Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([SH:9])[CH:6]=[CH:7][CH:8]=1.[C:10](OCC)(=[O:15])[CH2:11][C:12]([CH3:14])=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6]([C:10](=[O:15])[CH:11]=[C:12]([CH3:14])[S:9]2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: COc1cccc(S)c1
Product: COc1ccc2c(=O)cc(C)sc2c1
Temperature: 110 °C
Yield: 34 %

Procedure:
To a mixture of 3-methoxybenzenethiol (24 g, 28.5 mmol) in PPA (200 g) was added ethyl acetoacetate (22.8 g, 28.5 mmol) at room temperature under nitrogen. Then the reaction mixture was heated to 110° C. for 5 h with vigorous stirring and poured into ice-water (100 ml). The resultant mixture was extracted with ethyl acetate (500 ml×3). The combined organic phase was dried with anhydrous sodium sulfate, filtered and concentrated, then purified by silica gel column (PE/EtOAc=10/1) to afford desired product (2 g, 4%) as a yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH2:3][C@H:4]([CH3:17])[C@:5]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1)(O)[CH2:6][CH3:7].FC(F)(F)C(OC(=O)C(F)(F)F)=O.[H][H]>CC1CCCO1.[Pd]>[CH3:16][O:15][C:11]1[CH:10]=[C:9]([C@H:5]([CH2:6][CH3:7])[C@@H:4]([CH3:17])[CH2:3][N:2]([CH3:18])[CH3:1])[CH:14]=[CH:13][CH:12]=1
Reactant: [H][H]
Reactant: CC[C@](O)(c1cccc(OC)c1)[C@@H](C)CN(C)C
Agent: [Pd]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CC1CCCO1
Product: CC[C@@H](c1cccc(OC)c1)[C@@H](C)CN(C)C
Temperature: 5 °C
Yield: 97.9 %

Procedure:
A solution of compound (4) (50.3 g) dissolved in 2-methyltetrahydrofuran (120 ml) was stirred and cooled to 5° C. Then trifluoroacetic anhydride (30.6 ml) was added slowly over a period of 10 minutes while the temperature of the reaction mixture was kept below 20° C. After addition, the reaction mixture was allowed to stir for 1 hour at 20° C. b) Palladium 10% on activated carbon (50% wetted) (2.52 g) was added and the reaction mixture was stirred at 800 rpm and pressurized to 2 atmosphere (202.65 kPa) with hydrogen gas. The reaction mixture was heated to 40° C. and stirred for 4 hours at 40° C. The mixture was allowed to cool to 20° C. and filtered under nitrogen atmosphere. The filter was washed with 2-methyltetrahydrofuran (10 ml). Water (160 ml) was added to the filtrate and the mixture was stirred, then an aqueous NaOH solution (28.6 ml, 50% w/w) was added over a period of 10 minutes while the temperature was kept below 20° C. The organic and water layer were allowed to separate, the organic layer was isolated and washed with water (50 ml), and concentrated under reduced pressure to dryness, yielding (2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethyl-pentanamine (5) as a colourless oil (46.10 g).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=3)[C:6]=2[CH:17]=1.[C:18]1([CH3:32])[CH:23]=[CH:22][C:21]([N:24]2[C:28](B(O)O)=[CH:27][CH:26]=[N:25]2)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.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:13]1([CH3:16])[CH:14]=[CH:15][C:10]([N:7]2[C:6]3[CH:17]=[C:2]([C:28]4[N:24]([C:21]5[CH:22]=[CH:23][C:18]([CH3:32])=[CH:19][CH:20]=5)[N:25]=[CH:26][CH:27]=4)[CH:3]=[CH:4][C:5]=3[N:9]=[CH:8]2)=[CH:11][CH:12]=1
Reactant: Cc1ccc(-n2cnc3ccc(Br)cc32)cc1
Reactant: Cc1ccc(-n2nccc2B(O)O)cc1
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: COCCOC
Solvent: O
Product: Cc1ccc(-n2nccc2-c2ccc3ncn(-c4ccc(C)cc4)c3c2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 43.4 %

Procedure:
To a mixture of 6-bromo-1-p-tolyl-1H-benzo[d]imidazole (intermediate F) (100 mg, 348 μmol) and 1-p-tolyl-1H-pyrazol-5-ylboronic acid (intermediate B) (91.5 mg, 453 μmol) in 1,2-dimethoxyethane (3 ml) was added 2M sodium carbonate solution (696 μl, 1.39 mmol) and the reaction mixture was purged with argon for 10 min in an ultrasonic bath. To the stirred mixture tetrakis(triphenylphosphine)palladium(0) (80.5 mg, 69.6 μmol) was added at room temperature and the reaction mixture was allowed to stir under reflux conditions for 15 h. The reaction mixture was cooled to room temperature, poured into water (20 ml) and extracted with ethyl acetate (2×20 ml). The combined organic layers were washed with brine (1×20 ml), dried (MgSO4) and evaporated. The crude material (200 mg) was purified by flash chromatography on silica gel (heptane/ethyl acetate 1:1) and trituration from diethyl ether/heptane to yield the title compound as a off-white solid (55 mg, 43%), MS (ISP) m/z=365.2 [(M+H)+], mp 165° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:15]([O-:17])=[O:16])[CH:5]=[CH:6][C:7]=1[O:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.Br[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1>N1C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N+:15]([O-:17])=[O:16])[CH:5]=[CH:6][C:7]=1[O:8][CH:9]1[CH2:14][CH2:13][N:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:11][CH2:10]1
Reactant: Brc1ccccn1
Reactant: O=[N+]([O-])c1ccc(OC2CCNCC2)c(Cl)c1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(OC2CCN(c3ccccn3)CC2)c(Cl)c1
Temperature: 150 °C
Reaction time: 16 h
Yield: 20 %

Procedure:
To a suspension of 3-chloro-4-(piperidin-4-yloxy)nitrobenzene (3.00 g) obtained in reference example 8 in pyridine (30 ml) was added 2-bromopyridine (1.25 ml) at room temperature, and the resulting mixture was stirred at 150° C. for 16 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, and the organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:2) as the eluent to afford the title compound (0.80 g, yield: 20%) as a yellow solid.
Reaction SMILES: Br[C:2]([F:25])([F:24])[C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[C:4]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[F-:26].[K+].CC#N>O>[CH3:17][S:14]([C:11]1[CH:12]=[CH:13][C:8]([C:5]2[C:4]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:3]([C:2]([F:25])([F:26])[F:24])[O:7][N:6]=2)=[CH:9][CH:10]=1)(=[O:16])=[O:15]
Reactant: [F-]
Reactant: CS(=O)(=O)c1ccc(-c2noc(C(F)(F)Br)c2-c2ccccc2)cc1
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(-c2noc(C(F)(F)F)c2-c2ccccc2)cc1
Reaction time: 0.39 h
Yield: 48.2 %

Procedure:
A mixture of 7 (5.4 mg, 0.013 mmol), anhydrous KF (1.1 mg, 0.019 mmol), Kryptofix® 222 (7.0 mg, 0.019 mmol) and dry MeCN (1.0 mL) was refluxed for 50 min. The reaction mixture was diluted with H2O (5 mL) and passed through a Waters Sep-Pak® C-18 cartridge (1 mL). The cartridge was washed with H2O (3×3 mL) and with MeCN (3 mL). The MeCN eluate was purified by semi-preparative HPLC (Phenomenex® HPLC column: aqua, 5μ, C-18, 10 mm×250 mm) with MeCN—H2O (3:1) containing 0.075% TFA (5 mL/min). The fractions at 22-25 min were combined and concentrated to yield 8 (2.3 mg, 50%) as a colorless solid. The 1H NMR spectrum was identical with those reported (Habeeb, A. G.; Rao, P. N. P.; Knaus, E. E. Drug Dev. Res. 2000, 51, 273-286).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@H:4]1[CH2:8][O:7][C:6]([CH3:10])([CH3:9])[N:5]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].[H-].[Na+].Cl[C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=1>C1COCC1.C(OCC)(=O)C>[C:14]([O:13][C:11]([N:5]1[C@@H:4]([CH2:3][CH2:2][O:1][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=2)[CH2:8][O:7][C:6]1([CH3:10])[CH3:9])=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1[C@@H](CCO)COC1(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1[C@@H](CCOc2ccc(C(F)(F)F)cn2)COC1(C)C
Temperature: 50 °C
Yield: 82.3 %

Procedure:
To a stirred solution of tert-butyl(S)-4-(2-hydroxyethyl)-2,2-dimethyloxazolidine-3-carboxylate (300 mg; CAS 147959-18-0) in THF (4 ml) under an argon atmosphere was added sodium hydride (59 mg, 60% dispersion in oil). The resulting suspension was heated at 50° C. for 20 min and then cooled to 0° C. A solution of 2-chloro-5-trifluoromethyl-pyridine (222 mg) in THF (2 ml) was then added dropwise and the resulting mixture was heated at 70° C. for 3 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The mixture was washed with saturated brine, the phases were separated and the organic phase was dried over sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography (SiO2; gradient: heptane/EtOAc) to give (S)-2,2-dimethyl-4-[2-(5-trifluoromethyl-pyridin-2-yloxy)-ethyl]-oxazolidine-3-carboxylic acid tert-butyl ester (393 mg, 82%) as a colourless oil. MS (ISP): 391.3 ([M+H]+).
Reaction SMILES: [NH2:1][C:2]([CH3:18])([CH2:5][N:6]1[N:10]=[C:9]2[C:11]([Cl:17])=[CH:12][C:13]([Cl:16])=[C:14]([F:15])[C:8]2=[N:7]1)[C:3]#[N:4].[F:19][C:20]([F:31])([F:30])[C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[S:26])=[CH:23][CH:22]=1>>[C:3]([C:2]([NH:1][C:25](=[S:26])[C:24]1[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:30])[F:31])=[CH:29][CH:28]=1)([CH3:18])[CH2:5][N:6]1[N:10]=[C:9]2[C:11]([Cl:17])=[CH:12][C:13]([Cl:16])=[C:14]([F:15])[C:8]2=[N:7]1)#[N:4]
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Reactant: CC(N)(C#N)Cn1nc2c(Cl)cc(Cl)c(F)c2n1
Product: CC(C#N)(Cn1nc2c(Cl)cc(Cl)c(F)c2n1)NC(=S)c1ccc(C(F)(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-3-(5,7-dichloro-4-fluoro-2H-benzotriazol-2-yl)-2-methylpropionitrile (90 mg, described in Example 46) and 4-trifluoromethylthiobenzoyl chloride (0.06 mL), the title compound was isolated as a white solid (95 mg, 62%). Rf=0.55 (1:1 EA/heptane). MS (ES): M/Z [M+H]=492. NMR: (400 MHz, DMSO-d6): 1.76 (s, 3H), 5.47 (d, J=13.3 Hz, 1H), 5.60 (d, J=13.3 Hz, 1H), 7.58-8.22 (m, 5H) and 8.94 (s, 1H). 19F NMR (376 MHz, DMSO-d6): −127.6 (d, J=5.3 Hz, 1F) and −42.0 (s, 3F).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].[F:19][C:20]([F:36])([F:35])[C:21]1[CH:26]=[CH:25][C:24]([C:27]2[S:28][CH:29]=[C:30]([CH2:32][CH2:33]O)[N:31]=2)=[CH:23][CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>>[C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:33][CH2:32][C:30]3[N:31]=[C:27]([C:24]4[CH:23]=[CH:22][C:21]([C:20]([F:36])([F:19])[F:35])=[CH:26][CH:25]=4)[S:28][CH:29]=3)[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Cn1ccc2ccc(O)cc21
Reactant: OCCc1csc(-c2ccc(C(F)(F)F)cc2)n1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)OC(=O)Cn1ccc2ccc(OCCc3csc(-c4ccc(C(F)(F)F)cc4)n3)cc21

Procedure:
In analogy to the procedure described in example 3 c], (6-hydroxy-indol-1-yl)-acetic acid tert-butyl ester (example 6 b]) was reacted with 2-[2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-ethanol in the presence of triphenylphosphine and di-tert-butyl azodicarboxylate to yield (6-{2-[2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-ethoxy]-indol-1-yl)-acetic acid tert-butyl ester as yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][N:12]([CH:15]([CH3:19])[C:16]([OH:18])=O)[C:11](=[O:20])[CH:10]=1.[NH2:21][C:22]1[CH:34]=[CH:33][C:25]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:24][CH:23]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][N:12]([CH:15]([CH3:19])[C:16]([NH:21][C:22]2[CH:34]=[CH:33][C:25]([C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])=[CH:24][CH:23]=2)=[O:18])[C:11](=[O:20])[CH:10]=1
Reactant: CC(C(=O)O)n1ccc(-c2cc(Cl)ccc2Br)cc1=O
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Product: CC(C(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1)n1ccc(-c2cc(Cl)ccc2Br)cc1=O

Procedure:
153 mg (purity 93%, 0.4 mmol) of 2-[4-(2-bromo-5-chlorophenyl)-2-oxopyridin-1(2H)-yl]propanoic acid (racemate) and 1.2 eq. of tert-butyl 4-aminobenzoate were reacted according to General Method 5A. Yield: 96 mg (44% of theory)
Reaction SMILES: C[O:2][C:3](=[O:43])[CH2:4][C:5]1[CH:42]=[CH:41][CH:40]=[CH:39][C:6]=1[CH2:7][CH2:8][C:9]1[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:12]=[C:11]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([CH:26]3[O:31][CH2:30][CH2:29][N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:27]3)=[CH:22][CH:21]=2)[N:10]=1.O.[OH-].[Li+]>C1COCC1.O>[C:35]([O:34][C:32]([N:28]1[CH2:29][CH2:30][O:31][CH:26]([C:23]2[CH:24]=[CH:25][C:20]([NH:19][C:11]3[N:10]=[C:9]([CH2:8][CH2:7][C:6]4[CH:39]=[CH:40][CH:41]=[CH:42][C:5]=4[CH2:4][C:3]([OH:43])=[O:2])[C:14]([C:15]([F:16])([F:17])[F:18])=[CH:13][N:12]=3)=[CH:21][CH:22]=2)[CH2:27]1)=[O:33])([CH3:38])([CH3:36])[CH3:37]
Reactant: COC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C3CN(C(=O)OC(C)(C)C)CCO3)cc2)ncc1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(=O)O)n3)cc2)C1
Yield: 85 %

Procedure:
tert-Butyl 2-(4-((4-(2-(2-methoxy-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)morpholine-4-carboxylate (I89) (46 mg, 0.077 mmol) was dissolved in THF (2 mL), and lithium hydroxide hydrate (6.0 mg, 0.15 mmol) in water (0.5 mL) was added. After 18 hours the mixture was concentrated, diluted with water (5 mL) and the pH adjusted to 3 with 6 M HCl. The mixture was extracted with ethyl acetate (3×10 mL), and the combined organic extracts washed with brine (20 mL), dried over sodium sulfate and evaporated to give the title compound (I90) (39 mg, 85% yield) as a pale yellow syrup; 1H NMR (400 MHz, CDCl3) δ 8.52 (s, 1H), 7.54 (d, J=8.4 Hz, 2H), 7.35-7.27 (m, 4H), 4.38 (d, J=10.1 Hz, 1H), 4.07-3.80 (m, 5H), 3.67 (td, J=11.7, 2.7 Hz, 1H), 3.06 (s, 4H), 2.84 (s, 2H), 1.47 (s, 9H). LCMS Method C: rt 6.49 min; m/z 587.1 [M+H]+, 531.0 [M−tBu+2H]+, 487.1 [M-Boc+2H]+; m/z 585.2 [M−H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH3:9].C1C(=O)[N:14](Br)[C:12](=O)C1.CC(N=NC(C#N)(C)C)(C#N)C.[C-]#N.[Na+]>C(Cl)(Cl)(Cl)Cl.O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][C:12]#[N:14]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(F)cccc1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: [C-]#N
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: N#CCc1c(F)cccc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
A suspension of 2-bromo-6-fluorotoluene (5.00 g, 26.45 mmol), NBS (5.18 g, 29.10 mmol), and VAZO (323 mg, 1.32 mmol) in CCl4 (100 mL) was heated to reflux under vigoroue stirring overnight. The reaction mixture was cooled to room temperature, concentrated and the residue was removed by filtration. The filtrate was concentrated and the residue was re-dissolved in ethanol (90 mL), treated with a solution of NaCN (2.59 g, 52.9 mmol) in water (20 mL) and the combined mixture was heated to reflux for 5 hrs. Ethanol was removed under reduced pressure, the aqueous residue was diluted with water and extracted with AcOEt. The organic layer was successively washed with water and brine, concentrated, adsorbed on silica gel and purified by flash column chromatography (eluents AcOEt/hexanes: 10/90 to 20/80) to afford title compound 329 (3.92 g, 69% yield over 2 steps, slightly contaminated) as a pale yellow sticky solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.62-7.57 (m, 1H), 7.45-7.35 (m, 2H), 4.08 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C@H:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[N:19]12[CH2:26][CH2:25][CH:22]([CH2:23][CH2:24]1)[C@H:21](O)[CH2:20]2.CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[N:19]12[CH2:26][CH2:25][CH:22]([CH2:23][CH2:24]1)[C@@H:21]([O:11][C:10](=[O:12])[C@H:9]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH2:20]2
Reactant: O[C@@H]1CN2CCC1CC2
Reactant: O=C(O)[C@H](Nc1ccc(F)cc1)c1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(O[C@H]1CN2CCC1CC2)[C@H](Nc1ccc(F)cc1)c1ccccc1
Yield: 79.2 %

Procedure:
To a solution of (R)-(4-fluoro-phenylamino)-phenyl-acetic acid (I253) (420 mg, 1.71 mmol) in dry THF (40 mL), are sequentially added (S)-quinuclidin-3-ol (218 mg, 1.71 mmol), DEAD (407 ul, 2.57 mmol) and triphenylphosphine (674 mg, 2.57 mmol). The reaction is refluxed for 30 minutes under N2 flowstream and then the solvent is evaporated. The residue is partitioned between water and EtOAc, the organic layer is separated, dried over Na2SO4, filtered and evaporated to dryness. The resulting crude is purified by flash chromatography (DCM/MeOH=95/5) to obtain the title compound as a pale yellow oil (480 mg, 79% yield).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[O:10][CH3:11])[CH:5]=[O:6].[SH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21]O.Cl>ClCCl>[S:14]1[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:21][O:6][CH:5]1[C:4]1[CH:7]=[C:8]([O:12][CH3:13])[C:9]([O:10][CH3:11])=[C:2]([OH:1])[CH:3]=1
Reactant: COc1cc(C=O)cc(O)c1OC
Reactant: OCc1ccccc1S
Agent: Cl
Solvent: ClCCl
Product: COc1cc(C2OCc3ccccc3S2)cc(O)c1OC

Procedure:
Following the same procedure as outlined in Example 1 step b), 3-hydroxy-4,5-dimethoxybenzaldehyde (1.08 g, 5.95 mmol) and (2-mercaptophenyl)methanol (1 g, 7.14 mmol) in dichloromethane (30 ml) %% ere treated with hydrogen chloride gas. After workup and chromatography, as in example 1 step b), the subtitle compound was obtained (1.06 g, 59%) as a white solid. 1H NMR (300 MHz, CDCl3, ppm) δ 3.88 (s, 3H); 3.89 (s, 3H); 5.04-5.14 (m, 2H); 5.85 (s, 1H); 6.01 (s, 1H); 6.72 (d, J=2 Hz, 1H); 6.76 (d, J=2 Hz, 1H); 6.98-7.04 (m, 1H); 7.05-7.19 (m, 3H); 13C NMR (75 MHz, CDCl3, ppm) δ 56.1; 61.1; 70.5; 82.9; 102.4; 106.7; 125.1; 126.0; 127.48; 127.5; 129.8; 132.9; 134.2; 136.1; 149.4; 152.8; MS calculated for C16H16O4S+H 305 observed 305.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][N:9]=[C:10]([C:15]([O:20][CH2:21][CH3:22])([O:17][CH2:18][CH3:19])[CH3:16])[C:11]([O:13][CH3:14])=[O:12].S(Cl)([Cl:26])(=O)=O>C(Cl)(Cl)Cl>[CH3:7][O:8][N:9]=[C:10]([C:15]([O:20][CH2:21][CH3:22])([O:17][CH2:18][CH3:19])[CH2:16][Cl:26])[C:11]([O:13][CH3:14])=[O:12]
Reactant: CCOC(C)(OCC)C(=NOC)C(=O)OC
Reactant: O=S(=O)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CCOC(CCl)(OCC)C(=NOC)C(=O)OC
Reaction time: 0.17 h
Yield: 97.9 %

Procedure:
Anhydrous potassium carbonate (8.89 g) was added to a solution of methyl 2-methoxyimino-3,3-diethoxybutyrate (syn isomer, 10 g) in chloroform (40 ml). Sulfuryl chloride (6.94 g) was added to the suspension at -6° to -2° C. over 50 minutes, and stirred at -5° to -2° C. for 10 minutes. After removing the solvent from the resultant mixture, ethanol (10 ml) was added to the residue and stirred for 30 minutes. Water (25 ml) was added to the mixture, and the mixture was extracted with diisopropyl ether (20 ml) twice. The extract was washed with water (10 ml) and a saturated aqueous solution of sodium chloride (5 ml) subsequently, and dried over magnesium sulfate. The solution was evaporated in vacuo to give methyl 2-methoxyimino-3,3-diethoxy-4-chlorobutyrate (syn isomer, 11.23 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[CH:5]=[C:4]([CH3:15])[N:3]=1.[I:16][C:17]1[N:18]=[CH:19][NH:20][CH:21]=1>>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:5]=[C:4]([CH3:15])[N:3]=[C:2]([N:20]3[CH:21]=[C:17]([I:16])[N:18]=[CH:19]3)[N:7]=2)=[CH:9][CH:10]=1
Reactant: Cc1cc(-c2ccc(Cl)cc2)nc(Cl)n1
Reactant: Ic1c[nH]cn1
Product: Cc1cc(-c2ccc(Cl)cc2)nc(-n2cnc(I)c2)n1

Procedure:
The title compound was prepared from 2-chloro-4-(4-chloro-phenyl)-6-methyl-pyrimidine (example A.11) (1.67 g, 7.0 mmol) and commercially available 4-iodo-imidazole (2.04 g, 10.5 mmol) according to the general procedure IVa. Obtained as a light yellow solid (1.97 g, 71%). MS (ISP) 397.1 [(M+H)+]; mp 184° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[C:10]([C:19]([OH:21])=O)=[CH:9]2)=[CH:5][CH:4]=1.Cl.[CH3:25][NH:26][O:27][CH3:28].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C(#N)C>[CH3:28][O:27][N:26]([CH3:25])[C:19]([C:10]1[C:11](=[O:18])[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:8]([CH2:7][C:6]2[CH:22]=[CH:23][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:9]=1)=[O:21]
Reactant: COc1ccc(Cn2cc(C(=O)O)c(=O)c3ccccc32)cc1
Reactant: CNOC
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(Cn2cc(C(=O)N(C)OC)c(=O)c3ccccc32)cc1

Procedure:
Experimental conditions analogous to those described for Step 5 of Example 60, from crude 1-(4-Methoxy-benzyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid, 1.03 g (10.6 mmol) of N,O-dimethylhydroxylamine hydrochloride, 6.1 mL (4.43 g, 43.8 mmol) of triethylamine and 6.3 mL (6.80 g, 10.7 mmol) of 50% 1-propanephosphonic acid cyclic anhydride in 30 mL acetonitrile to give 1.90 g of the product as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][O:11][C@H:10]([CH2:15][NH:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:9]2)[CH:5]=[C:4]([C:23]2[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[C:25](F)[CH:24]=2)[N:3]=1.O.[NH2:33][NH2:34]>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][O:11][C@H:10]([CH2:15][NH:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:9]2)[CH:5]=[C:4]([C:23]2[CH:24]=[C:25]3[C:26]([C:29]([NH2:30])=[N:33][NH:34]3)=[CH:27][CH:28]=2)[N:3]=1
Reactant: C[C@@H]1CO[C@H](CNC(=O)C(C)(C)C)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Reactant: NN
Solvent: O
Solvent: CCO
Product: C[C@@H]1CO[C@H](CNC(=O)C(C)(C)C)CN1c1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Temperature: 100 °C
Reaction time: 17 h
Yield: 63.7 %

Procedure:
A mixture of crude N-({(2R,5R)-4-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-5-methyl-2-morpholinyl}methyl)-2,2-dimethylpropanamide (0.29 mmol theoretical) and hydrazine monohydrate (0.28 mL, 5.78 mmol) in ethanol (3 mL) was stirred at 100° C. in a sealed tube for 17 hours. The mixture was concentrated in vacuo and the residue was purified on a Gilson reverse phase HPLC (CH3CN/water with 0.1% TFA). The product fractions were combined and concentrated in vacuo, taken up in EtOAc (15 mL), washed with saturated aqueous NaHCO3 (2×10 mL) and brine (10 mL), then dried (Na2SO4), filtered, and concentrated in vacuo to afford the title compound (81 mg) as a pale yellow solid. LC-MS (ES) m/z=439 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.13 (s, 9H), 1.17 (d, J=6.6 Hz, 3H), 2.64-2.84 (m, 1H), 3.20-3.30 (m, 2H), 3.42-3.52 (m, 1H), 3.63 (dd, J=11.4, 2.5 Hz, 1H), 3.77 (d, J=11.1 Hz, 1H), 3.98-4.79 (bs, 2H), 5.39 (s, 2H), 6.12 (s, 2H), 6.50 (s, 1H), 7.53 (d, J=8.3 Hz, 1H), 7.63 (t, J=5.7 Hz, 1H), 7.71 (d, J=8.3 Hz, 1H), 7.93 (s, 1H), 11.53 (s, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C@@H:5]1[C@@:25]2([CH3:26])[C:9](=[CH:10][CH:11]=[C:12]3[C@@H:24]2[CH2:23][CH2:22][C@@:21]2([CH3:27])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[CH:17]([CH:19]=[O:20])[CH3:18])[CH2:8][C@@H:7]([O:28][CH2:29][O:30][CH3:31])[CH2:6]1.C[O:33]C(O[C@@H]1[C@@]2(C)C(=CC=C3[C@@H]2CC[C@@]2(C)[C@H]3CC[C@@H]2C(C=O)C)C[C@@H](OC(OC)=O)C1)=O>>[CH3:1][O:2][CH2:3][O:4][C@@H:5]1[C@@:25]2([CH3:26])[C:9](=[CH:10][CH:11]=[C:12]3[C@@H:24]2[CH2:23][CH2:22][C@@:21]2([CH3:27])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[CH:17]([C:19]([OH:33])=[O:20])[CH3:18])[CH2:8][C@@H:7]([O:28][CH2:29][O:30][CH3:31])[CH2:6]1
Reactant: COCO[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C=O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OCOC)C1
Reactant: COC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C=O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OC)C1
Product: COCO[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C(=O)O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OCOC)C1
Yield: 73.5 %

Procedure:
The procedure of Example 6 was repeated except that 105 mg of 1α,3β-bis(methoxymethoxy)pregna-5,7-diene-20-carbaldehyde was used in lieu of 120 mg of 1α,3β-bis(methoxycarbonyloxy)pregna-5,7-diene-20-carbaldehyde to give 80 mg of 1α,3β-bis(methoxymethoxy)pregna-5,7-diene-20-carboxylic acid.