Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:21]([N:22]2[CH2:27][C@H:26]([CH3:28])[O:25][C@H:24]([CH3:29])[CH2:23]2)[CH2:20][C@@:19]2([CH3:30])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[C:17](=[O:31])[CH2:16][C@@:15]2([CH3:32])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1.[C:33]([OH:45])(=[O:44])[CH2:34][C:35]([CH2:40][C:41]([OH:43])=[O:42])([C:37]([OH:39])=[O:38])[OH:36]>>[OH:1][C@@H:2]1[C@@H:21]([N:22]2[CH2:27][C@H:26]([CH3:28])[O:25][C@H:24]([CH3:29])[CH2:23]2)[CH2:20][C@@:19]2([CH3:30])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[C:17](=[O:31])[CH2:16][C@@:15]2([CH3:32])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1.[OH:36][C:35]([C:37]([O-:39])=[O:38])([CH2:40][C:41]([O-:43])=[O:42])[CH2:34][C:33]([O-:45])=[O:44]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](N5C[C@@H](C)O[C@@H](C)C5)C[C@]4(C)[C@H]3C(=O)C[C@]12C
Product: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]

Procedure:
With the cis-2,6-dimethyl-4-morpholinyl compound of Example 5 and citric acid as starting materials, (2β,3α,5α)-3-hydroxy-2-(cis-2,6-dimethyl-4-morpholinyl)pregnane-11,20-dione 2-hydroxy-1,2,3-propanetricarboxylate (1:1) salt was formed. [α]D +100.5° (c 1.09).
Reaction SMILES: C[O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12](=[O:14])[CH3:13])[CH:7]=[CH:6][C:5]=1[O:15][CH3:16].[OH-].[Na+].Cl>CO>[CH3:16][O:15][C:5]1[CH:6]=[CH:7][C:8]([O:10][CH2:11][C:12](=[O:14])[CH3:13])=[CH:9][C:4]=1[C:3]([OH:17])=[O:2]
Reactant: COC(=O)c1cc(OCC(C)=O)ccc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(OCC(C)=O)cc1C(=O)O
Yield: 80.7 %

Procedure:
Stir a mixture of 2-methoxy-5-(2-oxo-propoxy)-benzoic acid methyl ester (0.49 g, 2.1 mmol), methanol (20 mL) and 1N NaOH (20 mL, 20 mmol) for two hours at room temperatue. Acidify the reaction with 1N HCl (to pH 2) and extract with dichloromethane. Dry (MgSO4) the organic phase, filter and concentrate the filtrate in vacuo. Purify the residue by column chromatography (silica gel, step gradient elution with 3% methanol in dichloromethane to 10% methanol in dichloromethane and concentrate the appropriate fractions to afford 0.38 g of 2-methoxy-5-(2-oxo-propoxy)-benzoic acid, Rf=0.82 (silica gel, dichloromethane:methanol:acetic acid, 85:10:5).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[C:12]([OH:14])[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=1.C(O)(=O)C>CO.[Rh]>[CH3:10][O:9][C:7]([CH:6]1[CH2:11][CH:12]([OH:14])[CH2:13][CH:4]([C:3]([O:2][CH3:1])=[O:15])[CH2:5]1)=[O:8]
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1
Agent: [Rh]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)C1CC(O)CC(C(=O)OC)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.6 %

Procedure:
To a solution of dimethyl-5-hydroxyisophthalate (3.50 g, 16.6 mmol) in methanol (60.0 mL) was added 5% rhodium on alumina (0.80 g) at 0° C., followed by acetic acid (0.60 mL, 10.6 mmol). The reaction mixture was shaken under hydrogen (55 psi) at room temperature overnight and then filtered through Celite® and concentrated under reduced pressure. The residue was purified by CombiFlash® system (12 g silica gel cartridge; gradient: 0 to 50% ethyl acetate in DCM over 30 min) to give 3.00 g (83%) of the title compound, 5-hydroxy-cyclohexane-1,3-dicarboxylic acid dimethyl ester. 1H NMR (400 MHz, CDCl3): δ 3.56-3.78 (m, 7H), 2.15-2.51 (m, 5H), 1.25-1.66 (m, 3 H).
Reaction SMILES: [Br-].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([Mg]Br)=[CH:5][CH:4]=1>C1C=CC=CC=1.O1CCCC1>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:6]2[CH:7]=[CH:8][C:3]([Cl:2])=[CH:4][CH:5]=2)=[CH:5][CH:4]=1
Reactant: Clc1ccc([Mg]Br)cc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: Clc1ccc(-c2ccc(Cl)cc2)cc1

Procedure:
Thallous bromide (22.46 gm, 0.079 mole) is added to a solution of p-chlorophenyl magnesium bromide (0.0395 mole) in a mixture of benzene (25 ml.) and tetrahydrofuran (25 ml.) and the mixture stirred and refluxed under nitrogen for 7 hours. The reaction mixture is cooled, poured into 150 ml. of dilute hydrochloric acid, and the 4,4'-dichlorobiphenyl extracted with ether (2 × 30 ml.). The combined extracts are dried over anhydrous sodium sulfate, and the solvent removed to leave 2.9 gm. of crude white product. This is filtered through a short column of alumina using chloroform as eluent, to give, after removal of the solvent, 2.70 gm. (61%) of pure 4,4'-dichlorobiphenyl, m.p. 148°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][N:5]([CH2:9][CH:10]=[CH2:11])[CH2:6]C=C>ClC1C=CC=CC=1>[N:5]1([CH2:4][C:3]([O:2][CH3:1])=[O:12])[CH:6]=[CH:11][CH:10]=[CH:9]1
Reactant: C=CCN(CC=C)CC(=O)OC
Solvent: Clc1ccccc1
Product: COC(=O)Cn1cccc1
Temperature: 65 °C
Reaction time: 16 h
Yield: 27.7 %

Procedure:
0.22 g (1.3 mmole) of the diallylglycine methyl ester prepared in example 27 was dissolved in 3 ml chlorobenzene after which 0.046 g (0,064 mmole) of the bimetallic ruthenium complex 3.e prepared in example 24 was added. The mixture was stirred for 16 hours at 65° C. The catalyst was removed after evaporation of chlorobenzene by column chromatography, providing with 100% selectivity 0.05 g (0.36 mmole, yield 28%) methyl 1H-pyrrole-1-ylacetate. This product was further characterised by the following spectra:
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[C:5]([CH3:12])[C:6]=1[C:7](OCC)=[O:8].[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[CH3:1][C:2]1[O:3][CH:4]=[C:5]([CH3:12])[C:6]=1[CH2:7][OH:8]
Reactant: CCOC(=O)c1c(C)coc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: Cc1coc(C)c1CO
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2,4-Dimethyl-3-carbethoxyfuran (42.8 g.) prepared in accordance with J. Amer. Chem. Soc., v. 73, 356 (1951) was dissolved in ether (100 ml.) and added slowly to a cooled (0°) slurry of lithium aluminum hydride (10 g.) in ether (200 ml.) and the mixture was then stirred at room temperature for 18 hours. After this time, the mixture was cooled in an ice bath and quenched with an aqueous solution of sodium sulfate (60 ml.; saturated) followed by the addition of solid magnesium sulfate. The solids were filtered off, washed well with additional ether and the combined ether extract was concentrated to yield 2,4-dimethyl-3-hydroxymethylfuran. Distillation gave pure 2,4-dimethyl-3-hydroxymethylfuran (21.1 g.) bp 63°-65° at 2 mm Hg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[C:24]3[C:19](=[C:20]([CH2:25][S:26][CH3:27])[CH:21]=[CH:22][CH:23]=3)[N:18](C(OC(C)(C)C)=O)[CH:17]=2)[CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:16]2[C:24]3[C:19](=[C:20]([CH2:25][S:26][CH3:27])[CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)[CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)C(c1ccc(Cl)cc1)c1cn(C(=O)OC(C)(C)C)c2c(CSC)cccc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(C)C(c1ccc(Cl)cc1)c1c[nH]c2c(CSC)cccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.85 g (1.69 mmol) of the compound from Example 31A was dissolved in 10 ml of dichloromethane, and 2.61 ml (33.86 mmol) of trifluoroacetic acid were added. After stirring at RT for 2 h, the reaction solution was concentrated and the residue was purified twice by preparative HPLC (mobile phase: acetonitrile-water gradient). 0.42 g (61% of theory) of the title compound was obtained as mixture of diasteromers.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][CH:11]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])[C:12]([OH:14])=[O:13])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:20]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[Cl:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][CH:11]([CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[C:12]([OH:14])=[O:13])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)CCC(CSc1ccc(Cl)c(Cl)c1)C(=O)O
Solvent: CO
Product: COC(=O)CCC(CSc1ccc(Cl)c(Cl)c1)C(=O)O
Temperature: 40 °C
Reaction time: 2.5 h
Yield: 1656.8 %

Procedure:
A mixture of 2-(3,4-dichlorophenylthiomethyl)glutaric acid (3.00 g), methanol (30 ml), and p-toluenesulfonic acid (0.09 g) was stirred at 40° C. for 2.5 hours. The reaction mixture was concentrated in vacuo, and the resulting residue was purified by flash column chromatography on silica by eluting with chloroform/ethanol (10:1) to give 2.92 g of 3-(3,4-dichlorophenylthio)-2-(2-methoxycarbonylethyl)propionic acid as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([C:10]2[CH:15]=[CH:14][C:13](B3OC(C)(C)C(C)(C)O3)=[CH:12][C:11]=2[F:25])=[N:4][CH:3]=1.Br[C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][C:28]=1[S:37]([N:40]1[CH2:45][CH2:44][NH:43][C:42](=[O:46])[CH2:41]1)(=[O:39])=[O:38]>>[NH2:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([C:10]2[CH:15]=[CH:14][C:13]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:35])([F:36])[F:34])=[CH:29][C:28]=3[S:37]([N:40]3[CH2:45][CH2:44][NH:43][C:42](=[O:46])[CH2:41]3)(=[O:39])=[O:38])=[CH:12][C:11]=2[F:25])=[N:4][CH:3]=1
Reactant: CC1(C)OB(c2ccc(-c3ncc(N)nc3C#N)c(F)c2)OC1(C)C
Reactant: O=C1CN(S(=O)(=O)c2cc(C(F)(F)F)ccc2Br)CCN1
Product: N#Cc1nc(N)cnc1-c1ccc(-c2ccc(C(F)(F)F)cc2S(=O)(=O)N2CCNC(=O)C2)cc1F

Procedure:
The title compound was prepared using conditions analogous to those used to make Example 6 utilizing 6-amino-3-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazine-2-carbonitrile and 4-((2-bromo-5-(trifluoromethyl)phenyl)sulfonyl)piperazin-2-one. MS (ESI): mass calcd. for C22H16F4N6O3S, 520.09; m/z found, 520.8 [M+H]+. 1H NMR (600 MHz, DMSO-δ6) δ 8.29 (d, J=1.9, 1H), 8.26 (s, 1H), 8.19 (dd, J=8.2, 1.9, 1H), 8.07-8.01 (m, 1H), 7.77 (d, J=7.9, 1H), 7.70-7.64 (m, 1H), 7.49 (dd, J=10.8, 1.7, 1H), 7.44-7.36 (m, 3H), 3.39 (s, 2H), 3.07-2.96 (m, 4H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[C:4]([F:12])[CH:3]=1.[CH2:13]([O:15][C:16]1[C:17]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)=[N:18][CH:19]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:21]=1)[CH3:14].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.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]>[CH2:13]([O:15][C:16]1[CH:21]=[C:20]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[C:4]([F:12])[CH:3]=2)[CH:19]=[N:18][C:17]=1[O:31][CH2:32][C:33]1[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=1)[CH3:14]
Reactant: O=C(O)Cc1ccc(Br)cc1F
Reactant: CCOc1cc(B2OC(C)(C)C(C)(C)O2)cnc1OCc1ccc(OC)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CCOc1cc(-c2ccc(CC(=O)O)c(F)c2)cnc1OCc1ccc(OC)cc1
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 60.5 %

Procedure:
A suspension of 2-(4-bromo-2-fluorophenyl)acetic acid (300 mg, 1.287 mmol) in 1,4-dioxane (3 mL) and H2O (1.000 mL) was added to a solution of 3-ethoxy-2-((4-methoxybenzyl)oxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (496 mg, 1.287 mmol) in 1,4-dioxane (3 mL) and H2O (1.000 mL). PdCl2(dppf) (94 mg, 0.129 mmol) and Cs2CO3 (1049 mg, 3.22 mmol) were added and the mixture was stirred at 110° C. for 30 min under microwave. The mixture was cooled to rt and then the solution was concentrated and distributed between EA and saturated NaHCO3 solution. The combined organic extract was washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by preparative TLC (PE/EA=1:1, Rf=0.5) to yield a light yellow solid of 2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (320 mg, 0.778 mmol, 60.4% yield): 1H NMR (400 MHz, CD3OD) δ 7.93 (d, J=1.8 Hz, 1H), 7.18-7.50 (m, 6H), 6.78-7.00 (m, 2H), 5.28-5.54 (m, 2H), 4.04-4.21 (m, 2H), 3.74-3.84 (m, 3H), 3.30-3.38 (m, 2H), 1.32-1.52 (m, 3H); ES-LCMS m/z 412.0 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[F:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15](Cl)=[O:16].S1C=CC=C1C(Cl)=O>>[F:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1)=[O:16]
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: O=C(Cl)c1ccccc1F
Agent: O=C(Cl)c1cccs1
Product: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)c1ccccc1F

Procedure:
4-Fluoro-3-nitro-phenylamine was reacted with 2-fluorobenzoyl chloride according to the procedure of Example 256a substituting 2-fluorobenzoyl chloride for thiophene-2-carbonyl chloride to provide 2-fluoro-N-(4-fluoro-3-nitro-phenyl)-benzamide which was then reacted according to the procedures of Examples 256b and 256c to provide the title product.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:38]=[CH:37][C:8]([CH2:9][NH:10][C:11]([C:13]2[C:14](=[O:36])[N:15]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=3)[C:16]([CH3:25])=[C:17]([C:19]3[O:20][CH:21]=[C:22]([CH3:24])[N:23]=3)[CH:18]=2)=[O:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[CH:40](C)C(=O)C.C([O-])([O-])=O.[Ca+2].CN1C(=O)CCC1>C(#N)C>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH:10][C:11]([C:13]2[C:14](=[O:36])[N:15]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:33])([F:34])[F:35])[CH:27]=3)[C:16]([CH3:25])=[C:17]([C:19]3[O:20][C:21]([CH3:40])=[C:22]([CH3:24])[N:23]=3)[CH:18]=2)=[O:12])=[CH:37][CH:38]=1)(=[O:3])=[O:4]
Reactant: Cc1coc(-c2cc(C(=O)NCc3ccc(S(C)(=O)=O)cc3)c(=O)n(-c3cccc(C(F)(F)F)c3)c2C)n1
Reactant: CC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CC#N
Solvent: CN1CCCC1=O
Product: Cc1nc(-c2cc(C(=O)NCc3ccc(S(C)(=O)=O)cc3)c(=O)n(-c3cccc(C(F)(F)F)c3)c2C)oc1C
Temperature: 140 °C
Yield: 12.8 %

Procedure:
6-Methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3,5-dicarboxylic acid 5-amide 4-methanesulfonyl-benzylamide (see Example 60, 0.05 g, 0.098 mmol), 3-bromo-2-butanone (0.020 g, 0.20 mmol), CaCO3 (0.015 g, 0.15 mmol), NMP (1.5 ml) and a magnetic stirrer bar were placed in a tube designed for microwave synthesis. The vial was sealed and the mixture was heated in a CEM Discover Microwave apparatus (100 W, 140 ° C.) for 2 h. The reaction was stopped and the crude mixture was dissolved in acetonitrile (2 ml) and water (2 ml) and was purified directly on preparative HPLC, giving the title compound (0.007 g, 13%) as a slightly brownish solid after freeze-drying the pure fractions.
Reaction SMILES: Cl[C:2]1[N:24]=[C:5]2[C:6]([NH:10][C:11]3[CH:23]=[CH:22][CH:21]=[CH:20][C:12]=3[CH2:13][N:14]([CH3:19])[S:15]([CH3:18])(=[O:17])=[O:16])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:25][N:26]1[CH2:31][CH2:30][CH:29]([C:32]2[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=2)[CH2:28][CH2:27]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:19][N:14]([CH2:13][C:12]1[CH:20]=[CH:21][CH:22]=[CH:23][C:11]=1[NH:10][C:6]1[C:5]2[N:4]([N:3]=[C:2]([NH:38][C:35]3[CH:36]=[CH:37][C:32]([CH:29]4[CH2:28][CH2:27][N:26]([CH3:25])[CH2:31][CH2:30]4)=[CH:33][CH:34]=3)[N:24]=2)[CH:9]=[CH:8][CH:7]=1)[S:15]([CH3:18])(=[O:17])=[O:16]
Reactant: CN(Cc1ccccc1Nc1cccn2nc(Cl)nc12)S(C)(=O)=O
Reactant: CN1CCC(c2ccc(N)cc2)CC1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCC(c2ccc(Nc3nc4c(Nc5ccccc5CN(C)S(C)(=O)=O)cccn4n3)cc2)CC1

Procedure:
N-Methyl-N-(2-{2-[4-(1-methyl-piperidin-4-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino}-benzyl)-methanesulfonamide was prepared from N-[2-(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-benzyl]-N-methyl-methanesulfonamide (75.0 mg, 0.205 mmol) and 4-(1-methyl-piperidin-4-yl)-phenylamine (44.0 mg, 0.231 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a tan foam (0.068 g, 64%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.96 (d, J=6.5 Hz, 1H), 7.54 (d, J=8.3 Hz, 2H), 7.46-7.38 (m, 2H), 7.35 (t, J=7.5 Hz, 1H), 7.21 (d, J=8.4 Hz, 2H), 7.13 (t, J=7.5 Hz, 1H), 7.00 (s, 1H), 6.83 (d, J=7.8 Hz, 1H), 6.76 (s, 1H), 6.70 (t, J=7.0 Hz, 1H), 4.36 (s, 2H), 2.95 (d, J=11.2 Hz, 2H), 2.91 (s, 3H), 2.78 (s, 3H), 2.50-2.40 (m, 1H), 2.33 (s, 3H), 2.10-2.00 (m, 2H), 1.87-1.73 (m, 4H). MS=520 (MH)+.
Reaction SMILES: [CH:1]1[CH2:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[CH2:9][CH2:10][CH2:11][Si:12]([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15]>O1CCCC1>[C:2]1([CH2:9][CH2:10][CH2:11][Si:12]([O:13][CH2:14][CH3:15])([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])[CH2:1][CH:5]=[CH:4][CH:3]=1
Reactant: CCO[Si](CCCCl)(OCC)OCC
Reactant: C1=CCC=C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCO[Si](CCCC1=CC=CC1)(OCC)OCC
Yield: 90 %

Procedure:
27.5 g (417 mmol) of freshly distilled cyclopentadiene are added dropwise to a suspension of 15 g (417 mmol) of sodium hydride in 250 ml of absolute tetrahydrofuran at room temperature over a period of one hour. 100.3 g of (3-chloropropyl)triethoxysilane are subsequently added dropwise over a period of 30 minutes. The solution becomes warm during this process. After taking off the solvent, the mixture is fractionally distilled in an oil pump vacuum to give 96.1 g of (3-cyclopenta-dienylpropyl)triethoxysilane (yield: 90%).
Reaction SMILES: [CH:1]1([NH:7][C:8]([NH2:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH:12]([C:18]([C:20]([F:23])([F:22])[F:21])=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14]>>[CH:1]1([NH:7][C:8]2[O:9][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:18]([C:20]([F:21])([F:23])[F:22])[N:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC(=O)NC1CCCCC1
Reactant: CCOC(=O)C(Cl)C(=O)C(F)(F)F
Product: CCOC(=O)c1oc(NC2CCCCC2)nc1C(F)(F)F
Yield: 38.7 %

Procedure:
By the procedure of Example 4, 8.52 g (60 mmol) of cyclohexyl urea was reacted with 10.9 g (50 mmol) of ethyl 2-chloro-4,4,4-trifluoroacetoacetate at 140°-150° C. for 72 hours. The product was separated and then recrystallized several times from methylcyclohexane to yield 5.92 g of a fine white powder product (m.p.=73°-74° C.) identified in Table I.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[CH:12](O)[CH3:13])=[N:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(P([N:64]=[N+:65]=[N-:66])(C2C=CC=CC=2)=O)C=CC=CC=1>O1CCCC1>[N:64]([CH:12]([C:11]1[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=1[C:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:1][N:2]=1)[CH3:13])=[N+:65]=[N-:66]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CC(O)c1ccccc1-c1noc2ccccc12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(N=[N+]=[N-])c1ccccc1-c1noc2ccccc12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of 0.6 g of 2-[2-(1,2-benzisoxazol-3-yl]-a-methylbenzyl alcohol and 0.65 g of triphenylphosphine in 10 ml tetrahydrofuran at 0° C. was added 0.39 ml of diethyl azodicarboxylate followed by a solution of 0.54 ml of diphenylphosphoryl azide in 5 ml of tetrahydrofuran. The solution was warmed to room temperature and stirred for 1.5 h. The reaction was evaporated and purified by flash chromatography eluting with 1:1 toluene-heptane to yield 0.27 g of 3-[2-(1-azidoethyl)-phenyl]-1,2-benzisoxazole as a colourless gum, 1H-NMR (200 MHz, CDCl3) dH 5.10 (CHN3).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1([OH:21])[C:18]2[C:13](=[CH:14][CH:15]=[C:16](I)[CH:17]=2)[NH:12][C:11]1=[O:20])[CH3:2].[CH3:22][N:23](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[C:22]([C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:20])[C:10]2([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[O:3][CH2:1][CH3:2])[OH:21])#[N:23]
Reactant: CCOc1ccccc1C1(O)C(=O)Nc2ccc(I)cc21
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CCOc1ccccc1C1(O)C(=O)Nc2ccc(C#N)cc21
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
37.2 g (94 mmol) of the product 1a and 11.1 g (94 mmol) of zinc cyanide in 300 ml of DMF were heated to 95° C. Then 1.6 g (1.38 mmol) of tetrakis(triphenylphosphine)palladium(0) were added in portions every 10 minutes. After 45 minutes, the reaction mixture was poured into ice-water and extracted with ethyl acetate. The organic phase was washed with saturated NaCl solution, dried and concentrated in vacuo. The residue obtained in this way crystallizes from a little ethyl acetate. 24 g of the product were obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[C:14]4[C@:19]([CH2:21][OH:22])([CH2:20][C:11]=3[CH:10]=[N:9]2)[CH2:18][N:17]([S:23]([C:26]2[CH:27]=[N:28][C:29]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[CH:30][CH:31]=2)(=[O:25])=[O:24])[CH2:16][CH2:15]4)=[CH:4][CH:3]=1.FS([C:42]([F:47])([F:46])C(O)=O)(=O)=O>[Cu](I)I.C(#N)C>[F:46][CH:42]([F:47])[O:22][CH2:21][C@@:19]12[CH2:18][N:17]([S:23]([C:26]3[CH:27]=[N:28][C:29]([N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)=[CH:30][CH:31]=3)(=[O:24])=[O:25])[CH2:16][CH2:15][C:14]1=[CH:13][C:12]1[N:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[N:9]=[CH:10][C:11]=1[CH2:20]2
Reactant: O=S(=O)(c1ccc(N2CCOCC2)nc1)N1CCC2=Cc3c(cnn3-c3ccc(F)cc3)C[C@]2(CO)C1
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Agent: I[Cu]I
Solvent: CC#N
Product: O=S(=O)(c1ccc(N2CCOCC2)nc1)N1CCC2=Cc3c(cnn3-c3ccc(F)cc3)C[C@]2(COC(F)F)C1
Temperature: 50 °C

Procedure:
A mixture of [(R)-1-(4-fluorophenyl)-6-[[6-(4-morpholinyl)-3-pyridinyl]sulfonyl]-1,4,7,8-tetrahydro-1,2,6-triazacyclopenta[b]naphthalen-4a-yl]methanol (0.21 g), copper iodide (0.0080 g) and acetonitrile under argon was treated with 2-(fluorosulfonyl)difluoroacetic acid (0.062 mL), and the resulting mixture was heated at 50° C. for 30 hours. The mixture was cooled to room temperature, partitioned between water and ethyl acetate and the aqueous phase extracted with ethyl acetate. The combined organic phase was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (1:0 to 1:1 by volume), and then by preparative reverse-phase HPLC, eluting with a mixture of acetonitrile and water containing 0.1% formic acid (1:1 to 7:3 by volume) to afford the title compound as a white solid (0.021 g). LCMS (Method C): 576 (M+H)+, Retention time 11.6 minutes.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([CH3:16])([CH3:15])[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[N:5]=[C:4]([N:17]2[CH2:23][CH:22]3[CH2:24][CH2:25][CH:19]([CH2:20][CH2:21]3)[CH2:18]2)[N:3]=1.[C:26](N)([CH3:29])([CH3:28])[CH3:27]>>[C:26]([C:2]1[N:7]=[C:6]([NH:8][C:9]([CH3:16])([CH3:15])[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[N:5]=[C:4]([N:17]2[CH2:23][CH:22]3[CH2:24][CH2:25][CH:19]([CH2:20][CH2:21]3)[CH2:18]2)[N:3]=1)([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)CC(C)(C)Nc1nc(Cl)nc(N2CC3CCC(CC3)C2)n1
Reactant: CC(C)(C)N
Product: CC(C)(C)CC(C)(C)Nc1nc(N2CC3CCC(CC3)C2)nc(C(C)(C)C)n1

Procedure:
Eight grams (0.022 mole) of 3-[4-chloro-6-(1,1,3,3-tetramethylbutylamino)-s-triazin-2-yl]-3-azabicyclo[3.2.2]nonane and 23 ml. (0.22 mole) of t-butylamine is placed in a glass liner in a bomb and then heated in an oil bath maintained at 185°-200° C. for about 40 hours. After cooling, the contents of the bomb are rinsed with chloroform and water into a flask and 50 ml. of 10 N NaOH is added. The solution is then evaporated in vacuo and the aqueous solution remaining is extracted with chloroform. The combined chloroform extracts are washed with water, dried over magnesium sulfate, filtered through Magnesol® and the Magnesol® washed with chloroform. Removal of solvent in vacuo and recrystallization from acetone gives 5.8 g. of colorless crystals, m.p. 163.5°-167.5° C.