Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[CH3:36][O:37][C:38](=[O:77])[C@H:39]([CH2:68][S:69]CC1C=CC=CC=1)[NH:40][C:41]([C:43]1[NH:44][C:45]2[C:50]([CH:51]=1)=[CH:49][C:48]([O:52][CH2:53][CH2:54][O:55][CH3:56])=[CH:47][C:46]=2[N:57]([CH3:67])[S:58]([C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][N:62]=1)(=[O:60])=[O:59])=O.C1(SC)C=CC=CC=1.C(=O)([O-])O.[Na+]>ClCCl>[CH3:56][O:55][CH2:54][CH2:53][O:52][C:48]1[CH:49]=[C:50]2[C:45](=[C:46]([N:57]([CH3:67])[S:58]([C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][N:62]=3)(=[O:60])=[O:59])[CH:47]=1)[NH:44][C:43]([C:41]1[S:69][CH2:68][C@@H:39]([C:38]([O:37][CH3:36])=[O:77])[N:40]=1)=[CH:51]2
Reactant: COCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C(=O)N[C@@H](CSCc3ccccc3)C(=O)OC)cc2c1
Agent: O=C([O-])O
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CSc1ccccc1
Solvent: ClCCl
Product: COCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C3=N[C@H](C(=O)OC)CS3)cc2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87.3 %

Procedure:
To a solution of triphenylphosphine oxide (8.9 g) in dichloromethane (12 mL) was added dropwise trifluoromethanesulfonic anhydride (3.9 mL) at 0° C., and the mixture was stirred for 30 min at 0° C. The obtained suspension was diluted with dichloromethane (38 mL), and a solution of S-benzyl-N-({5-(2-methoxyethoxy)-7-[methyl(pyridin-2-ylsulfonyl)amino]-1H-indol-2-yl}carbonyl)-L-cysteine methyl ester (3.2 g) and thioanisole (5.0 mL) in dichloromethane (50 mL) was added. The reaction mixture was stirred at 0° C. for 2 hr, and saturated aqueous sodium hydrogencarbonate solution was added. The mixture was concentrated, and the residue was extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography, and eluted with hexane-ethyl acetate (4:1-1:1, volume ratio) to give a mixture (2.3 g) of methyl (4R)-2-{5-(2-methoxyethoxy)-7-[methyl(pyridin-2-ylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazole-4-carboxylate and triphenylphosphine oxide. A mixture of the obtained mixture (1.3 g), 2N aqueous sodium hydroxide solution (2.0 mL), tetrahydrofuran (2.0 mL) and methanol (2.0 mL) was stirred at room temperature for 2 hr. Diethyl ether was added to the reaction mixture, and the aqueous layer was separated, and acidified with 1N hydrochloric acid. The mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated brine, dried (MgSO4), and concentrated to give the title compound (1.1 g, yield 43%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:9])[C:5]([Cl:8])=[N:6][CH:7]=1.[Cl-].[C:11]([O:15][C:16](=[O:19])[CH2:17][Zn+])([CH3:14])([CH3:13])[CH3:12].CCOCC>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].CC(P(C(C)(C)C)[C-]1C=CC=C1)(C)C.C1C=CC([C-]2C(C3C=CC=CC=3)=C(C3C=CC=CC=3)C(C3C=CC=CC=3)=C2C2C=CC=CC=2)=CC=1.[Fe+2].C1COCC1>[Cl:8][C:5]1[N:6]=[CH:7][C:2]([CH2:17][C:16]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:19])=[CH:3][C:4]=1[F:9]
Reactant: Fc1cc(Br)cnc1Cl
Reactant: CC(C)(C)OC(=O)C[Zn+]
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Cc1cnc(Cl)c(F)c1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a sealed tube were added 5-bromo-2-chloro-3-fluoropyridine 190-1 (210 mg, 1.0 mmol), 0.5 M (2-tert-butoxy-2-oxoethyl) zinc(II) chloride 86-5 in ether (2.4 mL, 1.2 mmol), Pd(dba)2 (29 mg, 0.005 mmol), Q-phos (71 mg, 0.10 mmol) and THF (3 mL). The reaction mixture was bubbled with nitrogen for 1 minute and stirred at 100° C. for 1 hour. After cooling to room temperature, all the solvents were evaporated and the residue was redissolved in ethyl acetate, washed with water and brine, dried over Na2SO4 and concentrated to dryness by rotary evaporation. The crude product was purified by silica gel flash chromatography and eluted with 20% ethyl acetate in hexane to give tert-butyl 2-(6-chloro-5-fluoropyridin-3-yl)acetate 190-3. MS m/z 246.1 (M+1).
Reaction SMILES: [S:1](=[O:24])(=[O:23])([O:3][C:4]1[CH:21]=[CH:20][C:19]2[C@@H:18]3[C@H:9]([C@H:10]4[C@@:14]([CH2:16][CH2:17]3)([CH3:15])[C:13](=[O:22])[CH2:12][CH2:11]4)[CH2:8][CH2:7][C:6]=2[CH:5]=1)[NH2:2].[BH4-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C.O>[S:1](=[O:23])(=[O:24])([O:3][C:4]1[CH:21]=[CH:20][C:19]2[C@@H:18]3[C@H:9]([C@H:10]4[C@@:14]([CH2:16][CH2:17]3)([CH3:15])[C@@H:13]([OH:22])[CH2:12][CH2:11]4)[CH2:8][CH2:7][C:6]=2[CH:5]=1)[NH2:2]
Reactant: C[C@]12CC[C@@H]3c4ccc(OS(N)(=O)=O)cc4CC[C@H]3[C@@H]1CCC2=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C[C@]12CC[C@@H]3c4ccc(OS(N)(=O)=O)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Temperature: 3.5 °C
Reaction time: 20 h

Procedure:
To a cold (2-5° C.) suspension of moist 17-Oxoestra-1,3,5(10)-trien-3-yl sulfamate (171.7 mmol, from procedure I) in ethanol (450 ml), a solution of sodium borohydride (156.23 mmol) in water (94 ml) was added at 2-5° C. within a period of 20 minutes. The resulting mixture was stirred at 2-5° C. for another 20 hours. A solution of citric acid (495.86 mmol) in water (668 ml) was then added at this temperature within a period of 15 minutes to adjust the pH to 3. Water (668 ml) was added. The resulting crystalline solid was filtered and washed three times with water (500 ml). The wet crystals were suspended in acetone (2010 ml) and the resulting suspension was heated under reflux until complete dissolution. Removal of acetone (1700 ml) by destination resulted in a suspension, which was cooled to ambient temperature and filtered. The crystalline solid was washed with cold acetone (50 ml) and dried in vacuum. Yield: 45.06 g white crystals, purity (HPLC): 99.61%.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:9](O)=[O:10]>>[Cl:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:9]([Cl:3])=[O:10]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCCCOc1ccc(C(=O)O)cc1Cl
Product: CCCCCCCCCCOc1ccc(C(=O)Cl)cc1Cl

Procedure:
In 100 ml of ethanol were dissolved 18 g of 1-bromo-n-decane and 9 g of 3-chloro-4-hydroxybenzoic acid, an aqueous solution of 40 g of sodium hydroxide in 100 ml of water was added to the above solution, and the mixture was heated and refluxed for 10 hours. Then the reacted solution was made weakly acidic by an addition of 1N hydrochloric acid and thrown in an enough quantity of water to precipitate the reaction product. The precipitate was recovered by filtration and recrystallized from ethanol to obtain 5 g of 3-chloro-4-decyloxybenzoic acid, then 15 g of thionyl chloride was added to 3 g of 3-chloro-4-decyloxybenzoic acid, and a reaction was carried out under reflux for 3 hours. The unreacted thionyl chloride was removed by distillation under a reduced pressure to obtain 3-chloro-4-decyloxybenzoic acid chloride quantitatively. Then the product was dissolved in a diethyl ether/THF (1/1) mixed solvent, 2.3 g of 4,4'-acetoxybiphenol and 2 g of triethylamine were added to the solution successively, and a reaction was carried out at room temperature with stirring overnight. The reacted solution was washed three times with 1N hydrochloric acid, a 1N aqueous solution of sodium hydrogencarbonate and water, in this order, and the organic phase was dried with anhydrous sodium sulfate. The solvent was evaporated, the reaction product was recovered by the silica gel chromatography, then the reaction product was dissolved in 100 ml of a THF/methanol (9/1) mixed solvent, a 1N aqueous solution of lithium hydroxide was added to the resulting solution which was cooled with ice-cold water, and a reaction was carried out with stirring for 30 minutes. Then the reacted solution was made weakly acidic by addition of 1N hydrochloric acid, extracted with a diethyl ether/benzene (1/1) mixed solvent, and the extract was washed three times with 1N hydrochloric acid, a 1N aqueous solution of sodium hydrogencarbonate and water in this order. The organic phase was recovered and dried with anhydrous magnesium sulfate, and the organic solvent was evaporated to obtain a product. The product was recrystallized from an n-hexane/ethanol mixed solvent. The compound in which Z is fluorine can be similarly obtained by using 3-fluoro-4-hydroxybenzoic acid instead of 3-chloro-4-hydroxybenzoic acid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][CH:15]([CH:19]=[CH:20][O:21]C)[O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl(O)(=O)(=O)=O.[NH4+].[OH-]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][CH:15]([CH2:19][CH:20]=[O:21])[O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC=CC1CCc2ccc(OCc3ccccc3)cc2O1
Agent: [NH4+]
Agent: [O-][Cl+3]([O-])([O-])O
Agent: [OH-]
Solvent: C1CCOC1
Product: O=CCC1CCc2ccc(OCc3ccccc3)cc2O1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 50 %

Procedure:
A solution of 7-(benzyloxy)-2-[2-methoxyethenyl]-chroman (1.0 g, 3.3 mmol) in THF is treated with perchloric acid (0.3 ml), stirred at room temperature for 15 minutes, poured into dilute NH4OH and extracted with ether. The combined extracts are dried over MgSO4 and concentrated in vacuo. The resultant residue is chromatographed (silica gel/20% EtOAc in hexanes as eluent) to give the title product as a colorless oil, 0.484 g (50% yield), identified by NMR and mass spectral analyses.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH2:16])=[C:11]([Cl:17])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2].ClC1C=C(O)C=CC=1C=O.C(CC(Br)(C)C([O-])=O)C.[F:38][C:39]([F:60])([F:59])[C:40]1[C:45]([C:46](O)=[O:47])=[CH:44][N:43]=[C:42]([C:49]2[CH:54]=[CH:53][C:52]([C:55]([F:58])([F:57])[F:56])=[CH:51][CH:50]=2)[N:41]=1.C(OC(C1C(C(F)(F)F)=NC(C2C=CC(C(F)(F)F)=CC=2)=NC=1)=O)C>>[CH2:1]([O:3][C:4](=[O:18])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:46]([C:45]2[C:40]([C:39]([F:60])([F:38])[F:59])=[N:41][C:42]([C:49]3[CH:50]=[CH:51][C:52]([C:55]([F:57])([F:58])[F:56])=[CH:53][CH:54]=3)=[N:43][CH:44]=2)=[O:47])=[C:11]([Cl:17])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: O=C(O)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1C(F)(F)F
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CN)c(Cl)c1
Agent: CCCC(C)(Br)C(=O)[O-]
Agent: CCOC(=O)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1C(F)(F)F
Agent: O=Cc1ccc(O)cc1Cl
Product: CCOC(=O)C(C)(C)Oc1ccc(CNC(=O)c2cnc(-c3ccc(C(F)(F)F)cc3)nc2C(F)(F)F)c(Cl)c1

Procedure:
In analogy to the procedures described in example 26B] and 26C], 2-(4-aminomethyl-3-chloro-phenoxy)-2-methyl-propionic acid ethyl ester (prepared from 2-chloro-4-hydroxy-benzaldehyde by reaction with ethyl-bromoisobutyrate as described in example 52A] followed by oxim formation and reduction as described in examples 97A] and 97B]) was reacted with 4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid (prepared by saponification from 4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid ethyl ester (example 107B]) in analogy to example 53B]) to give 2-[3-chloro-4-({[4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carbonyl]-amino}-methyl)-phenoxy]-2-methyl-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as amorphous light yellow solid.
Reaction SMILES: [P:1](Cl)([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)([S:3][CH2:4][CH2:5][CH2:6][CH3:7])=[S:2].[OH:20][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[C:29]=1[C:28](=[O:30])[CH2:27][CH2:26]2.C(N(CC)CC)C>C1(C)C=CC=CC=1>[P:1]([O:20][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[C:29]=1[C:28](=[O:30])[CH2:27][CH2:26]2)([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)([S:3][CH2:4][CH2:5][CH2:6][CH3:7])=[S:2]
Reactant: CCCCSP(=S)(Cl)Oc1ccc(C(F)(F)F)cc1
Reactant: O=C1CCc2cccc(O)c21
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCSP(=S)(Oc1ccc(C(F)(F)F)cc1)Oc1cccc2c1C(=O)CC2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
S-n-Butyl O-(4-trifluoromethylphenyl) chlorodithiophosphate (0.015 mole) dissolved in dry toluene (80) is charged into a glass reaction vessel equipped with a stirrer, thermometer and gas inlet tube. The solution is cooled to about 0° C. and a solution of 7-hydroxyindan-1-one (0.015 mole) and triethylamine (0.0175 mole) in toluene (20 ml) is slowly added with stirring. After the addition is completed the reaction mixture is allowed to warm to room temperature and stirring is continued for a period of about 8 hours. After this time the reaction mixture is filtered and the filtrate is washed with water. The washed solution is then dried and is stripped of solvent leaving a residue. This residue is chromatographed through a 200 ml clay column using ethyl acetate and hexane mixtures as the eluant. Ten separate fractions each containing increasing percentages of ethyl acetate are collected and analyzed by IR for the product. The appropriate fractions are then combined stripped of solvent and subjected to vacuum to yield the desired product S-n-butyl O-(4-trifluoromethylphenyl) O-indan-1-on-7-yl dithiophosphate.
Reaction SMILES: C([O:3][C:4](=O)[NH:5][CH2:6][CH2:7][C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)C.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>O=P(Cl)(Cl)Cl>[S:9]1[C:8]2[CH2:7][CH2:6][NH:5][C:4](=[O:3])[C:12]=2[CH:11]=[CH:10]1
Reactant: CCOC(=O)NCCc1cccs1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O=P(Cl)(Cl)Cl
Product: O=C1NCCc2sccc21
Temperature: 110 °C
Reaction time: 4 h
Yield: 33.5 %

Procedure:
Using an analogous procedure and workup as described in Example 1, step 4, (2-thiophen-2-yl-ethyl)-carbamic acid ethyl ester (I-7c: 800 mg, 3.50887 mmol) in POCl3 (10 mL) was reacted with P2O5 (996 mg, 7.0175 mmol). The resulting mixture was stirred at 110° C. for 4 hours to afford the crude product. Purification by column chromatography on silica gel (2% methanol in CHCl3) afforded 180 mg of the product (33.5% yield).
Reaction SMILES: [CH3:1][C:2]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)=[CH:23][N:22]=1)([C:6]1[CH:11]=[CH:10][C:9](B2OC(C)(C)C(C)(C)O2)=[CH:8][CH:7]=1)[CH:3]([CH3:5])[CH3:4].[Cl:35][C:36]1[N:37]=[N:38][C:39](Cl)=[CH:40][CH:41]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>CCO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:35][C:36]1[N:37]=[N:38][C:39]([C:9]2[CH:10]=[CH:11][C:6]([C:2]([CH3:1])([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)=[CH:23][N:22]=3)[CH:3]([CH3:4])[CH3:5])=[CH:7][CH:8]=2)=[CH:40][CH:41]=1
Reactant: CC(C)C(C)(c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)c1ccc(OCc2ccccn2)cn1
Reactant: Clc1ccc(Cl)nn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)C(C)(c1ccc(-c2ccc(Cl)nn2)cc1)c1ccc(OCc2ccccn2)cn1
Temperature: 95 °C

Procedure:
[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (69.0 mg, 0.0950 mmol) was added to a stirred solution of 5a (1.45 g, 3.16 mmol), 3,6-dichloropyridazine (660 mg, 4.43 mmol) and sodium carbonate (3.20 mL of a 2.0 M aqueous solution, 6.32 mmol) in EtOH:toluene (10.0 mL of an 80:20 mixture, respectively) at rt. The resulting solution was heated to 95° C. for approximately 4 h. After cooling to rt, the reaction mixture was filtered through a short column of CELITE®, eluting with EtOAc. The filtrate was washed with water, brine, dried (sodium sulfate) and concentrated in vacuo. The crude residue was purified by flash chromatography on silica gel (gradient elution; 20%-80% EtOAc/hexanes as eluent) to furnish the title compound 5b. m/z (ES) 445 (MH)+. 1HNMR (500 MHz, CDCl3): δ 8.63 (d, 1H, J=4.1 Hz), 8.41 (d, 1H, J=1.8 Hz), 7.96 (d, 2H, J=8.7 Hz), 7.80 (d, 1H, J=8.9 Hz), 7.76 (dt, 1H, J=1.7, 7.7 Hz), 7.53 (m, 4H), 7.27 (dd, 1H, J=5.1, 7.1 Hz), 7.19 (m, 2H), 5.24 (s, 2H), 3.11 (m, 1H, J=6.7 Hz), 1.61 (s, 3H), 0.89 (d, 3H, J=6.6 Hz), 0.83 (d, 3H, J=6.9 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[Br:12]Br>C(Cl)(Cl)(Cl)Cl.[W]>[Br:12][CH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(C)cc1
Reactant: BrBr
Agent: [W]
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CBr)cc1
Yield: 96.2 %

Procedure:
A solution of 15.0 g (0.1 mole) of methyl 4-methylbenzoate in 150 ml of carbon tetrachloride was stirred and heated to reflux with a 350 watt tungsten lamp. A solution of 16.0 g (0.1 mole) of bromine in 150 ml of carbon tetrachloride was added over 3 minutes by an addition funnel. The colorless reaction mixture was evaporated to give 22.03 g (97% yield) of the title compound as colorless prisms.
Reaction SMILES: [C:1]([O:4][C:5](=[CH:10][C:11]1[CH:19]=[C:18]([CH3:20])[C:17]2[C:13](=[CH:14][N:15]([CH2:21][O:22][CH3:23])[N:16]=2)[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])(=[O:3])[CH3:2]>ClCCl>[C:1]([O:4][C@H:5]([CH2:10][C:11]1[CH:19]=[C:18]([CH3:20])[C:17]2[C:13](=[CH:14][N:15]([CH2:21][O:22][CH3:23])[N:16]=2)[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])(=[O:3])[CH3:2]
Reactant: COCn1cc2cc(C=C(OC(C)=O)C(=O)OC)cc(C)c2n1
Solvent: ClCCl
Product: COCn1cc2cc(C[C@@H](OC(C)=O)C(=O)OC)cc(C)c2n1
Reaction time: 8 h

Procedure:
A solution of methyl 2-acetoxy-3-(2-(methoxymethyl)-7-methyl-2H-indazol-5-yl)acrylate (2.80 g, 8.8 mmol) in dichloromethane (20 mL) was degassed by passing a stream of nitrogen through the solution. To this solution was quickly added (−)-1,2-bis((2R,5R)-2,5-diethylphospholano)benzene(cyclooctadiene) rhodium (I) trifluoromethylsulfonate (100 mg, 0.016 equiv) as a solid. The reaction was placed under a hydrogen atmosphere (55 psi) and shaken overnight. The reaction was concentrated and purified by column chromatography (50% ethyl acetate/hexanes) to give 2.74 g (97%) as a colorless oil. 1H-NMR (CDCl3, 500 MHz) δ 2.08 (s, 3H), 2.61 (s, 3H), 3.11 (dd, J=14.3, 8.9, 1H), 3.20 (dd, J=14.3, 4.6, 1H), 3.39 (s, 3H), 3.72 (s, 3H), 5.26 (dd, J=8.9, 4.6, 1H), 5.68 (s, 2H), 6.93 (s, 1H), 7.33 (s, 1H), 8.02 (s, 1H).
Reaction SMILES: [CH:1]12[C:7]([CH3:9])([CH3:8])[CH:6]1[C:5](=[O:10])[CH:4]=[C:3]([CH3:11])[CH2:2]2.[CH3:12][SH:13]>>[CH3:12][S:13][C:3]1([CH3:11])[CH2:4][C:5](=[O:10])[CH:6]2[C:7]([CH3:8])([CH3:9])[CH:1]2[CH2:2]1
Reactant: CC1=CC(=O)C2C(C1)C2(C)C
Reactant: CS
Product: CSC1(C)CC(=O)C2C(C1)C2(C)C

Procedure:
In accordance with the procedure of Example 8 car-3-en-5-one is reacted with methylmercaptan by heating the reaction mixture in a suitable pressure-vessel for 3 hours to yield 3-methylthio-caran-5-on, boiling point ca 70° at 0.5 mm Hg, nD20 = 1.5224.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:21]=[C:20]([C:22]#[N:23])[CH:19]=[CH:18][C:6]=1[NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)(=[O:10])=[O:9])#[N:4].[CH:24](I)([CH3:26])[CH3:25].O>CN(C=O)C>[C:3]([C:5]1[CH:21]=[C:20]([C:22]#[N:23])[CH:19]=[CH:18][C:6]=1[N:7]([CH:24]([CH3:26])[CH3:25])[S:8]([C:11]1[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=1)(=[O:10])=[O:9])#[N:4]
Reactant: CC(C)I
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(C#N)cc2C#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)N(c2ccc(C#N)cc2C#N)C(C)C)cc1
Temperature: 25 °C
Yield: 12.5 %

Procedure:
To a suspension of sodium hydride (65%, 0.12 g (3.30 mmol)) in 6.0 ml of DMF, 2′,4′-dicyano-p-toluenesulfonanilide (0.49 g (1.65 mmol)) was added with stirring at room temperature. To the resulting mixture, after 10 minutes' stirring at room temperature, isopropyl iodide (0.50 ml (4.94 mmol)) was added and the mixture was heated at 130° C. for 6 hours with stirring. The reaction mixture was then cooled to room temperature, poured into water and extracted with diethyl ether. The extract was washed with 1% aqueous sodium hydroxide solution and with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography with ethyl acetate-hexane (3:7) as eluent, to give 0.07 g (13%) of the title compound as white crystals.
Reaction SMILES: C([O:8][C:9]([C@@H:11]1[CH2:16][CH2:15][CH2:14][CH2:13][N:12]1[S:17]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1)(=[O:19])=[O:18])=[O:10])C1C=CC=CC=1>[Pd].C(O)C>[F:26][C:22]1[CH:21]=[C:20]([S:17]([N:12]2[CH2:13][CH2:14][CH2:15][CH2:16][CH:11]2[C:9]([OH:10])=[O:8])(=[O:18])=[O:19])[CH:25]=[CH:24][CH:23]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCCN1S(=O)(=O)c1cccc(F)c1
Agent: [Pd]
Solvent: CCO
Product: O=C(O)C1CCCCN1S(=O)(=O)c1cccc(F)c1
Reaction time: 3 h
Yield: 82.5 %

Procedure:
A mixture of (S)-1-(3-fluoro-benzenesulfonyl)-piperidine-2-carboxylic acid benzyl ester (6.51 g, 17.3 mmol), ethanol (200 mL) and 10% Pd on carbon (1.83 g, 1.70 mmol) was hydrogenated at 30 psi for 3 h. The suspension was then filtered through celite and washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The resulting oil was chromatographed on silica gel (dichloromethane/n-heptane, 9/1) to afford 4.10 g (82.9%) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:14][CH:13]=[C:12]([CH3:23])[N:11]=2)=[O:9])=[N:3]1.BrC1C=NC=C([F:31])C=1>>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:17]3[CH:18]=[N:19][CH:20]=[C:21]([F:31])[CH:22]=3)=[CH:14][CH:13]=[C:12]([CH3:23])[N:11]=2)=[O:9])=[N:3]1
Reactant: Cc1ccc(Nc2cccnc2)c(C(=O)Nc2ccn(C)n2)n1
Reactant: Fc1cncc(Br)c1
Product: Cc1ccc(Nc2cncc(F)c2)c(C(=O)Nc2ccn(C)n2)n1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (example 16) in accordance with the general method of example 20 using 3-Bromo-5-fluoropyridine instead of 3-Bromo-4-methylpyridine to yield the final compound as a yellow solid, MS (ISP): m/e=327.1 (M+H+).
Reaction SMILES: [C:1]1([C:10]2[C:11](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:12]([OH:14])=[O:13])[C:2](=[CH:6][CH:7]=[CH:8][CH:9]=1)[C:3]([OH:5])=O>S(=O)(=O)(O)O>[CH:8]1[CH:9]=[C:1]2[C:10]3[C:11]([C:12]([OH:14])=[O:13])=[CH:15][CH:16]=[CH:17][C:18]=3[C:3](=[O:5])[C:2]2=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccccc1-c1ccccc1C(=O)O
Agent: O=S(=O)(O)O
Product: O=C(O)c1cccc2c1-c1ccccc1C2=O
Yield: 100.2 %

Procedure:
Diphenic acid (500 g, 2.06 Mol) was reacted with concentrated sulfuric acid (1250 mL, S.G. 1.84) at 140° C. for 35 minutes following the procedure of Huntress et al.1The red solution was cooled and precipitated by pouring the mixture into 15 L of distilled water. The yellow precipitate was boiled with 10 L of water, filtered and boiled with a further 10 L of water. The dried yellow product 9-fluorenone-4-carboxylic acid (463 g, 81% yield) was used in the next step without further purification.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])[C:17]3=[O:27])=[C:12]([S:28][CH3:29])[CH:11]=2)=[CH:6][CH:5]=1)(=[NH:3])[NH2:2].BrBr.C([O-])(=[O:34])C.[Na+]>C(O)(=O)C>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])[C:17]3=[O:27])=[C:12]([S:28]([CH3:29])=[O:34])[CH:11]=2)=[CH:8][CH:9]=1)(=[NH:2])[NH2:3]
Reactant: COC(=O)CCN1CCN(c2ccc(-c3ccc(C(=N)N)cc3)cc2SC)C1=O
Reactant: CC(=O)[O-]
Agent: BrBr
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)CCN1CCN(c2ccc(-c3ccc(C(=N)N)cc3)cc2S(C)=O)C1=O

Procedure:
Prepared from 1-(4'-amidino-3-methylthio-4-biphenylyl)-3-(2-methoxycarbonyl-ethyl)-imidazolidin-2-one by oxidation with bromine in glacial acetic acid in the presence of sodium acetate at ambient temperature.