>[CH3:3][CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]([OH:26])/[CH:9]=[CH:10]/[C@@H:11]1[C@@H:16]([CH2:17]/[CH:18]=[CH:19]\[CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[C:14](=[O:15])[CH2:13][C@H:12]1[OH:1].[CH3:3][CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]([OH:26])/[CH:9]=[CH:10]/[C@@H:11]1[C@@H:16]([CH2:17]/[CH:18]=[CH:19]\[CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[C:14](=[O:15])[CH2:13][C@@H:12]1[OH:1]
Reactant: CCCCC[C@H](O)/C=C/[C@H]1C=CC(=O)[C@@H]1C/C=C\CCCC(=O)O
Reactant: OO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCC[C@H](O)/C=C/[C@H]1[C@@H](O)CC(=O)[C@@H]1C/C=C\CCCC(=O)O
Product: CCCCC[C@H](O)/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1C/C=C\CCCC(=O)O
Temperature: -20 °C

Procedure:
Hydrogen peroxide (0.35 ml.; 30% aqueous) is added to a solution of PGA2 (200 mg.) in 5 ml. of methanol. The mixture is cooled to -20°C., and 0.75 ml. of one N aqueous sodium hydroxide solution is slowly added with stirring. After one hour of stirring at -20°C., 1 ml. of one N hydrochloric acid is added, and the mixture is evaporated under reduced pressure. The residue is dissolved in ethyl acetate, and the resulting solution is washed successively with water and brine, dried with anhydrous sodium sulfate, and evaporated. The residue is treated with amalgamated aluminum as described in Example 8, using 2.5 ml. diethyl ether, 0.25 ml. methanol, and 0.03 ml. water, the amalgamated aluminum being added in 2 portions. When the reduction is complete, ethyl acetate and one N hydrochloric acid are added to the reaction mixture and the mixture is separated in a separatory funnel. The ethyl acetate layer is washed successively with one N hydrochloric acid, water, and brine, dried with anhydrous sodium sulfate, and evaporated. The residue is subjected to preparative thin layer chromatography to give PGE2 and 11β-PGE2 in the ratio 1:2.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][CH:8]=[C:7]([I:12])[N:6]=1)=[O:4].[OH-].[Li+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O.ClCCl>[NH2:11][C:10]1[C:5]([C:3]([OH:4])=[O:2])=[N:6][C:7]([I:12])=[CH:8][N:9]=1
Reactant: COC(=O)c1nc(I)cnc1N
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: Nc1ncc(I)nc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
3-amino-6-iodo-pyrazine-2-carboxylic acid methyl ester (45 g, 161 mmol) was dissolved in 750 ml of THF. 90 ml of water and 40 ml of a 4 M solution of lithium hydroxide in water was added. The mixture was stirred at room temperature for 2 hours or until TLC analysis showed only baseline material. A solution of 10% citric acid in water was added to adjust the pH to about 3-4. The mixture was diluted with dichloromethane and the organic phase was separated. The aqueous layer was extracted three times with dichloromethane and the combined organic phases were dried over sodium sulfate and evaporated. The residue was dried in vacuo to afford 37.0 g (140 mmol; 87% yield) of 3-amino-6-iodo-pyrazine-2-carboxylic acid as a yellow powder. 1H-NMR (d6-DMSO) δ: 11.70 s, weak, 8.44 [1H] s, 7.50 [2H] s, br. MS: m/z 266 [MH+].
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:34][C:35]1[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=1.[N:41]1[CH:46]=[CH:45][N:44]=[C:43]2[NH:47][C:48]([C:50]3[C:58]4[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=4)[N:52]([CH2:59][CH2:60][CH2:61]O)[CH:51]=3)=[CH:49][C:42]=12>O1CCCC1>[N:37]1[CH:38]=[CH:39][CH:40]=[C:35]([O:34][CH2:61][CH2:60][CH2:59][N:52]2[C:53]3[C:58](=[CH:57][CH:56]=[CH:55][CH:54]=3)[C:50]([C:48]3[NH:47][C:43]4=[N:44][CH:45]=[CH:46][N:41]=[C:42]4[CH:49]=3)=[CH:51]2)[CH:36]=1
Reactant: OCCCn1cc(-c2cc3nccnc3[nH]2)c2ccccc21
Reactant: Oc1cccnc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1cncc(OCCCn2cc(-c3cc4nccnc4[nH]3)c3ccccc32)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 43.6 %

Procedure:
A solution of diisopropylazodicarboxylate (269 μM) in tetrahydrofuran (0.5 mL) was added dropwise, over 2 minutes, to a solution of triphenylphosphine (359 mg) in tetrahydrofuran (2.5 mL) at 0° C. under an atmosphere of nitrogen. After stirring at that temperature for 20 minutes the mixture was treated with a solution of 3-hydroxypyridine (65 mg) in tetrahydrofuran (1 mL) over 1 minute then with a suspension of 3-[3-(5H-pyrrolo[2,3-b]pyrazin-6-yl)-indol-1-yl]-propan-1-ol [200 mg, Example 2(a)] in tetrahydrofuran (2 mL). The mixture was allowed to warm to ambient temperature over 18 hours then evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and methanol (9:1, v/v) to give the title compound (110 mg) as a yellow solid, m.p. 208–209° C. MS: 370 (MH+).
Reaction SMILES: [Na:1].[CH3:2][C:3]1([CH3:31])[O:8]C[CH:6]([CH2:9][O:10][C:11]2[C:16](C)=[CH:15][N:14]=[C:13]([CH2:18][S:19]([C:21]3[NH:25][C:24]4[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=4[N:22]=3)=[O:20])[C:12]=2[CH3:30])[CH2:5][O:4]1.CC1(C)OC(CO)CO1.ClC1C=C[N+]([O-])=C(C)C=1C.[F:51]C1C=CC2NC(S)=NC=2C=1>>[Na:1].[CH3:2][C:3]1([CH3:31])[O:8][CH:6]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([CH2:18][S:19]([C:21]3[NH:25][C:24]4[CH:26]=[CH:27][C:28]([F:51])=[CH:29][C:23]=4[N:22]=3)=[O:20])[C:12]=2[CH3:30])[CH2:5][O:4]1
Reactant: Cc1cnc(CS(=O)c2nc3ccccc3[nH]2)c(C)c1OCC1COC(C)(C)OC1
Reactant: Fc1ccc2[nH]c(S)nc2c1
Agent: Cc1c(Cl)cc[n+]([O-])c1C
Agent: [Na]
Solvent: CC1(C)OCC(CO)O1
Product: Cc1c(OCC2COC(C)(C)O2)ccnc1CS(=O)c1nc2cc(F)ccc2[nH]1
Yield: 14.1 %

Procedure:
The same procedure as in the step (10b) of Example 10 and the step (14b) of Example 14, the step (5f) of Example 5, the steps (11h) and (11i) of Example 11 was repeated using solketal, 4-chloro-2,3-dimethylpyridine 1-oxide, and 5-fluoro-1H-benzimidazole-2-thiol to obtain the title compound (210 mg, yield: 14.1%) as a white solid. Note that methanol was used as a solvent instead of ethanol in the same operation as in the step (5f).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH:6]=[O:7].[C-:15]#[N:16].[K+].[CH3:18][Si:19](Cl)([CH3:21])[CH3:20]>[I-].[Zn+2].[I-].C(#N)C>[CH3:14][O:13][C:9]1[CH:8]=[C:5]([CH:6]([O:7][Si:19]([CH3:21])([CH3:20])[CH3:18])[C:15]#[N:16])[CH:4]=[C:3]([O:2][CH3:1])[C:10]=1[O:11][CH3:12]
Reactant: C[Si](C)(C)Cl
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: [C-]#N
Agent: [I-]
Agent: [K+]
Agent: [Zn+2]
Solvent: CC#N
Product: COc1cc(C(C#N)O[Si](C)(C)C)cc(OC)c1OC

Procedure:
3,4,5-Trimethoxybenzaldehyde, acetonitrile, potassium cyanide, zinc (II) iodide and trimethylsilyl chloride are treated in the same manners as in the above procedure (1-a) to give (3,4,5-trimethoxyphenyl)(trimethylsilyloxy)acetonitrile as oily product.