Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([SiH](CC)CC)C.[F:8][C:9]([F:32])([C:13]([F:31])([F:30])[C:14]([F:29])([F:28])[C:15]([F:27])([F:26])[C:16]([F:25])([F:24])[C:17]([F:23])([F:22])[C:18]([F:21])([F:20])[F:19])[C:10](Cl)=[O:11]>[Pd].C([SiH](CC)CC)C>[C:9]([CH:10]=[O:11])([C:13]([C:14]([C:15]([C:16]([C:17]([C:18]([F:19])([F:20])[F:21])([F:22])[F:23])([F:25])[F:24])([F:27])[F:26])([F:29])[F:28])([F:31])[F:30])([F:32])[F:8]
Reactant: O=C(Cl)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: [Pd]
Agent: CC[SiH](CC)CC
Product: O=CC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 112.9 %

Procedure:
A sample of triethylsilane (4.24 g, 36.5 mmol) was cooled to 0° C. and treated with 10% Pd/C (0.35 g) . After the exotherm subsided, perfluorooctanoyl chloride (15.8 g, 36.5 mmol) was added dropwise, controlling the temperature below ca. 6°-8° C. The mixture was stirred for 1.0 hr at 0° C., Another 0.59 g triethylsilane was added, and the mixture was stirred for 1.5 hr. An additional 0.13 g of triethylsilane was added. After 1.0 hr, vacuum transfer gave 16.4 g of liquid which was cooled at -25° C. for several hours. The top liquid layer was removed from the solid to provide ca. 10.5 g of the titled product. 19F NMR: -81.3 (t of t's, J=9.8, 2.3), -121.8 (m), -122.3 (m), -123.0 (m), -123.7 (m), -125.4 (t of m's, with JFCCH =3 Hz), -126.5 (m).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([NH:9][C:10]([C:12]2[N:13]=[CH:14][O:15][C:16]=2[C:17]2[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=2)=[O:11])C=N1.[NH:24]1C=C(N)N=[CH:25]1>>[NH2:1][CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([NH:9][C:10]([C:12]2[N:13]=[CH:14][O:15][C:16]=2[C:17]2[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=2)=[O:11])[N:24]=[CH:25]1
Reactant: Cc1cccc(-c2ocnc2C(=O)Nc2cnn(CCN)c2)c1
Reactant: Nc1c[nH]cn1
Product: Cc1cccc(-c2ocnc2C(=O)Nc2cn(CCN)cn2)c1

Procedure:
The title compound was synthesized according to above mentioned procedure for N-(1-(2-aminoethyl)-1H-pyrazol-4-yl)-5-(m-tolyl)oxazole-4-carboxamide, starting from 1H-imidazol-4-amine. LC-MS conditions B: tR=0.47 min, [M+H]+=312.29.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[C:6]([N+:11]([O-])=O)[C:5]=1[NH2:14].[BH4-].[Na+]>CO.O.[Ni](Cl)Cl>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[C:6]([NH2:11])[C:5]=1[NH2:14]
Reactant: COC(=O)c1cc(Br)cc([N+](=O)[O-])c1N
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1cc(Br)cc(N)c1N
Temperature: 0 °C

Procedure:
To a solution of 2-amino-5-bromo-3-nitro-benzoic acid methyl ester (5 g, 18.18 mmol) in methanol (15 mL) was added nickel chloride (10.8 g, 45.4 mmol) and was cooled to 0° C. To this cold solution, sodium borohydride (3.45 g, 90 mmol) was added in small portions. After the addition, the reaction mixture was diluted with water, extracted with ethyl acetate. The combined organic layers were dried, concentrated and the resulting residue was purified by column chromatography using 30% ethyl acetate in hexane to obtain the title compound as grey coloured solid.
Reaction SMILES: S(Cl)([Cl:3])=O.[Br:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([OH:15])=O)[CH:9]=[CH:10][CH:11]=1>C(Cl)Cl>[Br:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([Cl:3])=[O:15])[CH:9]=[CH:10][CH:11]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)Cc1cccc(Br)c1
Solvent: ClCCl
Product: O=C(Cl)Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.3 %

Procedure:
Thionyl chloride (2.035 mL, 27.90 mmol) was added to 2-(3-bromophenyl)acetic acid (1.500 g, 6.98 mmol) in DCM (30 mL). The resulting solution was stirred at room temperature for 18 hours. The resulting mixture was evaporated to dryness and the residue was azeotroped with toluene to afford crude product (1.570 g, 96% yield), which was used without further purification.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[N:14]([S:30]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)(=[O:32])=[O:31])[C:15]([C:17]4[CH2:18][CH2:19][N:20]([C:23](OC(C)(C)C)=[O:24])[CH2:21][CH:22]=4)=[CH:16][C:9]=23)[C:5]([C:39]2[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=2)=[N:4]1)[CH3:2].Cl.[N:49]1(C(Cl)=O)[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1>O1CCOCC1>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[N:14]([S:30]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)(=[O:32])=[O:31])[C:15]([C:17]4[CH2:18][CH2:19][N:20]([C:23]([N:49]5[CH2:54][CH2:53][O:52][CH2:51][CH2:50]5)=[O:24])[CH2:21][CH:22]=4)=[CH:16][C:9]=23)[C:5]([C:39]2[CH:40]=[CH:41][C:42]([N+:45]([O-:47])=[O:46])=[CH:43][CH:44]=2)=[N:4]1)[CH3:2]
Reactant: CCn1cc(-c2ccnc3c2cc(C2=CCN(C(=O)OC(C)(C)C)CC2)n3S(=O)(=O)c2ccccc2)c(-c2ccc([N+](=O)[O-])cc2)n1
Reactant: O=C(Cl)N1CCOCC1
Agent: Cl
Solvent: C1COCCO1
Product: CCn1cc(-c2ccnc3c2cc(C2=CCN(C(=O)N4CCOCC4)CC2)n3S(=O)(=O)c2ccccc2)c(-c2ccc([N+](=O)[O-])cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
A solution of 1,1-dimethylethyl 4-[4-[1-ethyl-3-(4-nitrophenyl)-1H-pyrazol-4-yl]-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-3,6-dihydro-1(2H)-pyridinecarboxylate (0.38 mmol) methylene chloride (1 mL) was treated with 4N hydrochloric acid in dioxane (1 mL) and stirred for 1 h at room temperature. The reaction was concentrated in vacuo and evaporated one time from methylene chloride. The resultant residue was suspended in pyridine (5 mL) and treated with 4-morpholine carbonyl chloride (3.00 mmol) and stirred 48 h. The reaction was concentrated and purification of the residue by Gilson reverse phase HPLC provided the title compound (55%). ESMS [M+H]+: 668.4
Reaction SMILES: [CH2:1]([O:8][N:9]1[C@@H:13]([CH:14]([CH3:16])[CH3:15])[CH2:12][C@@H:11]([NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)(=[O:20])=[O:19])[C:10]1=[O:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH2:39][CH2:40][CH3:41].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH2:1]([O:8][N:9]1[C@@H:13]([CH:14]([CH3:16])[CH3:15])[CH2:12][C@@H:11]([N:17]([CH2:39][CH2:40][CH3:41])[S:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:28]=[CH:29][C:30]([C:33]([F:34])([F:35])[F:36])=[CH:31][CH:32]=3)=[CH:23][CH:22]=2)(=[O:20])=[O:19])[C:10]1=[O:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)[C@H]1C[C@@H](NS(=O)(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)C(=O)N1OCc1ccccc1
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCN([C@@H]1C[C@H](C(C)C)N(OCc2ccccc2)C1=O)S(=O)(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1

Procedure:
N-[(3R,5R)-1-(Benzyloxy)-5-isopropyl-2-oxopyrrolidinyl]-4′-(trifluoromethyl)[1,1′-biphenyl]-4-sulfonamide (0.030 g, 0.056 mmoles, Example 27b), 1-iodopropane (0.033 mL, 0.34 mmoles), cesium carbonate (0.028 g, 0.085 mmoles) and anhydrous N,N-dimethylformamide (0.40 mL) was stirred at 55° C. (oil temperature) over night, concentrated by rotary evaporation, taken up diethylether and washed with water once. The aqueous phase was washed with a second portion of diethylether, the combined organic phases were washed with brine, dried with potassium carbonate, filtered and concentrated by rotary evaporation. Flash chromatography of the crude product on silica using dichloromethane-methanol (99:1) as eluent gave the title compound as a colourless oil. LC-MS (APCI) m/z 575 (M+1). 1H NMR (CDCl3) δ 8.10 (d, J=9 Hz, 2H), 7.73 (d, J=9 Hz, 2H), 7.72 (app s, 5H), 7.43–7.34 (m, 4H), 5.09 (d, J=10 Hz, 1H), 4.92 (d, J=10 Hz, 1H), 4.54 (t, J=10 Hz, 1H), 3.34 (ddd, J1=4 Hz, J2=6 Hz, J3=10 Hz, 1H), 3.12 (t, J=8 Hz, 2H), 2.30 (ddd, J1=7 Hz, J2=10 Hz, J3=13 Hz, 1H), 2.24–2.14 (m, 1H), 1.88–1.58 (m's, 3H), 0.90 (d, J=7 Hz, 3H), 0.89 (d, J=7 Hz, 3H) and 0.84 (t, J=7 Hz, 3H) ppm.
Reaction SMILES: C(OCCO)(=O)C(C)=C.[CH2:10]([C:13]1(S(O)(=O)=O)[CH2:18][C:17](=[O:19])[O:16][C:14]1=[O:15])[CH:11]=[CH2:12]>>[CH2:10]([CH:13]1[CH2:18][C:17](=[O:19])[O:16][C:14]1=[O:15])[CH:11]=[CH2:12]
Reactant: C=CCC1(S(=O)(=O)O)CC(=O)OC1=O
Agent: C=C(C)C(=O)OCCO
Product: C=CCC1CC(=O)OC1=O

Procedure:
By procedure 7)a) above, β-hydroxyethyl methacrylate is esterified with an equimolar amount of allyl-sulfo-succinic anhydride obtained by the sulfonation of allyl-succinic acid anhydride obtained from propene and maleic anhydride by a procedure analogous to that of 8)b) hereinabove.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25](Cl)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:14])=[O:13])(C)(C)C.[C:31]1([CH3:40])[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][NH2:39])=[CH:33][CH:32]=1>>[NH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:39][CH2:38][CH2:37][C:34]3[CH:35]=[CH:36][C:31]([CH3:40])=[CH:32][CH:33]=3)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:13])=[O:14]
Reactant: CC(C)(C)OC(=O)NCCCN(Cc1cccc(-c2ccnc(Cl)n2)c1)S(C)(=O)=O
Reactant: Cc1ccc(CCN)cc1
Product: Cc1ccc(CCNc2nccc(-c3cccc(CN(CCCN)S(C)(=O)=O)c3)n2)cc1

Procedure:
Intermediate 4 was coupled to 2-p-tolyl-ethylamine following procedure F and the resulting product deprotected following procedure G. LC-MS showed the product had the expected M+H+ of 454. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 9.55 (br s, 1H) 8.1 (m, 2H) 7.6 (m, 4H) 7.2 (m, 4H) 4.4 (s, 2H) 3.81 (s, 2H) 3.37 (m, 2H) 2.97 (m, 4H) 2.94 (s, 3H) 2.25 (s, 3H) 1.75 (s, 2H) 1.69 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][NH:24][CH:25]([CH3:27])[CH3:26])[CH:18]=3)[CH:14]=[CH:13][N:12]=2)[CH:5]=[CH:4][C:3]=1[OH:28].[CH3:29][N:30]1[CH2:35][CH2:34][CH:33]([C:36](O)=[O:37])[CH2:32][CH2:31]1>>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=3)[CH2:23][N:24]([CH:25]([CH3:26])[CH3:27])[C:36]([CH:33]3[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]3)=[O:37])[CH:14]=[CH:13][N:12]=2)[CH:5]=[CH:4][C:3]=1[OH:28]
Reactant: CN1CCC(C(=O)O)CC1
Reactant: CC(C)NCc1cccc(-c2ccnc(NCCc3ccc(O)c(Cl)c3)n2)c1
Product: CC(C)N(Cc1cccc(-c2ccnc(NCCc3ccc(O)c(Cl)c3)n2)c1)C(=O)C1CCN(C)CC1

Procedure:
2-Chloro-4-(2-{4-[3-(isopropylamino-methyl)-phenyl]-pyrimidin-2-ylamino}-ethyl)-phenol (compound 132) was coupled with 1-methyl-piperidine-4-carboxylic acid following procedure D2. LC-MS showed the product had the expected M+H+ of 522. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 8.6 (s, 1H) 8.3 (m, 1H) 7.8 (m, 2H) 7.4 (m, 1H) 7.2 (s, 1H) 6.9 (m, 3H) 5.0 (s, br, 1H) 4.8 (m, 1H) 4.5 (d, 2H) 4.2 (m, 1H) 3.7 (m, 2H) 3.4 (s, 1H) 3.2 (m, 2H) 2.8 (m, 2H 2.5 (m, 5H) 2.0 (s, br, 2H) 1.9 (s, br, 1H) 1.2 (d, 3H) 1.0 (d, 3H).
Reaction SMILES: CS(O[CH:6]([CH:18]1[CH2:20][CH2:19]1)[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=O)=O.[OH-].[K+]>CS(C)=O>[N+:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH:8]1[CH2:7][CH:6]1[CH:18]1[CH2:20][CH2:19]1)([O-:17])=[O:16]
Reactant: CS(=O)(=O)OC(CCc1ccccc1[N+](=O)[O-])C1CC1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccccc1C1CC1C1CC1
Temperature: 0 °C
Reaction time: 5 h
Yield: 61 %

Procedure:
The 1-cyclopropyl-3-(2-nitrophenyl)-propyl methanesulfonate is dissolved in 15 ml of dimethyl sulfoxide and 0.17 g of potassium hydroxide (2.48 mmol) is added, and stirring is carried out for 5 hours at ambient temperature. The reaction mixture is added to ice-water. Extraction is carried out with ethyl acetate and the organic phase is dried over sodium sulfate and concentrated by evaporation. Chromatography on silica gel is carried out in order to remove by-products (eluant: ethyl acetate/hexane 1:15). After removal of the eluant, 0.28 g of 2-(2-nitrophenyl)-bicyclopropane (61% of theory) is obtained in the form of a brownish liquid (trans:cis ratio: 4.5:1). 1H-NMR of trans-2-(2-nitrophenyl)-bicyclopropane (CDCl3-ppm): 0.17/m/1H, 0.19/m/1H, 0.42/m/1H, 0.48/m/1H, 0.83/m/1H, 0.84/m/1H, 0.99/m/1H, 1.13/m/1H, 2.17/m/1H, 7.10/dd/1H, 7.25/m/1H, 7.45/m/1H, 7.78/dd/1H); 1H-NMR of cis-2-(2-nitrophenyl)-bicyclopropane (CDCl3-ppm): −0.09/m/1H, 0.02/m/1H, 0.06/m/1H, 0.27/m/1H, 0.71/m/1H, 0.85/m/1H, 0.98/m/1H, 1.10/m/1H, 2.53/m/1H, 7.35/m/1H, 7.45/m/1H, 7.52/m/1H, 7.92/dd/1H.
Reaction SMILES: Cl.[F:2][C:3]1[CH:24]=[CH:23][C:6]2[C:7]([CH2:10][CH2:11][CH2:12][N:13]3[CH2:22][CH2:21][C:16]4(OCC[O:17]4)[CH2:15][CH2:14]3)=[N:8][O:9][C:5]=2[CH:4]=1.O.Cl.[OH-].[Na+]>C(O)C>[F:2][C:3]1[CH:24]=[CH:23][C:6]2[C:7]([CH2:10][CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][C:16](=[O:17])[CH2:21][CH2:22]3)=[N:8][O:9][C:5]=2[CH:4]=1
Reactant: Fc1ccc2c(CCCN3CCC4(CC3)OCCO4)noc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C1CCN(CCCc2noc3cc(F)ccc23)CC1
Temperature: 25 °C
Yield: 93.7 %

Procedure:
A mixture of 51 g of 8-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-1,4-dioxa-8-azaspiro[4.5]decane hydrochloride, 100 ml of water, 100 ml of ethanol and 150 ml of 3N hydrochloric acid was heated at 75°-80° C. for 3 hrs and at ambient temperature overnight, with stirring. The mixture was cooled, basified with 3N sodium hydroxide solution and extracted with ethyl acetate-ether. The organic extracts were washed with water, saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated to give 37 g (96%) of product as an oil.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([NH:8][C@@H:9]([CH:13]([CH3:15])[CH3:14])[C:10]([OH:12])=O)=[N:5][CH:4]=1)=[O:2].[NH2:16][C@H:17]([C:19]([NH:21][C@H:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH3:23])=[O:20])[CH3:18].Cl.C(Cl)CCl.ON1C2N=CC=CC=2N=N1.CN1CCOCC1>C(Cl)Cl>[CH:1]([C:3]1[S:7][C:6]([NH:8][CH:9]([CH:13]([CH3:15])[CH3:14])[C:10]([NH:16][C@@H:17]([CH3:18])[C:19]([NH:21][C@@H:22]([CH3:23])[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:20])=[O:12])=[N:5][CH:4]=1)=[O:2]
Reactant: CC(C)[C@H](Nc1ncc(C=O)s1)C(=O)O
Reactant: C[C@H](N)C(=O)N[C@@H](C)C(=O)OC(C)(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)C(Nc1ncc(C=O)s1)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 42.1 %

Procedure:
To a material from Example 20 (560 mg, 1.227 mmol), H-Ala-Ala-OtBu.HCl (300 mg, 1.187 mmol), EDC (341 mg, 1.780 mmol), and 1-hydroxy-7-azabenzotriazole (97 mg, 0.712 mmol) in CH2Cl2 (12 mL) is added N-methylmorpholine (0.783 mL, 7.12 mmol) and the resulting solution is allowed to stir at room temp for 18 h. The solvent is removed in vacuo and the residue is purified by BIOTAGE® Silica gel chromatography on a 25 g Thompson Single Step silica cartridge using a linear gradient from 100% CH2Cl2 to 100% EtOAc over 12 column volumes to give 213 mg (42.1%) of the title compound as an off-white solid. LC/MS (Condition A): ret. T=3.17 min, (M+H)+ 427.22.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[O:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[O:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1.O.[OH-].[Na+]>C1COCC1>[O:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[O:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:18][NH2:19])=[CH:20][CH:21]=1
Reactant: N#Cc1ccc(OC2CCCCO2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: NCc1ccc(OC2CCCCO2)cc1

Procedure:
To a solution of lithium aluminum hydride (2.66 g, 70 mmol) in THF (2.00 mL) was added dropwise under ice cooling a solution of 4-(tetrahydropyran-2-yloxy)benzonitrile in THF (70 mL). The resulting solution was then refluxed for 1 hour. The resulting reaction solution was again cooled with ice, and then to the solution was added dropwise, in order, water (2.66 mL), 1 N aqueous sodium hydroxide (2.66 mL) and water (7.98 mL). Insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure, after which the residue was purified by silica gel column chromatography (chloroform methanol 7:1), to thereby yield 11.41 g of the title compound.
Reaction SMILES: [C:1]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][C@H:13]1[CH2:22][C@@H:21]([OH:23])[C@H:20](/[CH:24]=[CH:25]/[C@@H:26]([OH:32])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C@H:14]1[CH2:15]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[Pd]>[C:1]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][C@H:13]1[CH2:22][C@@H:21]([OH:23])[C@H:20]([CH2:24][CH2:25][C@@H:26]([OH:32])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C@H:14]1[CH2:15]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCC[C@H](O)/C=C/[C@@H]1[C@H]2Cc3cccc(OC(=O)c4ccccc4)c3C[C@H]2C[C@H]1O
Agent: [Pd]
Solvent: CO
Product: CCCCC[C@H](O)CC[C@@H]1[C@H]2Cc3cccc(OC(=O)c4ccccc4)c3C[C@H]2C[C@H]1O
Temperature: 25 °C
Reaction time: 5 h
Yield: 87 %

Procedure:
(1R,2R,3aS,9aS)-2,3,3a,4,9,9a-hexahydro-2-hydroxy-1-((S,E)-3-hydroxyoct-1-enyl)-1H-cyclopenta[b]naphthalen-5-yl benzoate (0.35 g, 0.8 mmol) in dry methanol (2.5 ml) was treated with 5% Pd/C (0.05 g, 20% wt) and stirred under hydrogen for 5 hours at room temperature. Then, the reaction mixture was filtered with celite pad. The solvent was evaporated off under vacuum. The crude product was purified by chromatography on silica gel using a mixture of hexane and ethyl acetate as a gradient eluent. Yield: 87%.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4](NC2C=CC(CP(=O)(OCC)OCC)=CC=2OC)[N:3]=1.[F:30][C:31]([F:53])([F:52])[CH2:32][O:33][P:34]([CH2:42][C:43]1[CH:48]=[CH:47][C:46]([NH2:49])=[C:45]([O:50][CH3:51])[CH:44]=1)(=[O:41])[O:35][CH2:36][C:37]([F:40])([F:39])[F:38].ClC1N=C(Cl)C(C(F)(F)F)=CN=1>>[Cl:1][C:2]1[C:7]([C:8]([F:10])([F:9])[F:11])=[CH:6][N:5]=[C:4]([NH:49][C:46]2[CH:47]=[CH:48][C:43]([CH2:42][P:34](=[O:41])([O:35][CH2:36][C:37]([F:38])([F:39])[F:40])[O:33][CH2:32][C:31]([F:30])([F:52])[F:53])=[CH:44][C:45]=2[O:50][CH3:51])[N:3]=1
Reactant: COc1cc(CP(=O)(OCC(F)(F)F)OCC(F)(F)F)ccc1N
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Agent: FC(F)(F)c1cnc(Cl)nc1Cl
Product: COc1cc(CP(=O)(OCC(F)(F)F)OCC(F)(F)F)ccc1Nc1ncc(C(F)(F)F)c(Cl)n1

Procedure:
This compound was prepared using the procedure for diethyl (4-{[4-chloro-5-(trifluoromethyl) pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate with Bis(2,2,2-trifluoroethyl) (4-amino-3-methoxybenzyl)phosphonate (Compound 114A) and 2,4-dichloro-5-(trifluoromethyl) pyrimidine. Purified using an ISCO Combiflash system eluting w/20-100% EtOAc in heptane and then MDP (ammonium bicarbonate basic buffer pH9). 1H NMR (DMSO-d6) δ ppm 9.73 (s, 1H), 8.69 (s, 1H), 7.47 (d, J=8.0 Hz, 1H), 7.03 (s, 1H), 6.90 (d, J=7.9 Hz, 1H), 4.67 (quin, J=8.5 Hz, 4H), 3.76 (s, 3H), 3.56 (d, J=22.1 Hz, 2H). MS (ES+): m/z 562.00/564.02 (100/38) [MH+]. HPLC: tR=3.86 min (ZQ3, polar—5 min).
Reaction SMILES: C([N:8]([CH2:32][CH:33]1[CH2:35][CH2:34]1)[C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([O:24][Si:25]([CH2:30][CH3:31])([CH2:28][CH3:29])[CH2:26][CH3:27])([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17])[CH2:11][CH2:10]1)C1C=CC=CC=1>C(O)(=O)C.[Pd]>[CH:33]1([CH2:32][NH:8][C@H:9]2[CH2:10][CH2:11][C@H:12]([C:15]([O:24][Si:25]([CH2:28][CH3:29])([CH2:30][CH3:31])[CH2:26][CH3:27])([C:16]([F:17])([F:18])[F:19])[C:20]([F:23])([F:22])[F:21])[CH2:13][CH2:14]2)[CH2:34][CH2:35]1
Reactant: CC[Si](CC)(CC)OC([C@H]1CC[C@H](N(Cc2ccccc2)CC2CC2)CC1)(C(F)(F)F)C(F)(F)F
Agent: [Pd]
Solvent: CC(=O)O
Product: CC[Si](CC)(CC)OC([C@H]1CC[C@H](NCC2CC2)CC1)(C(F)(F)F)C(F)(F)F

Procedure:
1 g (ca 2.0 mmol) of crude trans benzyl-cyclopropylmethyl-[4-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-cyclohexyl]-amine was dissolved in 50 mL of acetic acid, treated with 300 mg of Pd/C (10%) and hydrogenated overnight at atmospheric pressure under intense stirring. Filtration and evaporation of the solvent gave 775 mg (ca 82%) of crude trans cyclopropylmethyl-[4-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-cyclohexyl]-amine as a yellow oil, MS: 434 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[N:10][N:11]([C:13]3[CH2:18][CH2:17][C:16](=[O:19])[NH:15][N:14]=3)[CH:12]=2)[CH:5]=[CH:4][N:3]=1.[CH:27]1([C:30](Cl)=[O:31])[CH2:29][CH2:28]1>>[CH:27]1([C:30]([NH:1][C:2]2[CH:7]=[C:6]([C:8]3[C:9]([C:20]4[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=4)=[N:10][N:11]([C:13]4[CH2:18][CH2:17][C:16](=[O:19])[NH:15][N:14]=4)[CH:12]=3)[CH:5]=[CH:4][N:3]=2)=[O:31])[CH2:29][CH2:28]1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1cc(-c2cn(C3=NNC(=O)CC3)nc2-c2ccc(F)cc2)ccn1
Product: O=C1CCC(n2cc(-c3ccnc(NC(=O)C4CC4)c3)c(-c3ccc(F)cc3)n2)=NN1
Yield: 45.3 %

Procedure:
The reaction was carried out in the same manner as in Example 9 except for using 27.0 mg (0.077 mmol) of 4-(2-aminopyridin-4-yl)-3-(4-fluorophenyl)-1-(1,4,5,6-tetrahydro-6-oxopyridazin-3-yl)-1H-pyrazole obtained in Example 50 in place of 4-(2-aminopyridin-4-yl)-3-(4-fluorophenyl)-1-([1,2,4]triazolo[4,3-b]pyridazin-6-yl)-1H-pyrazole, and using 8.9 mg (0.085 mmol) of cyclopropylcarbonyl chloride in place of acetic anhydride to obtain 14.6 mg of the title compound as a white powder. (Yield: 45%)
Reaction SMILES: [CH2:1]([N:3]([C:11]([CH3:15])([CH3:14])[CH2:12][OH:13])[C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7])C.[CH3:16]C(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>>[CH3:1][N:3]([C:11]([CH2:15][CH3:16])([CH3:14])[CH:12]=[O:13])[C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Reactant: CCN(C(=O)OC(C)(C)C)C(C)(C)CO
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Product: CCC(C)(C=O)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.7 %

Procedure:
To a solution of tert-butyl ethyl(1-hydroxy-2-methylpropan-2-yl)carbamate (2.18 g, 10 mmol, 1.0 equiv) DCM (150 mL) was added Dess-martin periodinane (4.24 g, 10 mmol, 1.0 equiv) portionwise at 0° C. The resulting mixture was stirred for 4 h at room temperature. Saturated solutions of aqueous sodium hydrogencarbonate and sodium thiosulfate were added. The resulting mixture was stirred for 0.5 h. The organic phase was separated, washed with saturated sodium hydrogencarbonate, brine, dried over sodium sulfate and concentrated to give 1.5 g (71%) of tert-butyl methyl(2-ethyl-1-oxopropan-2-yl)carbamate as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][S:10]1(=[O:19])=[O:18].[Br:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>>[Br:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][N:11]1[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:9]([C:3]2[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[S:10]1(=[O:18])=[O:19]
Reactant: O=S1(=O)Nc2ccccc2N1c1c(F)cccc1F
Reactant: BrCCOCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=S1(=O)N(CCOCCBr)c2ccccc2N1c1c(F)cccc1F
Yield: 75.3 %

Procedure:
In an analogous manner to general procedure IV, 1-(2,6-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide (2.69 g, 9.5 mmol) was treated with 1-bromo-2-(2-bromoethoxy)ethane (3.6 mL, 28.6 mmol) and cesium carbonate (3.1 g, 9.5 mmol) to give 1-[2-(2-bromoethoxy)ethyl]-3-(2,6-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide as a clear oil (3.1 g, 76%). MS (ES) m/z 432.7.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[N:13]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:12]3[CH:19]=[C:20]([F:24])[C:21]([F:23])=[CH:22][C:11]=3[N:10]=2)=[C:6]([OH:8])[CH:7]=1.Br[CH2:26][C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][C:28]=1[F:35]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[N:13]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:12]3[CH:19]=[C:20]([F:24])[C:21]([F:23])=[CH:22][C:11]=3[N:10]=2)=[C:6]([CH:7]=1)[O:8][CH2:26][C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][C:28]=1[F:35]
Reactant: N#Cc1ccc(CBr)c(F)c1
Reactant: CC(C)(C)Cn1c(-c2ccc(Cl)cc2O)nc2cc(F)c(F)cc21
Product: CC(C)(C)Cn1c(-c2ccc(Cl)cc2OCc2ccc(C#N)cc2F)nc2cc(F)c(F)cc21

Procedure:
The title compound was prepared in analogy to Example 5, intermediate a, from 5-chloro-2-[1-(2,2-dimethyl-propyl)-5,6-difluoro-1H-benzoimidazol-2-yl]-phenol and 4-bromomethyl-3-fluoro-benzonitrile (CAS Reg. No. 105942-09-4). Light brown solid (95%). MS (Turbo Spray): m/z=483.8 (M+H).