Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([CH:14]([O:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH3:25])[C:15]([O:17]C)=[O:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1>CO.O1CCCC1.[OH-].[Na+]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][C:8]2[CH:9]=[CH:10][C:11]([CH:14]([O:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH3:25])[C:15]([OH:17])=[O:16])=[CH:12][CH:13]=2)=[CH:26][CH:27]=1
Reactant: COCCOCOC(C(=O)OC)c1ccc(OCc2ccc(F)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COCCOCOC(C(=O)O)c1ccc(OCc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.6 %

Procedure:
Methyl 2-{4-[(4-fluorobenzyl)oxy]phenyl}-2-[(2-methoxyethoxy)methoxy]acetate (0.421 g, 1.11 mmol) was dissolved in a mixture of methanol (6 ml) and tetrahydrofuran (6 ml), and 1N sodium hydroxide (3 ml) was added thereto. After being stirred for 1 hour at room temperature, the reaction mixture was neutralized and then extracted with ethyl acetate. The organic layer dried over MgSO4, and then the solvent was evaporated out. The obtained residue was purified by silica gel column chromatography (50% ethyl acetate/hexane), to give 2-{4-[(4-fluorobenzyl)oxy]phenyl}-2-[(2-methoxyethoxy)methoxy]acetic acid (0.156 g, 39%).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH2:21][CH3:22])[C:5]([NH:10][C@@H:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][C@@H:12]2[OH:20])=[N:6][C:7]=1[CH2:8][CH3:9].[CH:23]1(C2C(N[C@@H]3C4C(=CC=CC=4)C[C@@H]3O)=NC(CC)=CN=2)CC1>>[Br:1][C:2]1[N:3]=[C:4]([CH:21]2[CH2:23][CH2:22]2)[C:5]([NH:10][C@@H:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][C@@H:12]2[OH:20])=[N:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCc1cnc(C2CC2)c(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Reactant: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(CC)nc1Br
Product: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(C2CC2)nc1Br

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting (1R,2S)-1-[(3-cyclopropyl-6-ethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol and making non-critical variations provided the title compound as a solid: 1H NMR (CDCl3) δ 0.86–1.08, 1.23–1.30, 1.70–1.79, 2.77–2.84, 3.03–3.09, 3.23–3.30, 4.77–4.81, 5.44, 5.56, 7.23–7.32; MS (ESI+) for C18H20BrN3O m/z 374 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([C:14]([O:16][CH3:17])=[O:15])[CH:8]=2)[CH:2]([CH3:4])[CH3:3].[C:18](Cl)(=[O:22])[CH:19]([CH3:21])[CH3:20]>>[CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13]=1[C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])=[CH:11][CH:10]=[C:9]([C:14]([O:16][CH3:17])=[O:15])[CH:8]=2)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C(=O)Cl
Reactant: COC(=O)c1ccc2cc(CC(C)C)[nH]c2c1
Product: COC(=O)c1ccc2c(C(=O)C(C)C)c(CC(C)C)[nH]c2c1

Procedure:
Methyl 2-isobutyl-3-isobutyrylindole-6-carboxylate (246 mg) was prepared from methyl 2-isobutylindole-6-carboxylate (300 mg) and isobutyryl chloride (0.41 ml) in a similar manner to that of Preparation 1 (5).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:25]=[CH:24][C:23]3[CH2:22][CH2:21][CH2:20][CH:19]([O:26]S(C)(=O)=O)[C:18]=3[N:17]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.[CH2:31]([O-])C.[Na+]>CO.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:25]=[CH:24][C:23]3[CH2:22][CH2:21][CH2:20][CH:19]([O:26][CH3:31])[C:18]=3[N:17]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: COc1cc(Nc2ncc3c(n2)C(OS(C)(=O)=O)CCC3)ccc1-n1cnc(C)c1
Reactant: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cc(Nc2ncc3c(n2)C(OC)CCC3)ccc1-n1cnc(C)c1
Temperature: 25 °C
Yield: 31.5 %

Procedure:
To a solution of methanesulfonic acid 2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-5,6,7,8-tetrahydro-quinazolin-8-yl ester (86 mg, 0.2 mmol) in methanol (2 mL) was added sodium ethanolate (17 mg, 0.3 mmol). The reaction was stirred at room temperature over night under nitrogen, heated to reflux for 1 hour. The reaction was diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed with dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. The residue was purified by reversed phase preparative HPLC using a mixture of water containing formic acid and acetonitrile to yield the title compound (23 mg, 28%) as a yellow gum. MS ISP (m/e): 366.2 (100) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=8.35 (s, 1H), 8.26 (s, 1H), 7.85 (d, 1H), 7.75 (s, 1H), 7.16 (d, 1H), 7.09 (d, 1H), 6.88 (s, 1H), 4.19 (t, 1H), 3.88 (s, 3H), 3.58 (s, 3H), 2.55-2.80 (m, 2H), 2.33 (s, 3H), 2.15 (m, 1H), 1.72-2.05 (m, 3H).
Reaction SMILES: [F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7](OC3CCCCO3)=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]([CH2:28][CH2:29][CH:30]([O:35][SiH](C)C)C(C)(C)C)[CH3:27].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]([CH2:28][CH2:29][CH2:30][OH:35])[CH3:27]
Reactant: CN(CCCCC[C@@H]1Cc2cc(OC3CCCCO3)ccc2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F)CCC(O[SiH](C)C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(CCCO)CCCCC[C@@H]1Cc2ccccc2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F
Reaction time: 2 h
Yield: 97.8 %

Procedure:
2.3 g of 11β-fluoro-7α-{5-[(3-tert-butyldimethylsilyl-oxypropyl)methylamino]pentyl}-3-(tetrahydropyran-2-yloxy)oestra-1,3,5(10)-trien-17-one in 23 ml of tetra-hydrofuran are reacted at room temperature with 6 ml of tetrabutylammonium fluoride solution (1M in tetra-hydrofuran). After 2 hours, the mixture is diluted with ethyl acetate, washed with saturated sodium chloride solution, dried and concentrated in vacuo. Chromatography of the crude product on silica gel using a methylene chloride-methanol gradient affords 1.5 g of 11β-fluoro-7α-{5-[(3-hydroxypropyl)methylamino]-pentyl}oestra-1,3,5(10)-trien-17-one as a foam.
Reaction SMILES: [C:1]([O:6][CH:7]1C2O[CH:15]3[CH:8]1OC(=O)[CH:11]3C2)(=[O:5])[C:2]([CH3:4])=[CH2:3].C(O[C:23]1[CH:28]=[CH:27][CH:26]=[C:25](O)[C:24]=1[CH3:30])(=O)C(C)=C>>[C:1]([O:6][CH:7]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:23][C:24]=2[CH2:30][CH2:11][CH2:15][CH2:8]1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)OC1C2CC3C(=O)OC1C3O2
Reactant: C=C(C)C(=O)Oc1cccc(O)c1C
Product: C=C(C)C(=O)OC1CCCCc2ccccc21

Procedure:
3-oxo-2,7-dioxatricyclo[4.2.1.04,8]nonan-9-yl methacrylate:PAG Monomer 1=0.30:0.30:0.30:0.10
Reaction SMILES: C[C:2]1[C:12]2[CH2:11][CH2:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[S:7](=[O:17])[C:6]=2[CH:5]=[C:4]([C:18]([O-:20])=[O:19])[CH:3]=1.[OH-].[Na+].C(O)C>O>[CH:2]1[C:12]2[CH2:11][CH2:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[S:7](=[O:17])[C:6]=2[CH:5]=[C:4]([C:18]([OH:20])=[O:19])[CH:3]=1
Reactant: Cc1cc(C(=O)[O-])cc2c1CCc1ccccc1S2=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc2c(c1)S(=O)c1ccccc1CC2

Procedure:
520 Mg. methyl-10,11-dihydrodibenzo[b,f]thiepin-3-carboxylate 5-oxide is stirred at 65° C. in a mixture of 20 cc. 20% aqueous sodium hydroxide and 20 cc. ethanol until a clear solution results (1 hour). The mixture is diluted with water, extracted with ether, then acidified with hydrochloric acid. The white precipitate is filtered and dried to yield 245 mg. of material which is recrystallized from methanol to yield 180 mg., m.p. 261°-265° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2.[SH:18][C:19]1[NH:20][C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=1>>[N:20]1[C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[NH:23][C:19]=1[S:18][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2
Reactant: O=C1CCc2cc(OCCCCCl)ccc2N1
Reactant: Sc1nc2ccccc2[nH]1
Product: O=C1CCc2cc(OCCCCSc3nc4ccccc4[nH]3)ccc2N1

Procedure:
Prepared analogous to Example 1 from 6-(4-chlorobutoxy)-3,4-dihydro-carbostyril (m.p. 147°-148° C.) and 2-mercapto-benzimidazole.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][C@@H:7]([C@H:9]([C@@H:11]([C@@H:13]([CH2:15][OH:16])[OH:14])[OH:12])[OH:10])[OH:8])[CH2:2][CH2:3][CH3:4].Cl>O>[CH2:1]([NH:5][CH2:6][C@@H:7]1[O:8][C@:13]([OH:14])([CH2:15][OH:16])[C@@H:11]([OH:12])[C@@H:9]1[OH:10])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: Cl
Solvent: O
Product: CCCCNC[C@@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O
Temperature: 15 °C
Reaction time: 77 h
Yield: 75 %

Procedure:
A reaction solution is prepared by adding 46 gm N-n-butylglucamine to 620 ml of water in a 1-L bioreactor. The suspension is adjusted to pH 5 (with concentrated hydrochloric acid) and cooled to about 15° C. A total of 30 gm (wet weight) of washed G. oxydans cell paste is added and the reaction mixture is agitated (350 rpm) and aerated (0.2 vvm) while controlling the temperature at 15° C. and pH at 5. After 77 hours, the HPLC assay indicates that over 97% of the substrate has been converted for a 75% yield of 6-n-butylamino-6-deoxy-α-L-sorbofuranose.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9]2)=[O:4].[I-].[K+].C(N(CC)CC)C.[CH2:25]([CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(#N)C>[CH2:25]([CH:32]1[CH2:37][CH2:36][N:35]([CH2:2][C:3]([NH:5][C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10](=[O:15])[CH2:9]3)=[O:4])[CH2:34][CH2:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(CCl)Nc1ccc2c(c1)CC(=O)N2
Reactant: c1ccc(CC2CCNCC2)cc1
Agent: [I-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(CN1CCC(Cc2ccccc2)CC1)Nc1ccc2c(c1)CC(=O)N2
Yield: 64.2 %

Procedure:
A mixture of 0.9 g (4 mmol) of 2-chloro-N-(2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide, 0.7 g (4 mmol) of potassium iodide, 0.6 ml (4 mmol) of triethylamine, 0.53 ml (3 mmol) of 4-benzyl-piperidine and 50 ml of acetonitrile is refluxed for 20 hours. The reaction mixture is concentrated and 30 ml of water and 30 ml of chloroform are added to the residue. The organic layer is separated and the water phase is extracted three times with 10 ml of chloroform. The combined organic layers are dried over sodium sulfate, concentrated and the residue is treated with diethylether and the precipitated crystals are filtered off to yield 0.7 g (64%) of the title compound. Melting Point: 176-180° C. (diethylether)
Reaction SMILES: CO[C:3]1([O:9][CH3:10])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.[C:11]([N+:15]#[C-])(C)(C)C.C(=O)([O-])O.[Na+]>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:10][O:9][C:3]1([C:11]#[N:15])[CH2:4][CH2:5][O:6][CH2:7][CH2:8]1
Reactant: [C-]#[N+]C(C)(C)C
Reactant: COC1(OC)CCOCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC1(C#N)CCOCC1
Temperature: -78 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
Under an argon atmosphere, 4,4-dimethoxytetrahydropyran (4.39 g, 30.0 mmol) was dissolved in dichloromethane (60 mL), and tert-butyl isocyanide (3.73 mL, 33.0 mmol) and titanium tetrachloride (3.95 mL, 36.8 mmol) were added thereto at −78° C., and then, the mixture was stirred overnight at room temperature. To the mixture, an aqueous sodium hydrogen carbonate solution was added, and the mixture was filtered through Celite, and then, the filtrate was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=80/20) to give 4-methoxytetrahydropyran-4-carbonitrile (3.30 g, 23.4 mmol, yield: 78%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][CH2:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:4])([CH3:3])[CH3:2].[CH:18](I)([CH3:20])[CH3:19]>>[C:1]([O:5][C:6](=[O:17])[CH:7]([CH:18]([CH3:20])[CH3:19])[CH2:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CCNC(=O)OC(C)(C)C
Reactant: CC(C)I
Product: CC(C)C(CNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Yield: 42 %

Procedure:
N-t-Butyloxycarbonyl-β-alanine t-butyl ester (2.0 g) was isopropylated by the same procedure as in Comparative Example 4-(1) using isopropyl iodide (1.8 ml) to yield an oil of N-t-butyloxycarbonyl-α-isopropyl-β-alanine t-butyl ester (990 mg, 42%).
Reaction SMILES: C[CH:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]2[CH:14]=[CH:15][CH:16]=[CH:17][C:3]1=2.CCN(CC)CC.[Si]([I:29])(C)(C)C.II>C(Cl)Cl>[I:29][N:7]1[C:8](=[O:9])[CH2:2][C:3]2[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=2[C:5]2[CH:13]=[CH:12][CH:11]=[CH:10][C:6]1=2
Reactant: C[Si](C)(C)I
Reactant: CC1C(=O)Nc2ccccc2-c2ccccc21
Agent: II
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1Cc2ccccc2-c2ccccc2N1I
Temperature: 7.5 °C

Procedure:
A solution of 5,7-dihydro-6H-dibenz[b,d]azepin-6-one (1.0 g, 4.77 mmol) (Example 3-A) and Et3N (2.66 mL, 19.12 mmol) was stirred for 5.0 minutes at −15° C. in CH2Cl2 and treated with TMSI (1.36 mL, 9.54 mmol). After stirring for 15 minutes I2 (1.81 g, 7.16 mmol) was added in a single portion and the reaction allowed to warm to 5-10° C. over 3 h. The reaction was quenched with sat. Na2SO3, diluted with CH2Cl2 and separated. The organics were washed with Na2SO3 and NaHSO3 and dried over MgSO4. After filtration, the organics were concentrated to approximately 20 mL and diluted with an additional 20 mL of hexanes. The title compound was isolated as a tan precipitate by filtration.
Reaction SMILES: O[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:3]=12.P(Cl)(Cl)([Cl:25])=O>>[Cl:25][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:3]=12
Reactant: CCOC(=O)c1cnc2c(c1O)CCCCCCCCCC2
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cnc2c(c1Cl)CCCCCCCCCC2

Procedure:
A solution of 2 g of ethyl 5,6,7,8,9,10,11,12,13,14-decahydro-4-hydroxycyclododeca[b]pyridine-3-carboxylate in 25 ml phosphorus oxychloride is refluxed for 2 hours and evaporated to dryness under reduced pressure. The residue is dissolved in methylene chloride, treated with ice and basified with saturated sodium carbonate solution. The layers are separated, the aqueous phase re-extracted with methylene chloride, and the combined organic layers dried with magnesium sulfate, filtered, and evaporated to dryness to obtain ethyl 4-chloro-5,6,7,8,9,10,11,12,13,14-decahydrocyclododeca[b]pyridine-3-carboxylate as an oil.
Reaction SMILES: [CH2:1]([NH:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][C:10]1([F:16])[F:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-].[Na+].C(N(CC)CC)C.Cl[CH2:27][CH2:28][CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=1>>[CH2:1]([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:27][CH2:28][CH2:29][O:30][C:31]2[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=2)[CH2:11][C:10]1([F:16])[F:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1ccc(OCCCCl)cc1
Reactant: FC1(F)CNCCC1NCc1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Product: Fc1ccc(OCCCN2CCC(NCc3ccccc3)C(F)(F)C2)cc1
Temperature: 120 °C
Reaction time: 30 h
Yield: 48.1 %

Procedure:
In a 100 mL flask, a mixture of 1.22 g (5.4 mmol) of benzyl-(3,3-difluoro-piperidin-4-yl)amine 14, 0.81 g (5.4 mmol; 1 equiv) of sodium iodide, 2.73 g (27.0 mmol; 5 equiv) of triethylamine and 1.05 g (5.4 mmol; 1 equiv) of 1-(3-chloropropoxy)-4-fluorobenzene in 70 mL was stirred at 120° C. during 30 hours. Another portion of 2.73 g (27.0 mmol; 5 equiv) of triethylamine was added and the mixture stirred at 120° C. during 16 hours. Then 1.05 g (5.4 mmol; 1 equiv) of 1-(3-chloropropoxy)-4-fluorobenzene was added and the mixture was stirred at 120° C. during 54 hours until the reaction was completed. The solvent was removed under vacuum and the crude oil was redissolved in 100 mL of EtOAc and washed with brine and dried over MgSO4. Filtration of the solids and evaporation of the solvent resulted in a crude oil which was purified via flash chromatography (hexane/EtOAc 1:1, Rf=0.19-0.38) yielding 1.00 g (2.6 mmol; 49% yield) of benzyl-{3,3-difluoro-1-[3-(4-fluoro-phenoxy)propyl]piperidin-4-yl}amine 15 as a brown oil.
Reaction SMILES: C(OP([CH:9]([F:11])[F:10])(=O)OCC)C.C([Li])(C)(C)C.[OH:17][C:18]1[CH:35]=[CH:34][C:33]2[C@:32]3([CH:36]=O)[C@H:23]([C@H:24]4[C@@:28]([CH2:30][CH2:31]3)([CH3:29])[CH2:27][C@H:26]([OH:38])[CH2:25]4)[CH2:22][CH2:21][C:20]=2[CH:19]=1.[Cl-].[NH4+]>C(COC)OC.CCCCC>[F:11][C:9]([F:10])=[CH:36][C@:32]12[CH2:31][CH2:30][C@@:28]3([CH3:29])[C@@H:24]([CH2:25][C@@H:26]([OH:38])[CH2:27]3)[C@@H:23]1[CH2:22][CH2:21][C:20]1[CH:19]=[C:18]([OH:17])[CH:35]=[CH:34][C:33]2=1
Reactant: CCOP(=O)(OCC)C(F)F
Reactant: C[C@]12CC[C@]3(C=O)c4ccc(O)cc4CC[C@H]3[C@@H]1C[C@@H](O)C2
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: CCCCC
Solvent: COCCOC
Product: C[C@]12CC[C@]3(C=C(F)F)c4ccc(O)cc4CC[C@H]3[C@@H]1C[C@@H](O)C2
Temperature: -75 °C

Procedure:
1.5 ml of dimethoxyethane (molecular sieve), 0.3 ml of pentane and 0.13 ml (0.77 mmol) of diethyl(difluoromethyl)-phosphonate are introduced into a reaction flask that was rendered inert, and cooled to about −75° C. After 0.72 ml (1.07 mmol) of tert-butyllithium (1.5 M in pentane) is added and after 30 minutes of reaction time, 0.14 g (0.31 mmol) of 3,16α-dihydroxy-estra-1,3,5(10)-triene-9-carbaldehyde, dissolved in a mixture of 1.5 ml of dimethoxyethane/0.3 ml of pentane, is added to the reaction solution. The reaction solution is refluxed until the reaction is completed. After being added into cooled ammonium chloride solution, it is extracted with ethyl acetate. The organic phase is concentrated by evaporation under vacuum, the residue is taken up in 5 ml of methanol and mixed with 0.5 ml of dilute hydrochloric acid (1/1). Ethyl acetate is added to the reaction solution, the organic phase is washed with sodium bicarbonate solution and concentrated by evaporation under vacuum. The crude product that is obtanied is purified by column chromatography on silica gel (cyclohexane/ethyl acetate, 2/1).
Reaction SMILES: O[C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[N:8]1[C:32](=[O:33])[C:11]2=[CH:12][N:13]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH:31]=[CH:30][CH:29]=[N:28]4)=[CH:23][CH:22]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:10]2=[N:9]1.COCCN(S(F)(F)[F:44])CCOC.C(=O)(O)[O-].[Na+]>ClCCl>[F:44][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[N:8]1[C:32](=[O:33])[C:11]2=[CH:12][N:13]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH:31]=[CH:30][CH:29]=[N:28]4)=[CH:23][CH:22]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:10]2=[N:9]1
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: O=c1c2cn(Cc3ccc(-n4cccn4)cc3)c3ccccc3c-2nn1[C@@H]1CCCC[C@H]1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=c1c2cn(Cc3ccc(-n4cccn4)cc3)c3ccccc3c-2nn1[C@@H]1CCCC[C@@H]1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
(±)-2-(trans-2-Hydroxycyclohexyl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one (Example 508, 0.15 g, 0.35 mmol) was dissolved in dichloromethane (5 mL), cooled to 0° C. and treated with bis(2-methoxyethyl)aminosulfur trifluoride (0.15 mL, 0.70 mmol, 2 equiv). The mixture was stirred at 0° C. for 30 minutes and then treated with additional bis(2-methoxyethyl)aminosulfur trifluoride (75 μL, 0.35 mmol, 1 equiv). After stirring for an additional 30 minutes, the mixture was treated with sodium bicarbonate (5 mL, aqueous saturated) and stirred vigorously for 15 minutes. The mixture was poured into sodium bicarbonate (75 mL, aqueous saturated) and extracted with dichloromethane (2×75 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 85:15; ethyl acetate:methanol), providing the titled compound: 1H-NMR (400 MHz, CDCl3) δ 8.39 (1H, s), 8.38-8.35 (1H, m), 7.89 (1H, d, J=2.5 Hz), 7.71 (1H, d, J=1.8 Hz), 7.69 (2H, d, J=8.6 Hz), 7.47-7.42 (2H, m), 7.40-7.36 (1H, m), 7.28-7.26 (2H, m), 6.46 (1H, dd, J=2.4, 1.8 Hz), 5.45 (2H, s), 5.03 (1H, dtd, J=49.9, 10.6, 5.0 Hz), 4.61-4.52 (1H, m), 2.34-2.27 (1H, m), 2.06-1.98 (2H, m), 1.91-1.80 (2H, m), 1.74-1.59 (1H, m), 1.52-1.43 (2H, m) ppm; high resolution mass spectrometry (ES+) m/z 442.2051 [(M+H)+; calculated for C26H25FN5O: 442.2038].
Reaction SMILES: [CH3:1][C:2]([CH3:29])([OH:28])[CH2:3][N:4]([S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:21])=[O:20])[C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:6]=1[O:15]COC>C1COCC1.Cl.C(OCC)(=O)C>[CH3:1][C:2]([CH3:29])([OH:28])[CH2:3][N:4]([S:19]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)(=[O:20])=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:12])[F:13])=[CH:7][C:6]=1[OH:15]
Reactant: COCOc1cc(C(F)(F)F)ccc1N(CC(C)(C)O)S(=O)(=O)c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(O)CN(c1ccc(C(F)(F)F)cc1O)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 85.2 %

Procedure:
To a solution of 1,1-dimethyl-2-[N-(2-methoxymethoxy-4-trifluoromethylphenyl)-Phenylsulfonylamino]ethanol (380 mg; prepared in Reference Example 22.) in THF (4.0 ml), 6N HCl (0.8 ml) was added. The mixture was stirred for 2 days at room temperature. The reaction mixture was diluted with ethyl acetate, washed, dried over and concentrated under the reduced pressure. The residue was purified on silica gel column chromatography (hexane:AcOEt=2:1) to give the title compound (291 mg) having the following physical data.
Reaction SMILES: [C:1]([C:3]1([CH3:17])[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1)#[CH:2].Br[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1.C(OCC)(=O)C>C(Cl)Cl>[CH3:17][C:3]1([C:1]#[C:2][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1
Reactant: Brc1cccnc1
Reactant: C#CC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C#Cc1cccnc1)O2
Reaction time: 18 h

Procedure:
Rac-3,4-dihydro-2-ethynyl-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol, 4,6g, was reacted as described in Example 4 with 4.74 g of 3-bromopyridine. The reaction time was extended to 18 hours. The product was isolated by chromatography over 150 g of silica gel using 10 % (v/v) of ethyl acetate in methylene chloride for elution. Crystallization of the combined clean fractions from ethyl acetate/hexane gave off-white crystals with m.p. 172°-175° C. The analytical sample was recrystallized from tetrahydrofuran/hexane and had m.p. 175-178° C.
Reaction SMILES: [CH2:1](N(CC)CC)C.[Cl:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=1.ClC(OC)=O>ClCCl>[Cl:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([O:15][CH3:1])=[O:14])=[CH:11][N:10]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: CCN(CC)CC
Agent: COC(=O)Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylamine (28.4 g) was added to a solution of 6-chloronicotinic acid (40 g) in dry dichloromethane (900 ml). The mixture was cooled in an ice bath and methyl chloroformate (26.8 g) was added dropwise. The mixture was stirred at room temperature overnight, washed in turn with water, aqueous sodium hydrogen carbonate and brine. The organic phase was dried over magnesium sulfate, filtered and evaporated to give methyl 6-chloronicotinate.