Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:14])[CH2:10][CH2:11][CH2:12]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:15]1[CH:19]=[CH:18][N:17]=[CH:16]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:8][C:9](=[O:14])[CH2:10][CH2:11][CH2:12][N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1c[nH]cn1
Reactant: O=C(CCCBr)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(CCCn1ccnc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 32.4 %

Procedure:
A mixture of 4-bromobutyric acid benzyl ester (23.7 g), imidazole (8.1 g), potassium carbonate (14.0 g) and acetone (400 ml) was stirred under refluxing conditions for 6 hours. After the reaction mixture was cooled to room temperature, the insoluble solid was filtered off, the filtrate was concentrated. The residual oily substance was subjected to silica gel column chromatography and eluted with ethyl acetate-methanol (20:1, v/v) to yield 4-(1-imidazolyl)butyric acid benzyl ester (7.3 g, 33%) as an oily substance.
Reaction SMILES: C[C@@H]1CNC[C@H]1C1NC(=O)C2C=NN(C3CCOCC3)C=2N=1.C([N:30]1[CH2:34][C@@H:33]([CH3:35])[C@H:32]([C:36]2[NH:37][C:38](=[O:52])[C:39]3[C:44]([CH3:45])=[N:43][N:42]([CH:46]4[CH2:51][CH2:50][O:49][CH2:48][CH2:47]4)[C:40]=3[N:41]=2)[CH2:31]1)C1C=CC=CC=1>>[CH3:45][C:44]1[C:39]2[C:38](=[O:52])[NH:37][C:36]([C@H:32]3[C@H:33]([CH3:35])[CH2:34][NH:30][CH2:31]3)=[N:41][C:40]=2[N:42]([CH:46]2[CH2:51][CH2:50][O:49][CH2:48][CH2:47]2)[N:43]=1
Reactant: Cc1nn(C2CCOCC2)c2nc([C@@H]3CN(Cc4ccccc4)C[C@H]3C)[nH]c(=O)c12
Agent: C[C@@H]1CNC[C@H]1c1nc2c(cnn2C2CCOCC2)c(=O)[nH]1
Product: Cc1nn(C2CCOCC2)c2nc([C@@H]3CNC[C@H]3C)[nH]c(=O)c12

Procedure:
Following the procedure for the preparation of 6-[(3S,4S)-4-methylpyrrolidin-3-yl]-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one but substituting 6-[(3S,4S)-1-benzyl-4-methylpyrrolidin-3-yl]-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one provided the title compound. 400 MHz 1H NMR (CDCl3) δ 4.85-4.81 (m, 1H), 4.08-4.04 (m, 2H), 3.61-3.55 (m, 2H), 3.31-3.28 (m, 3H), 2.84-2.82 (m, 1H), 2.60-2.53 (m, 2H), 2.49 (s, 3H), 2.29-2.25 (m, 2H), 1.85-1.81 (m, 2H), 1.12 (d, J=6.62 Hz, 3H). MS: (M+H m/z=249.1).
Reaction SMILES: F[C:2]1[C:7]([I:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[S:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=[C:10]1[NH:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1CCCC1=O>[I:8][C:7]1[C:2]([O:25][C:22]2[CH:21]=[CH:20][C:19]([NH:18][C:10]3[S:9][C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=4[N:11]=3)=[CH:24][CH:23]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1ccc(Nc2nc3ccccc3s2)cc1
Reactant: Fc1ncccc1I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: Ic1cccnc1Oc1ccc(Nc2nc3ccccc3s2)cc1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
A suspension of 2-fluoro-3-iodopyridine (1.674 g, 7.51 mmol), 4-(benzo[d]thiazol-2-ylamino)phenol (2.73 g, 11.26 mmol) and cesium carbonate (4.16 g, 12.76 mmol) in N-methyl-2-pyrrolidinone (10 mL) was degassed and heated to 120° C. After 3 h 30 min, the reaction was cooled to 23° C., diluted with EtOAc (200 mL) and washed with water (100 mL) and brine (100 mL), dried over MgSO4, concentrated in vacuo and purified by silica gel chromatography (eluant: 0-1% methanol/dichloromethane), affording the product as an off-white solid. MS (ESI, pos. ion) m/z: 445.9 (M+1).
Reaction SMILES: [OH:1][CH:2]([CH2:29][OH:30])[CH2:3][NH:4][C:5](=[O:28])[C:6]1[C:19]([I:20])=[C:18]([NH:21][C:22](=[O:25])[CH2:23][Cl:24])[C:17]([I:26])=[C:8]([C:9]([NH:11][CH2:12][CH:13]([OH:16])[CH2:14][OH:15])=[O:10])[C:7]=1[I:27].[CH2:31]1[O:33][CH2:32]1.Cl>O>[OH:1][CH:2]([CH2:29][OH:30])[CH2:3][NH:4][C:5](=[O:28])[C:6]1[C:19]([I:20])=[C:18]([N:21]([CH2:31][CH2:32][OH:33])[C:22](=[O:25])[CH2:23][Cl:24])[C:17]([I:26])=[C:8]([C:9]([NH:11][CH2:12][CH:13]([OH:16])[CH2:14][OH:15])=[O:10])[C:7]=1[I:27]
Reactant: C1CO1
Reactant: O=C(CCl)Nc1c(I)c(C(=O)NCC(O)CO)c(I)c(C(=O)NCC(O)CO)c1I
Agent: Cl
Solvent: O
Product: O=C(NCC(O)CO)c1c(I)c(C(=O)NCC(O)CO)c(I)c(N(CCO)C(=O)CCl)c1I

Procedure:
The general procedure for the process of the invention involves reacting 5-amino-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide with N,N-dimethylacetamide and chloroacetyl chloride. The resulting product is hydrolyzed with a base (such as sodium hydroxide). A homogeneous solution is obtained by adding water. Precipitation is affected to yield N,N′-bis(2,3-dihydroxypropyl)-5-(2-chloroacetamido)-2,4,6-triiodoisophthalamide. Alternately, 5-amino-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide is reacted with N,N-dimethylacetamide, acetonitrile, and chloroacetyl chloride. The resulting product is hydrolyzed with a base. A homogeneous solution is obtained by adding water. Precipitation is affected to yield N,N′-bis(2,3-dihydroxypropyl)-5-(2-chloroacetamido)-2,4,6-triiodoisophthalamide. This product is combined with an aqueous base and deionized water. 2-Chloroethanol is added followed by heating. The addition of hydrochloric acid yields N,N′-bis(2,3-dihydroxypropyl)-5-[N-(2-hydroxyethyl)(2-chloroacetamido)]-2,4,6-triiodoisophthalamide. Alternately, N,N′-bis(2,3-dihydroxypropyl)-5-(2-chloroacetamido)-2,4,6-triiodoisophthalamide plus metal halide and deionized water are combined. Ethylene oxide is added followed by heating. The addition of hydrochloric acid yields N,N′-bis(2,3-dihydroxypropyl)-5-[N-(2-hydroxyethyl)(2-chloroacetamido)]-2,4,6-triiodoisophthalamide. This product is suspended in water with acetate ions and hydrochloric acid added. This suspended solution can take place at or above atmospheric pressure. Generally about 1 to about 2 atmospheres above atmospheric pressure is used. After adding aqueous sodium hydroxide to, maintain the pH, the reaction yields N,N′-bis(2,3-dihydroxypropyl)-5-N-(2-hydroxyethyl)glycolamido-2,4,6-triiodoisopthalamide. Finally, salts and low molecular weight impurities are removed.
Reaction SMILES: [C:1]([S:5][CH2:6][C@@:7]1([CH3:14])[NH:11][C:10](=[O:12])[NH:9][C:8]1=[O:13])([CH3:4])([CH3:3])[CH3:2].CO.S(=O)(=O)(O)[OH:18].C(O)(C)C.OO.O>[Cl-].[Na+]>[C:1]([S:5]([CH2:6][C@@:7]1([CH3:14])[NH:11][C:10](=[O:12])[NH:9][C:8]1=[O:13])=[O:18])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)SC[C@@]1(C)NC(=O)NC1=O
Reactant: O=S(=O)(O)O
Agent: OO
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC(C)O
Product: CC(C)(C)S(=O)C[C@@]1(C)NC(=O)NC1=O
Yield: 50 %

Procedure:
(5S)-5-[(Tert-butylthio)methyl]-5-methylimidazolidine-2,4-dione (1.00 eq, 46.2 mmol, 10.0 g) was charged to a vessel followed by methanol (2.64 mol, 107 mL, 84.5 g). The resulting clear solution was stirred and a solution of sulfuric acid, 4.40% w/w in iso-propanol (6.22 mmol, 13.9 mL, 13.9 g) was added. To this mixture was then added a solution of hydrogen peroxide, 11.68M, 35% w/w in water (107 mmol, 9.13 mL, 10.4 g) in one portion without external cooling (an exotherm from 22° C. to 41° C. over 10 min was noted). Hplc analysis of the reaction mixture approximately 1.5 h after the addition of the hydrogen peroxide revealed complete consumption of the starting material and the appearance of two new peaks (diastereoisomeric sulfoxides). The mixture was diluted with saturated aqueous sodium chloride solution (231 mL) and extracted with dichloromethane (2×250 mL). The combined organic phases were extracted with water (2×200 mL). The aqueous phase was evaporated to dryness under reduced pressure (water bath temperature 40° C.) to give (5S)-5-[(tert-butylsulfinyl)methyl]-5-methylimidazolidine-2,4-dione as white crystals (0.497 eq, 23.0 mmol, 5.34 g) in 50% yield as a 71:29 mixture of diastereoisomers (by comparison of 1H NMR integrals).
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([CH2:16][N:17]3[CH2:22][CH2:21][CH2:20][CH:19]([C:23](O)=[O:24])[CH2:18]3)=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].[NH:26]([CH3:28])[CH3:27].Cl.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.[Cl-].[Na+].O.CO.C(Cl)Cl>[CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([CH2:16][N:17]3[CH2:22][CH2:21][CH2:20][CH:19]([C:23]([N:26]([CH3:28])[CH3:27])=[O:24])[CH2:18]3)=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2]
Reactant: CCn1c2ccccc2c2cc(CN3CCCC(C(=O)O)C3)ccc21
Reactant: CNC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CO
Product: CCn1c2ccccc2c2cc(CN3CCCC(C(=O)N(C)C)C3)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.9 %

Procedure:
A 100-mL 3-necked round-bottomed flask was charged with a solution of 1-((9-ethyl-9H-carbazol-3-yl)methyl)piperidine-3-carboxylic acid (1 g, 2.98 mmol, 1.00 equiv) in DMF (50 mL), followed by HNMe2.HCl (723 mg, 8.93 mmol, 3.00 equiv) and triethylamine (1.2 g, 11.88 mmol, 4.00 equiv) at 0° C. To this mixture was added HATU (1.13 g, 2.97 mmol, 1.00 equiv) at 0° C. The resulting mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC (DCM:MeOH=10:1). Upon completion, the resulting mixture was diluted with brine (30 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered off and concentrated on a rotary evaporator. The residue was purified by a silica gel column chromatography eluted with dichloromethane/methanol (100:1) affording 1-((9-ethyl-9H-carbazol-3-yl)methyl)-N,N-dimethylpiperidine-3-carboxamide as a white solid (0.8 g, 74%). LCMS: [M+H]+: 364. 1H NMR (CDCl3, 300 MHz) δ 8.17 (t, 2H), 7.44 (m, 4H), 7.30 (t, 1H), 4.35 (m, 4H), 3.28 (m, 4H), 3.06 (s, 3H), 2.94 (d, 3H), 2.35 (s, 2H), 1.85 (m, 3H), 1.42 (t, 3H).
Reaction SMILES: [OH-].[Na+].[F:3][CH:4]([F:19])[CH2:5][O:6][C:7]1[CH:8]=[C:9]([F:18])[C:10]([C:13]([O:15]CC)=[O:14])=[N:11][CH:12]=1.Cl.O1CCOCC1>C1COCC1>[F:19][CH:4]([F:3])[CH2:5][O:6][C:7]1[CH:8]=[C:9]([F:18])[C:10]([C:13]([OH:15])=[O:14])=[N:11][CH:12]=1
Reactant: CCOC(=O)c1ncc(OCC(F)F)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: O=C(O)c1ncc(OCC(F)F)cc1F
Temperature: 25 °C
Reaction time: 120 h
Yield: 229.8 %

Procedure:
Sodium hydroxide (2 M in water, 2.43 mL, 4.86 mmol) is added to a solution of ethyl 5-(2,2-difluoroethoxy)-3-fluoro-pyridine-2-carboxylate (242 mg, 0.97 mmol) in THF (10 mL). The reaction is stirred at room temperature for 5 days. The reaction is quenched by the addition of 4 M HCl in dioxane (1.25 mL, 5 mmol) and the solution is concentrated to give the crude title compound (493 mg, 229%). ES/MS (m/e): 222.0 (M+1).
Reaction SMILES: [CH3:1][N:2]([C:4]1[CH:9]=[CH:8][C:7](N=NC2C=CC=CC=2)=[CH:6][CH:5]=1)[CH3:3].Cl(O)(=O)(=O)=O.[C:23](O)(=[O:25])C>>[CH3:3][N:2]([C:4]1[CH:5]=[CH:6][C:7]([CH:23]=[O:25])=[CH:8][CH:9]=1)[CH3:1]
Reactant: CC(=O)O
Reactant: CN(C)c1ccc(N=Nc2ccccc2)cc1
Agent: [O-][Cl+3]([O-])([O-])O
Product: CN(C)c1ccc(C=O)cc1

Procedure:
Ehrlichs Reagent is prepared by mixing 10 g DMAB with 420 ml glacial acetic acid, and 80 ml perchloric acid.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C(O[CH:12]=[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])C.CCCC(C)C>C1(C)C=CC=CC=1>[CH2:17]([O:16][C:14](=[O:15])[C:13](=[CH:12][NH:6][C:5]1[CH:7]=[CH:8][C:2]([Br:1])=[CH:3][CH:4]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH3:18]
Reactant: Nc1ccc(Br)cc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: Cc1ccccc1
Solvent: CCCC(C)C
Product: CCOC(=O)C(=CNc1ccc(Br)cc1)C(=O)OCC
Temperature: 150 °C
Reaction time: 0.25 h
Yield: 85.3 %

Procedure:
A 20 mL microwave vial was charged with 4-bromoaniline (6.881 g, 40.0 mmol), diethyl ethoxymethylenemalonate (8.650 g, 40.0 mmol) and toluene (5 mL). The vial was capped and the mixture was microwave heated at 150° C. for 30 min. After cooling, the solution was poured onto 50 mL of vigorously stirred iso-hexane. A thick, white precipitate formed and the suspension was stirred for another 15 min. The suspension was filtered and the product washed with 20 mL of iso-hexane. The product was dried under vacuum to give 11.678 g (85%) of 2-[(4-bromo-phenylamino)methylene]malonic acid diethyl ester. MS (ESI+) m/z 342, 344 (MH+).
Reaction SMILES: [CH3:1][C@@:2]12[C@@H:10]([OH:11])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH2:13][C:14]3[C@@H:20]([C@H:5]1[CH2:4][CH2:3]2)[CH2:19][CH2:18][C:16](=[O:17])[CH:15]=3.[C:21](O)(=[O:31])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].C1CCC(N=C=NC2CCCCC2)CC1.C(O)(=O)C>CN(C1C=CN=CC=1)C.C(Cl)Cl.CC1C=CC(S(O)(=O)=O)=CC=1.CO.O>[CH3:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][C:21]([O:11][C@@H:10]1[C@@:2]2([CH3:1])[CH2:3][CH2:4][C@@H:5]3[C@@H:20]4[C:14](=[CH:15][C:16]([CH2:18][CH2:19]4)=[O:17])[CH2:13][CH2:12][C@H:6]3[C@@H:7]2[CH2:8][CH2:9]1)=[O:31]
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2O
Reactant: CCCCCCCCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCCCCCCCCC(=O)O[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]12C
Yield: 88.8 %

Procedure:
To a stirred solution of 5,48 g 19-nortestosterone, 4 g decanoic acid, 0.24 g DMAP and 0.19 g pTSA in 35 ml CH2Cl2 is slowly added at 10° C. a solution of 5.6 g DCC in 30 ml CH2Cl2. After 5 h at room temperature 2 ml acetic acid is added. The same work-up procedure as in Example 6 gives 7.6 g of pure 19-nortestosterone decanoate (88% yield) as white crystals from methanol/water. M.P. 35°-36° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH:4]([CH2:5][C:6](Cl)([Cl:8])[Cl:7])[CH:3]1[C:10]([O:12]CC)=[O:11].[OH-].[K+]>>[CH3:1][C:2]1([CH3:15])[CH:4]([CH:5]=[C:6]([Cl:8])[Cl:7])[CH:3]1[C:10]([OH:12])=[O:11]
Reactant: CCOC(=O)C1C(CC(Cl)(Cl)Cl)C1(C)C
Agent: [K+]
Agent: [OH-]
Product: CC1(C)C(C=C(Cl)Cl)C1C(=O)O

Procedure:
Ethyl 2,2-dimethyl-3-(2,2,2-trichloroethyl)cyclopropanecarboxylate was hydrolyzed with caustic potash to give 2,2-dimethyl-3-(2,2-dichlorovinyl)-cyclopropanecarboxylic acid, and was converted into the diastereomeric (+)-octyl ester, which was analyzed by gas chromatography. The results were: (+)-cis, 83.6%; (-)-cis, 3.9%; (+)-trans, 7.5%; (-)-trans, 5.0%. The e.e. was calculated to be 91% for the cis isomer and 20% for the trans isomer.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:28]=[CH:27][C:7]([CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]3[S:19](=[O:21])(=[O:20])[CH2:18][CH2:17][C:16]([C:22]([O:24]C)=[O:23])=[CH:15][C:14]=3[CH:26]=2)=[CH:6][CH:5]=1)[CH3:2].[C:29](=O)([O-])[O-].[K+].[K+].Cl>C1COCC1.CO>[CH3:29][CH:18]1[CH2:17][C:16]([C:22]([OH:24])=[O:23])=[CH:15][C:14]2[CH:26]=[C:10]([O:9][CH2:8][C:7]3[CH:27]=[CH:28][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=3)[CH:11]=[CH:12][C:13]=2[S:19]1(=[O:20])=[O:21]
Reactant: O=C([O-])[O-]
Reactant: CCOc1ccc(COc2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)cc1
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: CCOc1ccc(COc2ccc3c(c2)C=C(C(=O)O)CC(C)S3(=O)=O)cc1
Temperature: 70 °C
Reaction time: 16.5 h
Yield: 73.5 %

Procedure:
Into a suspension of methyl 7-[(4-ethoxybenzyl)oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (200 mg) in THF/methanol (6/3 ml) was added at room temperature an aqueous solution (0.7 ml) of potassium carbonate (137 mg), and the resulting mixture was stirred at 70° C. for 16.5 hours. After cooling to room temperature, 1 N hydrochloric acid was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with water and an aqueous saturated solution of sodium chloride, and was dried with magnesium sulfate. After concentration under reduced pressure, the precipitated crystals were collected by filtration. The crystals were washed with diisopropyl ether to obtain methyl 7-[(4-ethoxybenzyl)oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (147 mg) as colorless crystals.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[CH:8]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1>ClCCl>[CH:3]12[CH2:4][CH2:5][CH2:6][C:1](=[O:7])[CH:2]1[CH:15]1[CH:8]2[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: C1=CCCCCCC1
Reactant: O=C1C=CCCC1
Solvent: ClCCl
Product: O=C1CCCC2C3CCCCCCC3C12
Yield: 83 %

Procedure:
A solution of 29.4 g. (0.3 mol.) of cyclohexenone and 200 ml. of cyclooctene in 2600 ml. of dichloromethane was irradiated at -65° C. in the low temperature photolysis apparatus described in Organic Prep. Proc. Int. 3, 61 (1971) with a 1000 watt G.E. mercury arc through a Corning 9700 glass filter for 4 hours. At the end of the photolysis the solution was concentrated in vacuo and the product was distilled through a short Vigreux-column to yield 51.8 g. (0.249 mol., 83% yield) of a mixture of four isomers having b.p. 108°-127° C./0.4 mm.Hg. IR: 1695 cm-1 confirmed the structure.
Reaction SMILES: COC1C=CC(C([NH:24][C:25]2[N:30]([CH3:31])[C:29](=[O:32])[C:28]([CH3:34])([CH3:33])[C@:27]([C:36]3[CH:41]=[C:40](Br)[CH:39]=[CH:38][C:37]=3[F:43])([CH3:35])[N:26]=2)(C2C=CC(OC)=CC=2)C2C=CC=CC=2)=CC=1.[NH2:44][C:45]1[CH:52]=[CH:51][C:48]([C:49]#[N:50])=[CH:47][C:46]=1[C:53]([F:56])([F:55])[F:54]>>[NH2:24][C:25]1[N:30]([CH3:31])[C:29](=[O:32])[C:28]([CH3:33])([CH3:34])[C@:27]([C:36]2[CH:41]=[C:40]([NH:44][C:45]3[CH:52]=[CH:51][C:48]([C:49]#[N:50])=[CH:47][C:46]=3[C:53]([F:54])([F:55])[F:56])[CH:39]=[CH:38][C:37]=2[F:43])([CH3:35])[N:26]=1
Reactant: N#Cc1ccc(N)c(C(F)(F)F)c1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(Br)ccc3F)C(C)(C)C(=O)N2C)(c2ccccc2)c2ccc(OC)cc2)cc1
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(Nc3ccc(C#N)cc3C(F)(F)F)ccc2F)N=C1N

Procedure:
The coupling of (S)-2-{[bis-(4-methoxy-phenyl)-phenyl-methyl]-amino}-6-(5-bromo-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate K) and 4-amino-3-trifluoromethyl-benzonitrile according to procedure B followed by deprotection yielded the title compound as a pale yellow solid. MS (ESI): m/z=448.2 [M+H]+.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[CH:12]([NH:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:18])[C:13]([OH:15])=[O:14]>CS(O)(=O)=O>[C:19]1([C:17]([NH:16][CH:12]([C:4]2[CH:5]=[CH:6][C:1]([CH2:7][C:8]([OH:10])=[O:9])=[CH:2][CH:3]=2)[C:13]([OH:15])=[O:14])=[O:18])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(NC(O)C(=O)O)c1ccccc1
Reactant: O=C(O)Cc1ccccc1
Agent: CS(=O)(=O)O
Product: O=C(O)Cc1ccc(C(NC(=O)c2ccccc2)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of phenyl acetic acid (10.0 g, 73.5 mmol) in 25 ml methanesulfonic acid is treated with α-hydroxyhippuric acid (3.58 g, 18.4 mmol) and the resulting solution stirred at room temperature for 24 hours. The reaction mixture is poured onto ice (200 g) and the product extracted into ethyl acetate (3×200 ml). The combined organic layers are dried (Na2SO4) and concentrated. The residue is recrystallized from THF/diisopropyl ether. A tan solid which is α-[(phenylcarbonyl)amino]-1,4-benzenediacetic acid is obtained (1.5 g, 26%), mp 180°-220° C.
Reaction SMILES: [F-:1].[K+].Cl[C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=[O:9])[C:7]2=[CH:13][CH:14]=1>>[F:1][C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=[O:9])[C:7]2=[CH:13][CH:14]=1
Reactant: [F-]
Reactant: O=C1OC(=O)c2cc(Cl)ccc21
Agent: [K+]
Product: O=C1OC(=O)c2cc(F)ccc21
Temperature: 220 °C

Procedure:
A mixture of 20 parts of anhydrous potassium fluoride, 20 parts of 4-chlorophthalic anhydride and 2 parts of Carbowax® m-peg 2000 catalyst was charged to a reaction vessel and heated at 220° C. for about 18 hours. The product was removed by distillation, then recrystallized from a chloroform-hexane solution to yield 8.13 parts of 4-fluorophthalic anhydride having a melting point of 76°-78° C. Following the procedure of Example 3B, the fluorophthalic anhydride is reacted with ammonia and the resultant mixture of ammonium salts of 4- and 5-fluorophthalamic acid is acidified to yield a mixture of 4-fluorophthalamic acid and 5-fluorophthalamic acid.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[C:15]1([CH2:21][CH2:22][CH2:23][CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:30]([OH:35])(=[O:34])[C:31]([OH:33])=[O:32].CO>C(OCC)(=O)C>[C:30]([OH:35])(=[O:34])[C:31]([OH:33])=[O:32].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:27]3[CH2:28][CH2:29][CH:24]([CH2:23][CH2:22][CH2:21][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH2:25][CH2:26]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OCC2CO2)c2cc[nH]c2c1
Reactant: c1ccc(CCCC2CCNCC2)cc1
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(CCCc2ccccc2)CC1

Procedure:
The title compound was prepared in similar fashion from S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-(3-phenylpropyl)piperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 73% overall yield. FDMS m/e=392 (M+ of free base). α[D]589 =-13.53 (c=0.58, methanol).
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH:12]2[S:24][C:16]3=[N:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[N:15]3[CH2:14][CH2:13]2)(=O)=O)=CC=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=1.[H-].[Na+].O>C(Cl)(Cl)Cl>[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][CH2:11][CH:12]2[S:24][C:16]3=[N:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[N:15]3[CH2:14][CH2:13]2)=[CH:30][CH:29]=1
Reactant: COc1ccc(N)cc1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCn3c(nc4ccccc43)S2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1ccc(NCC2CCn3c(nc4ccccc43)S2)cc1
Yield: 31 %

Procedure:
3,4-Dihydro-2-p-toluenesulfonyloxymethyl-2H-(1,3)-thiazino[3,2-a]benzimidazole in the amount of 1.12 g (3 m mole) was dissolved in 30 ml of chloroform. Then, 0.44 g of p-anisidine (3.6 m mole) and a catalytic amount of sodium hydride were added under ice-cooled stirring conditions. The temperature of the mixture was allowed to rise to room temperature, and then refluxed for 12 hours. The reaction mixture was cooled and washedwith water. After drying the chloroform layer over anhydrous magnesium sulfate, chloroform was evaporated under reduced pressure. The residue waschromatographed on silica gel and eluted with chloroform to obtain 0.28 g (yield: 31%) of the intended product, m.p. 155°-157° C.; IR νmaxKBr cm-1 : 3360, 3100-2800, 1430; Anal. Calcd. for C18H19N3OS: C, 66.44; H, 5.88; N 12.91; S, 9.85; Found: C, 66.91; H, 5.90; N, 12.88; S, 9.70.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9](Cl)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH:23]=[C:22](B(O)O)[CH:21]=[N:20]2)=[CH:15][CH:14]=1>>[F:12][C:13]1[CH:14]=[CH:15][C:16]([N:19]2[CH:23]=[C:22]([C:9]3[N:10]=[C:3]4[CH:2]=[CH:7][CH:6]=[CH:5][N:4]4[N:8]=3)[CH:21]=[N:20]2)=[CH:17][CH:18]=1
Reactant: Clc1nc2c(Br)cccn2n1
Reactant: OB(O)c1cnn(-c2ccc(F)cc2)c1
Product: Fc1ccc(-n2cc(-c3nc4ccccn4n3)cn2)cc1

Procedure:
2-Chloro-8-([1-(4-fluoro-phenyl)1H-pyrazol-4-yl]-[1,2,4]triazolo[1,5-a]pyridine was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine and 1-(4-fluorophenyl)pyrazole-4-boronic acid in a manner analogous to Example 2c (0.45 g, 67%).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][C:15]([OH:17])=O)[N:13]=2)=[O:7])=[CH:4][CH:3]=1.[N:20]1([C:25]([CH2:27][N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][C:15](=[O:17])[N:31]3[CH2:30][CH2:29][N:28]([CH2:27][C:25](=[O:26])[N:20]4[CH2:21][CH2:22][CH2:23][CH2:24]4)[CH2:33][CH2:32]3)[N:13]=2)=[O:7])=[CH:18][CH:19]=1
Reactant: O=C(O)Cc1csc(NC(=O)c2ccc(Cl)cc2)n1
Reactant: O=C(CN1CCNCC1)N1CCCC1
Product: O=C(Nc1nc(CC(=O)N2CCN(CC(=O)N3CCCC3)CC2)cs1)c1ccc(Cl)cc1

Procedure:
In analogy to example 1.3, [2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetic acid (example 1.2) was coupled with 1-(pyrrolidinocarbonylmethyl)piperazine to give 4-chloro-N-(4-{2-oxo-2-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethyl}-thiazol-2-yl)-benzamide, using general procedure A. Off-white solid. MS 476.1 ([M+H]+)