Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=4[CH3:30])[C:24](O)=[O:25])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[CH3:31][C:32]1[O:36][CH:35]=[N:34][C:33]=1[C:37]1([NH2:40])[CH2:39][CH2:38]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>ClCCl.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([C:24](=[O:25])[NH:40][C:37]5([C:33]6[N:34]=[CH:35][O:36][C:32]=6[CH3:31])[CH2:39][CH2:38]5)[CH:27]=[CH:28][C:29]=4[CH3:30])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:6][CH:7]=1
Reactant: Cc1ocnc1C1(N)CC1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)ccc3C)cc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ncoc5C)CC4)ccc3C)cc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (0.2 g, 0.5 mmol, 1 eq), 1-(5-methyloxazol-4-yl)cyclopropanamine (0.103 g, 0.74 mmol, 1.2 eq), EDCI.HCl (0.105 g, 0.54 mmol, 1.1 eq), HOBT (0.067 g, 0.5 mmol, 1.0 eq) and TEA (0.21 ml, 1.5 mmol, 3 eq) were dissolved in dichloromethane and the above mixture was stirred at room temperature for 18 h. The mixture was then added with water. The organic layer was separated, washed with water and concentrated to give the crude product which was purified by Prep. TLC (20 mm thickness) using 5% methanol/DCM as an eluent. Yield: 25 mg (25%) 1HNMR (400 MHz, DMSO-d6): δ 1.11 (m, 2H), 1.20-1.22 (m, 2H), 2.28 (s, 3H), 2.29 (s, 3H), 2.82 (d, J=4.4 Hz, 3H), 7.38-7.42 (m, 4H), 7.57 (s, 1H), 7.74-7.81 (m, 3H), 8.04 (s, 1H), 7.97-8.01 (m, 2H), 8.45-8.46 (m, 1H), 9.16 (s, 1H). LCMS: (ES+) m/z=524.2 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:3]=1[C:4]([NH:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([CH:13]=O)[CH2:9][CH2:8]1)=[O:5].[NH2:23][C:24]1[CH:25]=[N:26][CH:27]=[C:28]([CH3:30])[CH:29]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:3]=1[C:4]([NH:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([CH2:13][NH:23][C:24]2[CH:25]=[N:26][CH:27]=[C:28]([CH3:30])[CH:29]=2)[CH2:9][CH2:8]1)=[O:5]
Reactant: O=C[C@H]1CC[C@H](NC(=O)c2cc(C(F)(F)F)ccc2Cl)CC1
Reactant: Cc1cncc(N)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cncc(NC[C@H]2CC[C@H](NC(=O)c3cc(C(F)(F)F)ccc3Cl)CC2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a 50 mL round-bottomed flask containing trans-2-chloro-N-(4-formyl-cyclohexyl)-5-trifluoromethyl-benzamide (Ex. 1 step 3) (100 mg, 0.3 mmol) and 3-amino-5-methylpyridine (36 mg, 0.3 mmol) in dry DCM (5 mL) is added sodium triacetoxyborohydride (106 mg, 0.45 mmol) in one portion. The suspension is stirred at RT for 4 hours. The mixture is partitioned between DCM and saturated sodium bicarbonate, passed through a phase separator to recover the DCM layer and evaporated to give a colourless solid. The crude product is redissolved in DCM, absorbed directly onto silica gel and columned on silica gel using a 12 g pre-packed column and isohexane/EtOAc gradient elution (0% to 100% EtOAc). Product-containing fractions are combined and evaporated and the product is isolated as a colourless solid after trituration with 20% EtOAclisohexane, 55 mg, [MH+ 426.40].
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[CH:20]=[C:19]([C:21]3[N:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]4[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[C:33]([O:41][CH2:42][CH3:43])[CH:32]=4)[N:22]=3)[CH:18]=[CH:17][N:16]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH2:42]([O:41][C:33]1[CH:32]=[C:31]([C:23]2[CH:24]=[C:25]([C:27]([F:28])([F:29])[F:30])[N:26]=[C:21]([C:19]3[CH:18]=[CH:17][N:16]=[C:15]([C:11]4[CH:10]=[C:9]([S:6]([NH2:5])(=[O:7])=[O:8])[CH:14]=[CH:13][CH:12]=4)[CH:20]=3)[N:22]=2)[CH:36]=[CH:35][C:34]=1[C:37]([F:40])([F:39])[F:38])[CH3:43]
Reactant: CCOc1cc(-c2cc(C(F)(F)F)nc(-c3ccnc(-c4cccc(S(=O)(=O)NC(C)(C)C)c4)c3)n2)ccc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1cc(-c2cc(C(F)(F)F)nc(-c3ccnc(-c4cccc(S(N)(=O)=O)c4)c3)n2)ccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 15 h
Yield: 77.8 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-3-{4-[6-(3-ethoxy-4-trifluoromethylphenyl)-4-trifluoromethyl-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonamide (0.24 g) in dichloromethane (6 ml) was added TFA (6 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness, poured into saturated Na2CO3 solution (20 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. Further purification by crystallization (ethyl acetate/heptane) yielded the title compound as a white solid (0.17 g, 72%). MS (ISP) 569.2 [(M+H)+]; mp 223.5° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:11][CH3:12])=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>CO.C(Cl)(Cl)Cl>[CH3:12][O:11][C:3]1[C:2]([NH:1][S:14]([CH3:13])(=[O:16])=[O:15])=[CH:7][CH:6]=[CH:5][C:4]=1[C:8](=[O:10])[CH3:9]
Reactant: COc1c(N)cccc1C(C)=O
Reactant: CS(=O)(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1c(NS(C)(=O)=O)cccc1C(C)=O
Reaction time: 12 h

Procedure:
According to the method reported by A. A. Larsen in J. Med. Chem., 10, 462-472 (1967), the above compound was produced from Intermediate 66 (1.59 g) and methanesulfonyl chloride (750 μl). Here, however, the following alteration was incorporated in the purification step from the reaction mixture. Thus, the reaction was terminated with water (50 ml) and the mixture was agitated for 12 hours before extraction with ethyl acetate (once with 50 ml and twice with each 30 ml) with subsequent washing with 1 N hydrochloric acid (twice with each 25 ml) and with saturated aqueous sodium chloride solution, successively, followed by distilling off of the solvent under a reduced pressure, whereby the above-identified compound was obtained (1.93 g). Rf=0.55 (methanol/chloroform of 1/19).
Reaction SMILES: O=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])[CH:9]=2)[CH2:4][C:3]21[CH2:24][CH2:23][CH2:22][C:21]1[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=1[CH2:19]2.C[Si]([N:33]=[C:34]=[N:35][Si](C)(C)C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[C:14]([C:13]1[CH:12]=[C:11]([C:8]2[CH:7]=[C:6]3[C:5](=[CH:10][CH:9]=2)[CH2:4][C:3]2([CH2:19][CH2:20][CH2:28][C:27]4[CH:23]=[CH:22][CH:21]=[CH:25][C:26]=4[CH2:2]2)[C:24]3=[N:35][C:34]#[N:33])[CH:18]=[CH:17][CH:16]=1)#[N:15]
Reactant: N#Cc1cccc(-c2ccc3c(c2)C(=O)C2(CCCc4ccccc4C2)C3)c1
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: N#CN=C1c2cc(-c3cccc(C#N)c3)ccc2CC12CCCc1ccccc1C2
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 150 %

Procedure:
To a solution of 3-(1′-oxo-1′,3′,5,7,8,9-hexahydrospiro[benzo[7]annulene-6,2′-indene]-6′-yl)benzonitrile (31 mg, 0.086 mmol) in CH2Cl2 (2 mL) was added TiCl4 (66 mg). It was stirred in microwave at 50° C. for 5 minutes. Then bis-trimethylsilylcarbodiimide (112 mg, 0.6 mmol) was added. The resulting mixture was stirred in microwave at 60° C. for 10 minutes. The reaction mixture was poured into ice-water, extracted with DCM. The combined organic phases were dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated to give N-(5′-(3-cyanophenyl)-5,7,8,9-tetrahydrospiro[benzo[7]annulene-6,2′-indene]-3′(1′H)-ylidene)cyanamide (50 mg, crude).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1.[F:27][C:28]([F:34])([F:33])[CH2:29][CH2:30][CH2:31][OH:32]>>[F:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=3)[N:10]=2)=[C:2]([O:32][CH2:31][CH2:30][CH2:29][C:28]([F:34])([F:33])[F:27])[CH:7]=1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3F)n2)c1
Reactant: OCCCC(F)(F)F
Product: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3OCCCC(F)(F)F)n2)c1

Procedure:
Starting with 4-(2,4-difluorophenyl)-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine (70 mg; 0.184 mmol), intermediate 42.1, and 4,4,4-trifluorobutan-1-ol (94.3 mg; 0.736 mmol), example 59 was prepared analogously to the procedure for the preparation of example 42.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14])[CH2:6][C:5]2([CH3:20])[CH3:19].C(N(CC)CC)C.[C:28]1([S:34](Cl)(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH:14][S:34]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=[O:36])=[O:35])[CH2:6][C:5]2([CH3:20])[CH3:19]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC1(C)CC(c2ccccc2N)Nc2ccc(Cl)cc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)CC(c2ccccc2NS(=O)(=O)c2ccccc2)Nc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 2-(6-chloro-4,4-dimethyl-1,2,3,4-tetrahydroquinolin-2-yl)aniline (100 mg, 0.35 mmol) in dichloromethane (5 mL) was added triethylamine (100 mg) and benzenesulfonyl chloride (60.2 mg, 0.35 mmol) at ice-bath. The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was washed with water. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed by brine, dried over anhydrous sodium sulfate, concentrated in vacuo. The residue was purified by HPLC to give N-[2-(6-chloro-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-benzenesulfonamide LC/MS m/e obsd. (ESI+) [(M+H)+] 427.20.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][N:3]=1.[N:11]1[CH:16]=[CH:15][CH:14]=[C:13](B(O)O)[CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O.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>[N+:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:13]2[CH:12]=[N:11][CH:16]=[CH:15][CH:14]=2)[CH:7]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Reactant: OB(O)c1cccnc1
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: O
Solvent: CC#N
Product: O=[N+]([O-])c1ccnc(-c2cccnc2)c1
Temperature: 80 °C
Yield: 68 %

Procedure:
A mixture of 2-chloro-4nitropyridine (0.40 g, 2.56 mmol), pyridin-3-ylboronic acid (0.408, 3.32 mmol), tetrakis(triphenylphosphinepalladium(0) (0.18 g, 0.15 minol) and sodium carbonate (0.489 g, 4.6 mmol) in acetonitrile (9 mL) and water (9 mL) was heated at 80° C. overnight. Water was added and the mixture was extracted with EtOAc. The organic solutions were combined, washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on basic alumina to give 4-nitro-2,3′-bipyridine (350 mg, 70%) as a pale yellow solid. LCMS: (FA) ES+ 202.1.
Reaction SMILES: [CH3:1][Mg+].[Br-].CON(C)[C:7]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH3:18])=[CH:11][N:10]=1)=[O:8]>C1COCC1>[CH2:15]([C:12]1[CH:13]=[CH:14][C:9]([C:7](=[O:8])[CH3:1])=[N:10][CH:11]=1)[CH2:16][CH2:17][CH3:18]
Reactant: C[Mg+]
Reactant: CCCCc1ccc(C(=O)N(C)OC)nc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CCCCc1ccc(C(C)=O)nc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96.9 %

Procedure:
MeMgBr (1.98 ml, 5.94 mmol) was added to a solution of 5-butyl-pyridine-2-carboxylic acid methoxy-methyl-amide (I-2A-38a; 880 mg, 3.96 mmol) in THF (10 ml) at 0° C. The reaction mixture was allowed to warm to room temperature and was stirred for 1.5 h, quenched with saturated aqueous NH4Cl (1 ml), and saturated aqueous NaCl. The aqueous THF solution was extracted with EtOAc (2×), and the combined organic extracts were washed with saturated aqueous NaCl, dried, and concentrated under vacuum to yield the product I-2A-38b as an oil (680 mg): APcl MS 178.1 (M+1)+; 1H NMR (400 MHz, CDCl3) δ 8.47 (d, 1H, J=1.6 Hz), 7.95 (d, 1H, J=8.3 Hz), 7.60 (dd, 1H, J=1.6, 8.3 Hz), 2.69 (s, 3H), 2.67 (t, 2H, J=7.9 Hz), 1.65-1.56 (m, 2H), 1.40-1.30 (m, 2H), 0.92 (t, 3H, J=7.4 Hz).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][NH2:7])(=[O:3])[CH3:2].[Cl:8][C:9]1[N:14]=[C:13](Cl)[C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][N:10]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[Cl:8][C:9]1[N:10]=[C:11]([NH:7][CH2:6][CH2:5][NH:4][C:1](=[O:3])[CH3:2])[C:12]([C:16]([F:19])([F:17])[F:18])=[CH:13][N:14]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Reactant: CC(=O)NCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(=O)NCCNc1nc(Cl)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 72 h

Procedure:
1.84 g of 2-acetylamino-ethylamine dissolved in 10 ml of dioxane are added to 3.91 g of 2,4-dichloro-5-trifluoromethyl-pyrimidine in 20 ml dioxane at ambient temperature. Then 3.7 ml of 5 M potassium carbonate solution are added and the mixture is stirred for three days at ambient temperature. It is then filtered through Alox B and washed with dioxane. The filtrate is concentrated by evaporation and the residue separated by chromatography through a silica gel column with cyclohexane:ethyl acetate:methanol (5:4:1).
Reaction SMILES: [Na].[OH:2][CH:3]([C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:12]=1)=[CH2:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(O)(=O)C>C(O)C>[CH3:10][CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17](=[O:24])[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:12]=1)[C:3](=[O:2])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: C=C(c1cccc(C(=O)c2ccccc2)c1)C(O)C(=O)OCC
Agent: [Na]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C(=O)C(C)c1cccc(C(=O)c2ccccc2)c1
Yield: 73.3 %

Procedure:
To a solution of 0.5 g of metallic sodium in 50 ml of anhydrous ethanol was added a solution of 3.0 g of ethyl 2-hydroxy-3-(3-benzoylphenyl)-3-butenoate in 20 ml of anhydrous ethanol. The resulting mixture was refluxed for 20 minutes and then cooled. The reaction liquid was charged with 5 ml of glacial acetic acid, and the ethanol was removed therefrom by distillation at a low temperature and under reduced pressure. The residue was charged with ethyl acetate and water, thereby effecting ethyl acetate extraction. The ethyl acetate layer was successively washed with water, aqueous sodium bicarbonate solution and water, and then dried over anhydrous magnesium sulfate. Thereafter, the ethyl acetate was removed by distillation under reduced pressure to obtain 2.2 g of ethyl 3-methyl-3-(3-benzoylphenyl)-pyruvate. The yield was 73%.
Reaction SMILES: Br.[NH2:2][C:3]1[N:4]=[C:5]([Br:8])[S:6][CH:7]=1.[Cl:9][C:10]([Cl:15])([Cl:14])[C:11](Cl)=[O:12].N1C=CC=CC=1.C([O-])(=O)C.[Na+]>C(Cl)Cl>[Br:8][C:5]1[S:6][CH:7]=[C:3]([NH:2][C:11](=[O:12])[C:10]([Cl:15])([Cl:14])[Cl:9])[N:4]=1
Reactant: Nc1csc(Br)n1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Agent: Br
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1csc(Br)n1)C(Cl)(Cl)Cl
Yield: 53.9 %

Procedure:
4-Amino-2-bromo-thiazole hydrobromide (15.6g) and trichloroacetyl chloride (14.3 g) were suspended in methylene chloride (100 ml) with stirring and treated dropwise with pyridine (16 ml) over 15 minutes maintaining reaction temperatures at 0° C. with an ice bath. After completing the addition, the reaction mixture was stirred at room temperature for 3 hours, then poured onto 20% aqueous sodium acetate (250 ml.) and stirred for 30 minutes. The mixture was separated and the organic layer washed with 2N hydrochloric acid, water, sodium carbonate solution and water. The organic layer was dried (MgSO4) and the solvent removed in vacuo and the residue treated with charcoal in hexane and recrystallised from hexane to give the title compound (10.5g) m.p. 77°-80° C. (Found: C, 19.0; H, 0.7 N, 8.5. C5H2Cl3BrN2OS requires C, 18.5; H, 0.6; N, 8.6%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([Te:9](Cl)(Cl)[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[OH-:20].[Na+]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([Te:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[O:20])=[CH:5][CH:4]=1
Reactant: COc1ccc([Te](Cl)(Cl)c2ccc(OC)cc2)cc1
Reactant: [OH-]
Agent: [Na+]
Product: COc1ccc([Te](=O)c2ccc(OC)cc2)cc1
Yield: 81 %

Procedure:
The bis-(p-methoxyphenyl)tellurium dichloride (8.00 g, 19.4 mmol) was stirred at 95° in aqueous sodium hydroxide (100 ml, 5%) for 1 h. After cooling in an ice bath the white solid was filtered and dried under vacuum over phosphorus pentoxide to give bis-(p-methoxyphenyl)telluroxide (5.60 g, 81%), m.p. 187°-189° (lit., 190°-191°) νmax (Nujol) 1585,1575,1490,1460,1401,1380,1295,1247,1180,1172,1109,1068,1026,823,811 and 789 cm-1.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH2:6][CH2:7][NH2:8])[C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.BrC1C=CC(S(O[CH2:24][C@@H:25]2[O:39][C:29]3=[C:30]4[C:35](=[CH:36][CH:37]=[C:28]3[O:27][CH2:26]2)[N:34]=[C:33]([CH3:38])[CH:32]=[CH:31]4)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>CS(C)=O.O>[S:1]1[C:2]2[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=2[C:4]([CH2:6][CH2:7][NH:8][CH2:24][CH:25]2[O:39][C:29]3=[C:30]4[C:35](=[CH:36][CH:37]=[C:28]3[O:27][CH2:26]2)[N:34]=[C:33]([CH3:38])[CH:32]=[CH:31]4)=[CH:5]1
Reactant: Cc1ccc2c3c(ccc2n1)OC[C@H](COS(=O)(=O)c1ccc(Br)cc1)O3
Reactant: NCCc1csc2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc2c3c(ccc2n1)OCC(CNCCc1csc2ccccc12)O3
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a stirred solution of 2-benzo[b]thiophen-3yl-ethylamine (354 mg, 2.0 mmol) in 1 mL of anhydrous DMSO was added [(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl 4-bromo-benzenesulfonate (300 mg, 0.67 mmol). The reaction mixture was stirred at ambient temperature for 4 days. The reaction was diluted with H2O (10 mL), poured into saturated aqueous sodium bicarbonate (25 mL) and extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with 1:1 H2O/brine (40 mL) and brine (40 mL), then were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuum. Flash chromatography (2×20 cm SiO2, CH2Cl2 to 3% MeOH/CH2Cl2 gradient) afforded 225 mg (86%) of the (S)-enantiomer of the title compound as a thick oil. The fumarate salt was prepared by treating the amine in ethyl acetate with a solution of 66 mg (0.57 mmol) fumaric acid in methanol. The precipitated salt, a pale yellow solid, weighed 190 mg (m.p. 124-127° C.); MS (ESI) m/z 391 [M+H]+.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([O:8][CH2:9][C:10]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:11]=2[C:12]([O:14]C)=[O:13])[CH2:3]1.[F:21][C:22]1[CH:23]=[C:24]([C:28]2[O:29][C:30]([CH3:35])=[C:31]([CH2:33]I)[N:32]=2)[CH:25]=[CH:26][CH:27]=1>>[F:21][C:22]1[CH:23]=[C:24]([C:28]2[O:29][C:30]([CH3:35])=[C:31]([CH2:33][O:1][CH:2]3[CH2:7][CH2:6][CH2:5][CH:4]([O:8][CH2:9][C:10]4[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:11]=4[C:12]([OH:14])=[O:13])[CH2:3]3)[N:32]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: Cc1oc(-c2cccc(F)c2)nc1CI
Reactant: COC(=O)c1c(C)cccc1COC1CCCC(O)C1
Product: Cc1cccc(COC2CCCC(OCc3nc(-c4cccc(F)c4)oc3C)C2)c1C(=O)O

Procedure:
Using methyl 2-(3-hydroxycyclohexyloxymethyl)-6-methylbenzoate and 2-(3-fluorophenyl)-4-iodomethyl-5-methyloxazole as starting materials in the procedure of Example XXXI, gave the product 52 of molecular weight 453.52 (C26H28FNO5), MS(ESI): 454.35 (M+H+).
Reaction SMILES: [CH:1]([Mg]Cl)=[CH2:2].[O:5]=[C:6]([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:7]/[CH:8]=[CH:9]/[I:10]>O1CCCC1>[OH:5][C:6]([CH:1]=[CH2:2])([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:7]/[CH:8]=[CH:9]/[I:10]
Reactant: C=C[Mg]Cl
Reactant: CCCCC(=O)C/C=C/I
Solvent: C1CCOC1
Product: C=CC(O)(C/C=C/I)CCCC
Reaction time: 0.5 h

Procedure:
To a stirred solution of 7.8 ml of vinyl magnesium chloride (2.3 M in tetrahydrofuran), at -25° C. is added a solution of 3.55 g of 4-oxo-1-iodo-trans-1-octene in 20 ml of tetrahydrofuran during 15 minutes. After the addition, the solution is stirred at -20° C. to -15° C. for 30 minutes. The reaction is quenched with a mixture of hexane and ice. The aqueous phase is separated and extracted with additional hexane. The combined hexane extracts are washed successively with water and brine. The solution is dried over magnesium sulfate and concentrated. The residue is subjected to dry column chromatography on silica gel with benzene as developing solvent to give a liquid, pmr spectrum (CDCl3): 5.2 (m, terminal CH2) 5.83 (g, CH=CH2), 6.13 (d, l CH=) and 6.52 (m, ICM=CH).
Reaction SMILES: C([O:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11](=[O:12])[C:10]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:9]2[C:8]1=[O:17])=O.P(Cl)(Cl)(Cl)(Cl)Cl.[CH:24]([Cl:27])(Cl)[Cl:25]>CCOCC>[C:8]1(=[O:17])[N:7]([CH2:6][CH2:5][CH2:4][O:3][CH:24]([Cl:27])[Cl:25])[C:11](=[O:12])[C:10]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:9]12
Reactant: O=COCCCN1C(=O)c2ccccc2C1=O
Reactant: ClC(Cl)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCOCC
Product: O=C1c2ccccc2C(=O)N1CCCOC(Cl)Cl

Procedure:
A mixture of 3-(phthalimido)-propyl formate (17 g), phosphorus pentachloride (15.2 g) and alcoholfree chloroform was heated for 1 hour on the steam bath. After cooling and addition of ether, the crystalline product was isolated by filtration. M.p. 101°-103° C.
Reaction SMILES: [O:1]1[C:11](=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[O:13].[C:14]1([OH:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl-].[Cl-].[Cl-].[Al+3]>C(=S)=S>[OH:20][C:14]1[CH:19]=[CH:18][C:17]([C:2](=[O:13])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:1])=[O:12])=[CH:16][CH:15]=1
Reactant: Oc1ccccc1
Reactant: O=C1CCCCCCCCC(=O)O1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: O=C(O)CCCCCCCCC(=O)c1ccc(O)cc1
Reaction time: 72 h

Procedure:
To a 500 mL flask, equipped with mechanical stirrer and under inert atmosphere, was added Oxacycloundecane-2,11-dione (20 g, 108.5 mmol), phenol (10.22 g, 108.5 mmol), and 200 mL carbon disulfide. Aluminum (III) trichloride (72.34 g, 542 mmol) was added and the reaction was stirred for 72 hours. Carbon disulfide was decanted away, and ice was carefully added until most of mixture was dissolved. The insoluble material was collect by suction filtration and washed with 2×100 mL of water. The solid was then dissolved in 100 mL of 1 M aqueous sodium hydroxide and then carefully acidified with 1 M aqueous hydrochloric acid until pH=7.5 The solids that formed were removed by filtration and the parent solution was continued to be acidified until pH 2.5. The crude product precipitate was collected by filtration and was washed with 1×100 mL water. The crude product was dissolved in 100 mL of 1 M aqueous sodium hydroxide and then carefully acidified with 1 M aqueous hydrochloric acid until pH=7.5 and the impurities that precipitated were filtered off. The parent solution was further acidified until pH 2. The crude product was collected by filtration and washed with 2×50 mL water. The product was recrystallized form acetone. The isolated product (1.2 g, 4%) was collected by filtration. Found: C, 69.00; H, 7.81%; C16H22O4 requires C, 69.04; H, 7.97%; 1H NMR (d6-DMSO): δ 12.0, bs, 1H (COOH); δ 10.3, bs, 1H (aryl-hydroxyl); δ 7.8 d, 2H (aryl H's); δ 6.8, d, 2H, (aryl H's); δ 2.9, t, 2H (CH2 α to carbonyl); δ 2.2, t, 2H (CH2 α to COOH); δ 1.5, multiplet, 4H (CH2's β to carbonyl & β to COOH), δ 1.3, multiplet, 8H (rest of CH2's).