Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[OH:18][C:19]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:20]=1[NH2:21]>>[OH:18][C:19]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:20]=1[NH:21][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: Cc1ccc(O)c(N)c1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Product: Cc1ccc(O)c(Nc2cc(C(F)(F)F)nc(-c3cccnc3)n2)c1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 2-hydroxy-5-methylaniline (36 mg, 0.290 mmol) similar to Example 117 and isolated as a brown solid (10 mg, 15%). 1H NMR (Acetone-d6): 9.58 (s, 1H), 8.87 (s, 1H), 8.74 (s, 1H), 8.72–8.68 (m, 2H), 7.89 (s, 1H), 7.58–7.53 (m, 1H), 7.24 (s, 1H), 6.92 (s, 2H), 2.33 (s, 3H).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:11][CH2:10][CH:9]2[CH:7]([O:8]2)[CH2:6]1)(=[O:4])=[O:3].[N-:12]=[N+:13]=[N-:14].[Na+].O>CN(C)C=O>[N:12]([CH:9]1[CH2:10][CH2:11][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][CH:7]1[OH:8])=[N+:13]=[N-:14]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)N1CCC2OC2C1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)N1CCC(N=[N+]=[N-])C(O)C1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
To a stirred solution of rac-3-methanesulfonyl-7-oxa-3-aza-bicyclo[4.1.0]heptane (0.92 g, 5.19 mmol, Example 303) in dimethylformamide (20 mL), sodium azide (550 mg, 8.46 mmol) was added and the mixture was stirred at 80° C. for 6 hours. The mixture was cooled and poured into water and extracted with ethyl acetate (3×10 mL). The extracts were combined, washed with water, brine and dried with MgSO4. The solvent was removed to give the desired product as colorless oil. 304 mg, 30.4%. The compound was used directly for the next step.
Reaction SMILES: [OH:1][CH:2]([CH:4]([CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12])[C:5]([OH:7])=O)[CH3:3].ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.[NH2:42][CH:43]([C:45]1[C:46](=[O:62])[NH:47][C:48]([CH2:51][C:52]2[CH:57]=[CH:56][C:55]([O:58][CH3:59])=[C:54]([O:60][CH3:61])[CH:53]=2)=[N:49][N:50]=1)[CH3:44]>>[CH3:61][O:60][C:54]1[CH:53]=[C:52]([CH:57]=[CH:56][C:55]=1[O:58][CH3:59])[CH2:51][C:48]1[NH:47][C:46](=[O:62])[C:45]([CH:43]([NH:42][C:5](=[O:7])[CH:4]([CH:2]([OH:1])[CH3:3])[CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12])[CH3:44])=[N:50][N:49]=1
Reactant: C=CCCCC(C(=O)O)C(C)O
Reactant: COc1ccc(Cc2nnc(C(C)N)c(=O)[nH]2)cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Product: C=CCCCC(C(=O)NC(C)c1nnc(Cc2ccc(OC)c(OC)c2)[nH]c1=O)C(C)O

Procedure:
742 mg (4.31 mmol) of 2-(1-hydroxyethyl)-6-heptenoic acid (Example 22A) are reacted analogously to Example 23A with 580 mg (4.31 mmol) of 1-hydroxy-1H-benzotriazole, 870 mg (8.61 mmol) of 4-methylmorpholine, 830 mg (4.31 mmol) of N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride and 500 mg (1.72 mmol) of 6-(1-aminoethyl)-3-(3,4-dimethoxybenzyl)-1,2,4-triazin-5(4H)-one (Example 12A) to give N-{1-[3-(3,4-dimethoxybenzyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]ethyl}-2-(1-hydroxyethyl)-6-heptenamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([OH:20])[CH:16]=2)[N:11]=1)[C:5]#[N:6].[N-:21]=[N+:22]=[N-:23].[Na+].[Li+].[Cl-]>COCCOCCO>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[N:21]=[N:22][NH:23][N:6]=2)[CH:7]=[CH:8][C:9]=1[C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([OH:20])[CH:16]=2)[N:11]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(-c2ccc3cc(O)ccc3n2)c(Cl)c1
Agent: [Cl-]
Agent: [Li+]
Agent: [Na+]
Solvent: COCCOCCO
Product: Oc1ccc2nc(-c3ccc(-c4nn[nH]n4)cc3Cl)ccc2c1
Yield: 12.1 %

Procedure:
A mixture of 3-chloro-4-(6-hydroxyquinolin-2-yl)benzonitrile (230 mg, 0.819 mmol), NaN3 (55 mg, 0.820 mmol) and LiCl (70 mg, 1.64 mmol) in diethylene glycol monomethyl ether (5 mL) was refluxed for 4 hours. The resulting mixture was cooled, filtered through silica gel pad and purified by prep-HPLC (0.1% TFA as additive) to give Compound 23 (32 mg, yield 12%). 1H NMR (CD3OD, 400 MHz): δ 8.52 (d, J=8.4 Hz, 1H), 8.34 (s, 1H), 8.21 (d, J=8.0 Hz, 1H), 8.04 (d, J=9.2 Hz, 1H), 7.92-7.82 (m, 2H), 7.54 (dd, J=9.2, 2.0 Hz, 1H), 7.34 (d, J=2.0 Hz, 1H). MS (ESI): m/z 323.6 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][CH2:6][CH2:7][C:8]2[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]3[O:16][CH2:15]3)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[NH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:25]=[C:26]([C:30]2[CH2:31][CH2:32][C:33](=[O:36])[NH:34][N:35]=2)[CH:27]=[CH:28][CH:29]=1>>[CH:1]1([CH2:4][O:5][CH2:6][CH2:7][C:8]2[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]([OH:16])[CH2:15][NH:19][CH2:20][CH2:21][CH2:22][O:23][C:24]3[CH:25]=[C:26]([C:30]4[CH2:31][CH2:32][C:33](=[O:36])[NH:34][N:35]=4)[CH:27]=[CH:28][CH:29]=3)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1
Reactant: c1cc(OCC2CO2)ccc1CCOCC1CC1
Reactant: NCCCOc1cccc(C2=NNC(=O)CC2)c1
Product: O=C1CCC(c2cccc(OCCCNCC(O)COc3ccc(CCOCC4CC4)cc3)c2)=NN1

Procedure:
Prepared analogously to Example 1 from 1-[4-(2-cyclopropylmethoxyethyl)phenoxy]-2,3-epoxypropane and 6-[3-(3-aminopropoxy)phenyl]-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: F[P-](F)(F)(F)(F)F.[N:8]1(OC(N(C)C)=[N+](C)C)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2N=N1.NC1C=CC=CC=1.[CH2:32]([O:34][C:35](=[O:51])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH:41]([C:45]1[S:49][N:48]=[C:47]([CH3:50])[N:46]=1)[C:42](O)=[O:43])[CH3:33].C(N(CC)CC)C>ClCCl>[CH2:32]([O:34][C:35](=[O:51])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH:41]([C:45]1[S:49][N:48]=[C:47]([CH3:50])[N:46]=1)[C:42](=[O:43])[NH:8][C:12]1[CH:11]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:33]
Reactant: CCOC(=O)CCCCCC(C(=O)O)c1nc(C)ns1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: Nc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)CCCCCC(C(=O)Nc1ccccc1)c1nc(C)ns1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
To a stirred mixture of O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.56 g, 1.48 mmol) and aniline (0.13 g, 1.35 mmol) in dichloromethane (10 mL) was added over 5 min the solution of crude 2-(3-methyl[1,2,4]thiadiazol-5-yl)octanedioic acid 8-ethyl ester (2021039) and triethylamine in dichloromethane. The resultant reaction mixture was then stirred at room temperature overnight before being quenched with citric acid (5 g) in water (50 mL) and extracted with dichloromethane (3×50 mL). The combined organic fractions were dried (MgSO4) and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography (3:1 hexane/ethyl acetate followed by 1:1 hexane/ethyl acetate) to afford 7-(3-methyl[1,2,4]thiadiazol-5-yl)-7-phenylcarbamoyl heptanoic acid ethyl ester (2021040) (310 mg, 52% over two steps) as a yellow oil.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([C:12]([F:15])([F:14])[F:13])=[CH:6][C:5]=1S(C1C=CC(C)=CC=1)(=O)=O)([CH3:3])[CH3:2].[OH-:26].[Na+].Cl>CO.O>[CH:1]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([C:12]([F:15])([F:14])[F:13])=[CH:6][C:5]=1[OH:26])([CH3:3])[CH3:2]
Reactant: [OH-]
Reactant: COc1cc(C(C)C)c(S(=O)(=O)c2ccc(C)cc2)cc1C(F)(F)F
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cc(C(C)C)c(O)cc1C(F)(F)F
Yield: 80.4 %

Procedure:
A solution of 1-Isopropyl-5-methoxy-2-(toluene-4-sulfonyl)-4-trifluoromethyl-benzene (0.40 g, 1.03 mmol) and NaOH (0.5 g, 12.5 mmol) in MeOH (5 ml) and H2O (5 ml) was heated at 90° C. for 2 hrs. The cooled reaction mixture was acidified with 3N HCl and extracted into methylene chloride. The combined extracts was dried with Na2SO4, filtered and concentrated to give desired 2-Isopropyl-4-methoxy-5-trifluoromethyl-phenol (0.194 g, 81%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([NH2:11])[C:3]=1I.[CH3:13][Si:14]([C:17]#[CH:18])([CH3:16])[CH3:15]>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([NH2:11])[C:3]=1[C:18]#[C:17][Si:14]([CH3:16])([CH3:15])[CH3:13]
Reactant: Nc1ncc([N+](=O)[O-])c(Cl)c1I
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1c(N)ncc([N+](=O)[O-])c1Cl
Temperature: 60 °C
Yield: 16.1 %

Procedure:
To a solution of 4-chloro-3-iodo-5-nitropyridin-2-amine (5.30 g, 17.7 mmol) in THF (90 mL) was added TEA (15.0 mL, 108 mmol). The reaction mixture was degassed and purged with nitrogen 3 times. Bis(triphenylphosphine)-palladium(II) dichloride (0.62 g, 0.88 mmol, Strem), copper(I) iodide (0.17 g, 0.89 mmol), and trimethylsilylacetylene (5.4 mL, 39 mmol) were added to the reaction mixture, degassed, and purged 3 times with nitrogen. The reaction was heated at about 60° C. for about 16 h. The reaction mixture was cooled to ambient temperature. The reaction mixture was filtered and washed with THF (200 mL). The filtrate was concd under reduced pressure. DCM (100 mL) was added to the residue and the precipitate that formed was filtered and collected to give 4-chloro-5-nitro-3-((trimethylsilyl)ethynyl)pyridin-2-amine (0.77 g). The remaining filtrate was concd under reduced pressure and the crude material was purified by flash chromatography on silica gel eluting with a gradient of 0-100% EtOAc in DCM. The purified material was combined with the 0.77 g of precipitate to afford 4-chloro-5-nitro-3-((trimethylsilyl)ethynyl)pyridin-2-amine (2.22 g, 47%) as a yellow solid: LC/MS (Table 1, Method c) Rt=1.62 min; MS m/z 268 (M−H)−.
Reaction SMILES: [CH3:1][CH:2]([CH2:5][CH2:6][CH:7]1[CH2:11][CH:10]=[C:9]([CH3:12])[C:8]1([CH3:14])[CH3:13])[CH:3]=[O:4].[CH3:15][Li].S([O-])([O-])(=O)=O.[Na+].[Na+].O>C(OCC)C>[CH3:1][CH:2]([CH2:5][CH2:6][CH:7]1[CH2:11][CH:10]=[C:9]([CH3:12])[C:8]1([CH3:13])[CH3:14])[CH:3]([OH:4])[CH3:15]
Reactant: CC1=CCC(CCC(C)C=O)C1(C)C
Reactant: [Li]C
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CC1=CCC(CCC(C)C(C)O)C1(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
A solution of 20.8 g (0.12 mole) of 2-methyl-4-(2,2,3-trimethylcyclopent-3-en-1-yl)butanal dissolved in ethyl ether-anhydrous (50 ml) was added to a stirred solution of methyllithium (1.7 M) in ethyl ether (250 ml; 0.14 mole) which was previously cooled to 0° C. The mixture was stirred at 0°-5° C for 1.0 hour and then heated at reflux (36° C) for 3.0 hours. The mixture was cooled to 0° C and excess methyllithium was decomposed by slow dropwise addition of saturated sodium sulfate solution (50 ml). The mixture was poured into 150 ml of water, the lower aqueous layer was drawn off and extracted twice with 100 ml of ether. The ether extracts were combined, washed with 150 ml of brine, dried over sodium sulfate, filtered and the solvent removed by distillation. The residual oil was fractionally distilled to yield 3-methyl-5-(2,2,3-trimethylcyclopent-3-en-1-yl)pentan-2-ol: 20.4 g (81% yield); bp 96°-98° (0.9 mm); mol wt. 210 (ms).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[C:18]([CH2:22][CH2:23][C:24](Cl)=[O:25])([O:20][CH3:21])=[O:19]>ClCCl>[F:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:24](=[O:25])[CH2:23][CH2:22][C:18]([O:20][CH3:21])=[O:19])=[CH:14][CH:13]=2)=[CH:10][CH:11]=1
Reactant: Fc1ccc(-c2ccccc2)cc1
Reactant: COC(=O)CCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)CCC(=O)c1ccc(-c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.6 %

Procedure:
To a stirred suspension of anhydrous aluminum chloride (9.64 g, 0.0723 mol) in dichloromethane (90 mL) at 5° C. was added dropwise a solution of 4-fluorobiphenyl (4.97 g, 0.0289 mol) in dichloromethane (40 mL) followed by the dropwise addition of a solution of 3-carbomethoxypropionyl chloride (3.94 mL, 0.032 mol) in dichloromethane (30 mL), and the mixture stirred. After 2 hours at 5° C., the mixture was allowed to warm to room temperature. After 1 day, the reaction was cooled to 5° C. and quenched by the dropwise addition of water (160 mL). The layers were separated, and the organic layer washed with brine, dried (Na2SO4), and rotary evaporated. The residue was recrystallized from methanol (300 mL) to give 6.17 g of 4-(4′-fluoro-biphenyl-4-yl)-4-oxo-butyric acid, methyl ester as a pale yellow solid; mp 131.5-133.0° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5]C(C#N)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[C:12]([OH:15])(=[O:14])[CH3:13].S(=O)(=O)(O)O>O>[NH:1]1[C:9]2[C:4](=[CH:5][C:13]([C:12]([OH:15])=[O:14])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: CC(=O)O
Reactant: N#Cc1ccc2[nH]ncc2c1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)c1ccc2[nH]ncc2c1
Temperature: 110 °C
Reaction time: 10 h

Procedure:
To 867 mg of 1H-5-indazolecarbonitrile used in Production Example I-14-a were added 8 ml of glacial acetic acid, 2.5 ml of water and 2 ml of concentrated sulfuric acid, and the mixture was stirred at 110° C. for 10 hours. After standing to cool, the mixture was added with 50 ml of water, and the resulting crystals were collected by filtration and dried in vacuo, to give 911 mg of the title compound as white crystals.
Reaction SMILES: [C:1]1([C:7](Cl)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH2:28]([O:35][CH2:36][CH:37]([OH:40])[CH2:38][OH:39])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(O)(C)(C)C>[CH2:28]([O:35][CH2:36][CH:37]([CH2:38][O:39][C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[OH:40])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: OCC(O)COCc1ccccc1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC(C)(C)O
Solvent: CCN(CC)CC
Product: OC(COCc1ccccc1)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 80.1 %

Procedure:
To a stirred suspension of triphenylmethyl chloride (59.6 g, 0.21 mol) and triethylamine (32.6 mL, 0.23 mol) in tert-butyl alcohol (80 mL) at 60° C. was added a solution of 1-benzyloxy-2,3-propanediol (37.1 g, 0.20 mol) in tert-butyl alcohol (20 mL). The reaction was heated at reflux for 24 hours. The reaction mixture was evaporated to dryness, then purified using flash chromatography (0 to 30% EtOAc in hexanes) to afford the title compound (68 g, 75%) as an oil. m/z not found, r.t.=4.32 mins. 1H NMR (400 MHz; CDCl3) δ 7.46-7.41 (6H, m), 7.36-7.22 (14H, m), 4.52 (2H, s), 4.02-3.95 (1H, m), 3.63-3.54 (2H, m), 3.26-3.18 (2H, m), 2.40 (1H, s).
Reaction SMILES: [C:1]([N:8]([CH2:20][C:21]([CH3:25])([CH3:24])[CH2:22][OH:23])[C:9](=[O:19])[C@H:10]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[NH2:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1([CH:32]([S:39]([O:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)(=[O:41])=[O:40])[CH2:33][CH2:34][S:35](Cl)(=[O:37])=[O:36])C=CC=CC=1>N1C=CC=CC=1.ClCCl.ClCCl>[C:1]([N:8]([CH2:20][C:21]([CH3:25])([CH3:24])[CH2:22][O:23][S:35]([CH2:34][CH2:33][CH2:32][S:39]([O:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)(=[O:41])=[O:40])(=[O:36])=[O:37])[C:9](=[O:19])[C@H:10]([CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[NH2:11])([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2]
Reactant: CC(C)(CO)CN(C(=O)OC(C)(C)C)C(=O)[C@@H](N)Cc1ccccc1
Reactant: O=S(=O)(Cl)CCC(c1ccccc1)S(=O)(=O)Oc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(COS(=O)(=O)CCCS(=O)(=O)Oc1ccccc1)CN(C(=O)OC(C)(C)C)C(=O)[C@@H](N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a stirred solution of 3-(N-Boc-L-phenylalaninamido)-2,2-dimethylpropanol from Step 1 (2 mmol) in a mixture of pyridine/dichloromethane (5 mL:10 mL) was added a solution of phenyl 3-phenoxysulfonyl-1-propanesulfonyl chloride (Example 1 (b)) (2.2 mmol) in dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 15 h, then concentrated and rediluted with ethyl acetate and aqueous hydrochloric acid (1 N). The organic phase was isolated, washed with aqueous hydrochloric acid (1 N) and concentrated. The residual material was purified by silica gel chromatography using hexanes/ethyl acetate (70:30 to 50:50) as eluent to afford 3-phenoxysulfonyl-1-propanesulfonic acid 3-(N-Boc-L-phenylalaninamido)-2,2-dimethylpropyl ester.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:21]2[CH2:20][CH2:19][C@@:18]2([CH3:26])[C:11]3=[CH:12][CH2:13][C@@H:14]2[C:15](=O)[CH3:16])[CH2:6]1)(=[O:3])[CH3:2].C([BH3-])#N.[Na+]>CC(O)=O.CO.[I-].[Zn+2].[I-]>[C:1]([O:4][C@H:5]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:21]2[CH2:20][CH2:19][C@@:18]2([CH3:26])[C:11]3=[CH:12][CH2:13][C@@H:14]2[CH2:15][CH3:16])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)[C@H](CC[C@H]3C4=CC[C@H](C(C)=O)[C@@]4(C)CC[C@@H]32)C1
Agent: [BH3-]C#N
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC[C@H]1CC=C2[C@@H]3CC[C@@H]4C[C@@H](OC(C)=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Yield: 69.1 %

Procedure:
A solution of 27.4 g of 3β-acetoxy-5β-pregn-14-en-20-one (Bach, G. et al, Can J. Chem. 1968, 46, 733) and p-toluensulphonyl hydrazide (17.1 g) in AcOH (50 mL) was stirred at room temp. for 4 hrs. The solvent was evaporated to dryness under reduced pressure; the residue obtained was dissolved in MeOH (600 mL) and zinc iodide (3.0 g) was added. To this solution sodium cyanoborohydride (14.4 g) was added portionwise and the temperature was raised to the boiling point of the reaction mixture. After 4 hrs the solvent was evaporated to dryness under reduced pressure, the crude product was dissolved in ethyl acetate and neutralised with 0.1 N NaOH; the organic layer was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by flash-chromatography (SiO2) using n-hexane/ethyl acetate 95/5 as eluant to give 18.2 g of 3β-acetoxy-5β-pregn-14-ene as a white solid.
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]3[C:28]4[C:23](=[N:24][CH:25]=[CH:26][CH:27]=4)[N:22]([Si](C(C)C)(C(C)C)C(C)C)[CH:21]=3)=[CH:15][CH:14]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[NH:22]1[C:23]2=[N:24][CH:25]=[CH:26][CH:27]=[C:28]2[C:20]([CH2:19][C:16]2[CH:17]=[CH:18][C:13]([NH:12][C:10]([NH:9][C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:40])([F:1])[F:39])[CH:4]=3)=[O:11])=[CH:14][CH:15]=2)=[CH:21]1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(Cc2ccc(NC(=O)Nc3cccc(C(F)(F)F)c3)cc2)c2cccnc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1ccc(Cc2c[nH]c3ncccc23)cc1)Nc1cccc(C(F)(F)F)c1
Reaction time: 0.17 h

Procedure:
1-(3-Trifluoromethyl-phenyl)-3-[4-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenyl]-urea (114, 85.0 mg, 0.150 mmol) was dissolved in tetrahydrofuran (10.0 mL) and tetra-n-butylammonium fluoride (52.2 mg, 0.200 mmol) was added. After 10 minutes, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified with by silica gel chromatography to give the compound (P-0262, 23 mg, 38% over steps 6 & 7). MS(ESI)[M+H+]+=411.2
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:35])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:32][CH3:33])[CH2:25][S:26][CH2:27][Si](C)(C)C)[C:5]1=[O:34])[CH:2]=[CH2:3].O1CCCC1>[F-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:1]([C@@:4]1([CH3:35])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@@H:24]([CH2:32][CH3:33])[CH2:25][S:26][CH3:27])[C:5]1=[O:34])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CSC[Si](C)(C)C)C1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CSC)C1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(((trimethylsilyl)methyl)thio)butan-2-yl)piperidin-2-one (60 mg, 0.118 mmol, Example 301, Step A) was dissolved in a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (3.5 mL, 3.5 mmol) at room temperature. The resulting solution was stirred at ambient temperature for 16 h. After that time volatiles were removed under reduced pressure, and the residue was purified by chromatography on silica gel (4 g SiO2, 10, 20, 40% EtOAc/hexane) to provide the title compound.
Reaction SMILES: [K+].[N+:2]([C:5]1[CH:6]=[C:7]([S:15]([O-:18])(=O)=[O:16])[CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[C:10]=1[Cl:11])([O-:4])=[O:3].P(Cl)(Cl)([Cl:21])=O>C(#N)C.C1S(=O)(=O)CCC1>[N+:2]([C:5]1[CH:6]=[C:7]([S:15]([Cl:21])(=[O:18])=[O:16])[CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[C:10]=1[Cl:11])([O-:4])=[O:3]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)[O-])cc([N+](=O)[O-])c1Cl
Reactant: O=P(Cl)(Cl)Cl
Agent: [K+]
Solvent: CC#N
Solvent: O=S1(=O)CCCC1
Product: O=[N+]([O-])c1cc(S(=O)(=O)Cl)cc([N+](=O)[O-])c1Cl

Procedure:
760 g (2 moles) 3,5-dinitro-4-chlorobenzenesulfonic acid potassium salt (approx. 85%) and 614 g (4 moles) phosphorus oxychloride were reacted as in Example 1(a) in 800 ml acetonitrile and 800 ml tetramethylenesulfone.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:19]=[C:18]([F:20])[C:17]([Cl:21])=[CH:16][C:13]=1[CH2:14][OH:15].C(N(CC)CC)C>C(Cl)Cl>[Cl:11][C:12]1[CH:19]=[C:18]([F:20])[C:17]([Cl:21])=[CH:16][C:13]=1[CH:14]=[O:15]
Reactant: OCc1cc(Cl)c(F)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=Cc1cc(Cl)c(F)cc1Cl
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 97.9 %

Procedure:
To a solution of oxalyl chloride (1.72 mL, 19.74 mmol) in 20 mL methylene chloride at -78° C. was added a solution DMSO (2.8 mL, 39.5 mL) in 3 mL methylene chloride. The mixture was stirred for 5 minutes at -78° C. followed by the addition of a solution of Part A 2,5-dichloro-4-fluorobenzyl alcohol (3.5 g, 17.95 mmol) from above in 15 mL methylene chloride. The mixture was stirred at -40° C. for 15 min., cooled to -78° C. followed by the addition of triethylamine (8.26 mL, 59.2 mmol). The mixture was allowed to come to RT, washed sequentially with 10% HCl, saturated sodium bicarbonate solution and water. The organic layer was dried over magnesium sulfate and concentrated to afford the title compound 3.39 g as a white solid. ##STR266##