Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C@H:9]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH3:10])[C:4](OCC)=[O:5].C(N(CC)CC)C.Cl[Si](C)(C)C>O1CCCC1>[Si:12]([O:11][C@@H:9]([C@@H:3]1[CH2:2][NH:1][C:4]1=[O:5])[CH3:10])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: CCOC(=O)[C@@H](CN)[C@@H](C)O[Si](C)(C)C(C)(C)C
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H]1CNC1=O
Reaction time: 24 h
Yield: 47.3 %

Procedure:
To a solution of ethyl (2S,3R)-2-aminomethyl-3-(t-butyldimethylsilyloxy)butanoate (1.38 g) and triethylamine (0.84 ml) in tetrahydrofuran (10 ml) was added dropwise chlorotrimethylsilane (0.76 ml) at room temperature. After stirring for 1 day, the precipitate was filtered and the filtrate was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (50 ml) and 1.1N t-butylmagnesium chloride in tetrahydrofuran (15 ml) was added dropwise thereto at room temperature. After stirring for 30 minutes, the reaction mixture was quenched with water (10 ml), and diluted with ethyl acetate (50 ml) and 1N hydrochloric acid in water (20 ml). The aqueous layer was separated and extracted twice with ethyl acetate (25 ml×2) and the combined organic layer was washed in turn with 1N hydrochloric acid in water (20 ml), saturated aqueous sodium bicarbonate (20 ml), water (20 ml) and brine (20 ml), dried over magnesium sulfate and evaporated under reduced pressure. The residue was column-chromatographed on silica gel (hexane-ethyl acetate=3:1) to give (3S)-3-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-azetidin-2-one (0.543 g).
Reaction SMILES: Cl.ClC1C=C(C)C2CNCCC=2N=1.FC(F)(F)S([O:19][C:20]1[CH:25]=[C:24]([CH:26]([CH3:28])[CH3:27])[CH:23]=[CH:22][C:21]=1[CH3:29])(=O)=O.C(Cl)(Cl)Cl.C([O-])([O-])=O.[Cs+].[Cs+]>C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+].[Cl-].[Na+].O.C1(C)C=CC=CC=1.C(O)(C)(C)C.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH:25]1[C:24]([CH:26]([CH3:28])[CH3:27])=[CH:23][CH:22]=[C:21]([CH3:29])[C:20]=1[OH:19]
Reactant: Cc1ccc(C(C)C)cc1OS(=O)(=O)C(F)(F)F
Agent: [Pd]
Agent: Cc1cc(Cl)nc2c1CNCC2
Agent: Cl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1ccc(C(C)C)cc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.8 %

Procedure:
To a suspension of 2-chloro-4-methyl-5,6,7,8-tetrahydro-1,6-naphthyridine hydrochloride (4.03 g, 18.39 mmol) in DCM (100 mL), 2 M aq Na2CO3 (100 mL) was added. After stirring for 30 min, the mixture was diluted with brine (200 mL). The products were extracted twice with DCM. The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. A suspension of the residue (3.25 g), 5-isopropyl-2-methylphenyl trifluoromethanesulfonate (11.42 g, 40.5 mmol), Pd2(dba)3.CHCl3 adduct (0.762 g, 0.736 mmol), rac-BINAP (0.945 g, 1.471 mmol) and Cs2CO3 (17.98 g, 55.2 mmol) in toluene (17 mL) and t-butanol (3 mL) was allowed to stir at 90° C. for 23 h under argon. The reaction was cooled to rt, and diluted with EtOAc and brine. The products were extracted three times with EtOAc. The combined organic layer was dried over Na2SO4, and filtered. The filtrate was added to 60 g of silica gel and then concentrated. The residue was washed with EtOAc on a funnel, and then the filtrate was concentrated. The residue was purified by flash column chromatography on 330 g of silica gel (with 25 g pre-column; eluent: heptane/EtOAc=100:0 to 80:20) to give the desired product along with 18 mol % of Carvacrol (2.97 g). The mixture was purified by flash column chromatography on 55 g of NH-modified silica gel (with 20 g of aminopropyl-modified silca gel as pre-column; eluent: heptane/EtOAc=100:0 to 90:10) to give 2-chloro-6-(5-isopropyl-2-methylphenyl)-4-methyl-5,6,7,8-tetrahydro-1,6-naphthyridine (2.50 g) as a yellow oil: 1H NMR (400 MHz, CDCl3) δ ppm 7.16 (d, J=7.83 Hz, 1 H), 6.99-7.00 (m, 2 H), 6.92-6.95 (m, 1 H), 3.98 (s, 2 H), 3.28 (t, J=5.81 Hz, 2 H), 3.12 (br t, J=5.68 Hz, 2 H), 2.84-2.94 (m, 1 H), 2.29 (s, 3 H), 2.20 (s, 3 H), 1.26 (d, J=6.82 Hz, 6 H); MS (ESI+) m/z 315.34 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]#[CH:32])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C.CO.[OH-].[Na+]>C1COCC1>[Br:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][N:9]2[CH2:10][CH2:11][C:6]([S:20]([C:23]3[CH:24]=[CH:25][C:26]([O:29][CH2:30][C:31]#[CH:32])=[CH:27][CH:28]=3)(=[O:22])=[O:21])([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]2)=[CH:18][CH:17]=1
Reactant: C#CCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(Cc3ccc(Br)cc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C#CCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(Cc3ccc(Br)cc3)CC2)cc1

Procedure:
1-(4-Bromo-benzyl)-4-(4-prop-2-ynyloxy-benzenesulfonyl)-piperdine-4-carboxylic acid was prepared starting from 1-(4-bromo-benzyl)-4-(4-prop-2-ynyloxy-benzene-sulfonyl)-piperdine-4-carboxylic acid ethyl ester (5 g, 9.59 mmol) dissolved in THF:methanol (150:50 ml) and 10 N NaOH (15 ml). The resulting reaction mixture was worked up as outlined in Example 1 (Step 7). Yield 3.4 g (72%); brown low melting solid; MS: 491.9 (M−H)−
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([O:13][CH:14]([F:16])[F:15])[N:10]([CH3:17])[N:9]=2)=[C:4]([Cl:18])[CH:3]=1.[N+:19]([O-])([OH:21])=[O:20]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:3]=[C:4]([Cl:18])[C:5]([C:8]2[CH:12]=[C:11]([O:13][CH:14]([F:16])[F:15])[N:10]([CH3:17])[N:9]=2)=[CH:6][C:7]=1[N+:19]([O-:21])=[O:20]
Reactant: O=[N+]([O-])O
Reactant: Cn1nc(-c2ccc(Cl)cc2Cl)cc1OC(F)F
Agent: O=S(=O)(O)O
Product: Cn1nc(-c2cc([N+](=O)[O-])c(Cl)cc2Cl)cc1OC(F)F
Reaction time: 1 h

Procedure:
3.0 g (10.2 mmol) of 1,3-dichloro-4-(5-difluoromethoxy-1-methyl-1H-pyrazol-3-yl)benzene were dissolved in 10 ml of concentrated sulfuric acid. At 0° C., 0.7 g (11.2 mmol) of 100% strength nitric acid was added dropwise, and the mixture was then stirred at 0° C.-10° C. for 1 h. The reaction mixture was then poured onto ice and the precipitate was filtered off with suction, washed with 100 ml of water and dried. This gave 3.24 g of the nitrobenzene as a yellow solid of melting point 134-137° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].[CH3:32][O:33][CH2:34][CH2:35][NH2:36]>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:36][CH2:35][CH2:34][O:33][CH3:32])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31]
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: COCCN
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCNc1nc(-c2ccc(F)cc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Yield: 46.7 %

Procedure:
A solution of the product of Example 48 (150 mg, 0.34 mmol) and 2-methoxy-ethylamine (0.09 mL, 1.01 mmol) in DMF (2 mL) was stirred 23° for 16 h. The mixture was diluted with EtOAc and washed with H2O to give the crude material, which was purified as described in Example 198 to give the desired product 70 mg (47%). LC-MS: 441.2 (MH+, m/z), 2.10 (Rt, min).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[C:13](Cl)[C:12]([N+:16]([O-:18])=[O:17])=[C:11]([Cl:19])[C:10]=2[Cl:20])=[CH:4][N:3]=1.NC1N=C(N)C(C2C=CC=C(Cl)C=2Cl)=CN=1>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([N+:16]([O-:18])=[O:17])=[C:11]([Cl:19])[C:10]=2[Cl:20])=[CH:4][N:3]=1
Reactant: Nc1ncc(-c2cc(Cl)c([N+](=O)[O-])c(Cl)c2Cl)c(N)n1
Agent: Nc1ncc(-c2cccc(Cl)c2Cl)c(N)n1
Product: Nc1ncc(-c2ccc([N+](=O)[O-])c(Cl)c2Cl)c(N)n1

Procedure:
This compound was made in an analogous manner to the compound of Example 5 from 2,4-diamino-5-(2,3-dichlorophenyl)pyrimidine (Example 21). The reaction gave a mixture of the 4-nitro and 5-nitro derivatives from which the title compound was separated by column chromatography (SiO2, EtOAc), mp. 237°-9° C. Also separated in this manner was 2,4-diamino-5-(2,3-dichloro-5-nitrophenyl)pyrimidine, mp. 264°-6° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([OH:10])(=O)=[O:8])[CH:2]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:12]>O=P(Cl)(Cl)Cl.C(Cl)(Cl)Cl.Cl>[ClH:12].[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([Cl:12])(=[O:10])=[O:8])[CH:2]=1
Reactant: O=S(=O)(O)c1cccnc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=S(=O)(Cl)c1cccnc1
Temperature: 120 °C
Yield: 0 %

Procedure:
Pyridine-3-sulfonic acid (3.00 g, 18.8 mmol) and PCl5 (4.79 g, 23.0 mmol) were mixed in POCl3 (6 mL). The reaction was stirred and refluxed at 120° C. over night (15 h). Cooled to rt., diluted with CHCl3 (20 mL) and saturated with HCl (g). This gave a white precipitation, which was filtered off, washed with CHCl3 and dried under reduced pressure to give the title compound (3.36 μg, 83%) as a white powder.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH2:18][C@H:17]([C@:22]([NH:30]C(=O)OC(C)(C)C)([CH3:29])[CH2:23][O:24][P:25]([OH:28])([OH:27])=[O:26])[CH2:16][CH2:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.Cl>O>[P:25]([OH:27])([OH:28])([O:24][CH2:23][C@:22]([NH2:30])([C@@H:17]1[CH2:16][CH2:15][C:14]2[C:19](=[CH:20][CH:21]=[C:12]([O:11][C@H:8]3[CH2:9][CH2:10][C@H:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:6][CH2:7]3)[CH:13]=2)[CH2:18]1)[CH3:29])=[O:26]
Reactant: CC(C)(C)OC(=O)N[C@@](C)(COP(=O)(O)O)[C@@H]1CCc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2C1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3c(c2)CC[C@@H]([C@@](C)(N)COP(=O)(O)O)C3)CC1

Procedure:
tert-Butyl (R)-2-((R)-6-(trans-4-tert-butylcyclohexyloxy)-1,2,3,4-tetrahydronaphthalen-2-yl)-1-(phosphonooxy)propan-2-ylcarbamate (38.4 mg, 0.0000712 mol) was dissolved in acetic acid (2.2 mL, 0.039 mol) and 10 M hydrogen chloride in water (0.6 mL) was added and the mixture was stirred for Id. Lyophilizing gave (R)-2-amino-2-((R)-6-(trans-4-tert-butylcyclohexyloxy)-1,2,3,4-tetrahydronaphthalen-2-yl)propyl dihydrogen phosphate as a white solid (16.4 mg, 52%). LCMS: Rf=1.57 min 214 nm (440.22, [M+1]+, 100%). 1H NMR (400 MHz, MeOD) δ=7.03 (d, J=8.3 Hz, 1H), 6.70 (d, J=10.9 Hz, 1H), 6.66 (s, 1H), 4.26 (dd, J=5.3, 11.1 Hz, 1H), 4.18-4.09 (m, 1H), 4.06 (dd, J=4.2, 11.0 Hz, 1H), 2.98-2.64 (m, 4H), 2.27-2.14 (m, 3H), 2.05 (d, J=10.2 Hz, 1H), 1.89 (d, J=12.3 Hz, 2H), 1.62-1.42 (m, 1H), 1.32 (s, 3H), 1.32-1.29 (m, 1H), 1.28-1.02 (m, 3H), 0.92 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[CH2:11][CH2:12][N:13](C)[CH2:14][CH2:15][N:6]3[C:7]=2[C:3]=1[C:4]1[CH2:19][CH2:18][CH2:17][C:5]=13.ClC(OC(Cl)C)=O>ClC(Cl)C>[F:1][C:2]1[CH:10]=[CH:9][C:8]2[CH2:11][CH2:12][NH:13][CH2:14][CH2:15][N:6]3[C:7]=2[C:3]=1[C:4]1[CH2:19][CH2:18][CH2:17][C:5]=13
Reactant: CN1CCc2ccc(F)c3c4c(n(c23)CC1)CCC4
Agent: CC(Cl)OC(=O)Cl
Solvent: CC(Cl)Cl
Product: Fc1ccc2c3c1c1c(n3CCNCC2)CCC1
Temperature: 25 °C
Yield: 69.4 %

Procedure:
To a solution of 8-fluoro-3-methyl-2,3,4,5,10,11-hexahydro-1H,9H-cyclopenta[b][1,4]diazocino[7,8,1-hi]indole (0.90 g, 3.48 mmole) in dichloroethane (200 mL) was added 1-chloroethyl chloroformate (1.5 mL, 13.8 mmole) and the mixture refluxed for 24 hours. The reaction mixture was then cooled to room temperature and the solvent removed in vacuo and replaced with methanol (200 mL) and refluxed for another 3 h. The reaction mixture was cooled to room temperature and the solvent removed in vacuo. The dark residue was dissolved in methylene chloride (200 mL) and washed with aqueous sodium hydroxide (1N, 150 mL), saturated sodium chloride (150 mL), dried (sodium sulfate) and concentrated. Purification by flash column chromatography (silica gel, 1.5% to 3% methanol in dichloromethane) provided 0.59 g of the title compound as a white solid. 0.18 g of the above solid was further treated with one equivalent of fumaric acid in ethanol to form a fumarate salt, mp 199-200° C. MS (ES) m/z 245.11 ([M+H]+), MS (ES) m/z 286.14 ([M+ACN+H]+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-])=O)=[C:6]([O:8][CH3:9])[CH:7]=1>[Ni].CO.C1COCC1>[CH3:9][O:8][C:6]1[CH:7]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=1[NH2:10]
Reactant: COc1cc(C)ccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(C)ccc1N
Temperature: 25 °C
Reaction time: 20 h
Yield: 95.4 %

Procedure:
A mixture of 5-methyl-2-nitroanisole (2 g, 12 mmol) and Raney nickel (2.2 g) in MeOH/THF (120 mL, 3:1 v/v) was shaken for 20 h at RT and under 0.1 bar of H2. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated to afford 1.57 g of the title compound as colorless oil. HPLC: LtRet=1.44 min; LC-MS: m/z 138.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]2[CH:6]=[CH:7][CH2:8][O:9][C:4]=2[CH:3]=1.[H][H]>[Pd].C(O)C>[F:1][C:2]1[CH:11]=[CH:10][C:5]2[CH2:6][CH2:7][CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(c1)OCC=C2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Fc1ccc2c(c1)OCCC2
Yield: 85.2 %

Procedure:
A mixture of 12.1 grams (0.081 mole) of 7-fluoro-2H-1-benzopyran and a catalytic amount of 5% palladium on carbon in about 200 mL of ethanol was shaken in a Parr hydrogenator until the theoretical amount of hydrogen gas was taken up. After this time the reaction mixture was filtered and concentrated under reduced pressure, yielding 10.5 grams of 3,4-dihydro-7-fluoro-2H-1-benzopyran. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: II.[C:3]([O:7][C:8](=[O:80])[CH2:9][CH2:10][C@H:11]1[NH:26][C:25](=[O:27])[CH2:24][C@@H:23](/[CH:28]=[CH:29]/[CH2:30][CH2:31][S:32]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[O:22][C:21](=[O:52])[CH2:20][NH:19][C:18](=[O:53])[C@@H:17]([CH:54]([CH3:56])[CH3:55])[NH:16][C:15](=[O:57])[C@@H:14]([CH2:58][S:59]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[NH:13][C:12]1=[O:79])([CH3:6])([CH3:5])[CH3:4]>C(Cl)Cl.CO>[C:3]([O:7][C:8](=[O:80])[CH2:9][CH2:10][C@@H:11]1[C:12](=[O:79])[NH:13][C@@H:14]2[CH2:58][S:59][S:32][CH2:31][CH2:30][CH:29]=[CH:28][C@@H:23]([O:22][C:21](=[O:52])[CH2:20][NH:19][C:18](=[O:53])[C@@H:17]([CH:54]([CH3:56])[CH3:55])[NH:16][C:15]2=[O:57])[CH2:24][C:25](=[O:27])[NH:26]1)([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)[C@H]1NC(=O)[C@@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)NC(=O)[C@@H](CCC(=O)OC(C)(C)C)NC(=O)C[C@@H](/C=C/CCSC(c2ccccc2)(c2ccccc2)c2ccccc2)OC(=O)CNC1=O
Agent: CC(C)[C@H]1NC(=O)[C@H]2CSSCC/C=C/[C@H](CC(=O)N[C@H](CCC(=O)OC(C)(C)C)C(=O)N2)OC(=O)CNC1=O
Agent: II
Solvent: ClCCl
Solvent: CO
Product: CC(C)[C@H]1NC(=O)[C@H]2CSSCCC=C[C@H](CC(=O)N[C@H](CCC(=O)OC(C)(C)C)C(=O)N2)OC(=O)CNC1=O

Procedure:
To a solution of I2 (117 mg, 0.46 mmol) in CH2Cl2/MeOH (9:1, 130 mL) was added dropwise a solution of bis-trityl 8F (50 mg, 0.046 mmol) over 30 minutes. After a further 30 min the reaction was quenched by the addition of sodium thiosulfate (0.05M, 50 mL) followed by brine (20 mL). The organic phase was separated and the aqueous phase extracted with CH2Cl2 (3×25 mL). The combined organic phase was dried (MgSO4) before concentration in vacuo gave a white solid. Purification by column chromatography on silica gel (1-3% MeOH/CH2Cl2) gave bicyclic depsipeptide 9F (19 mg, 0.032 mmol, 69%) as a white solid: [α]25D −76.7 (c 0.60, MeOH); 1H-NMR (400 MHz, CDCl3) δ 8.15 (d, J=4.0 Hz, 1H), 7.35 (d, J=6.5 Hz, 1H), 7.23 (t, J=5.5 Hz, 1H), 7.11 (d, J=9.0 Hz, 1H), 6.05 (ddt, J=15.5, 7.0, 2.0 Hz, 1H), 5.84-5.73 (m, 2H), δ 4.97 (td, J=8.0, 4.5 Hz, 1H), 4.18-4.01 (m, 3H), 3.61 (dd, J=15.1, 8.0 Hz, 1H), 3.24 (dd, J=10.5, 6.5 Hz, 1H), 2.95-2.75 (m, 5H), 2.73-2.62 (m, 3H), 2.51 (dd, J=13.6, 2.0 Hz, 1H), 2.42 (ddd, J=18.0, 9.0, 3.5 Hz, 1H), 2.19-2.04 (m, 2H), 1.83 (s, 9H), 0.98 (d, J=6.5 Hz, 3H), 0.92 (d, J=6.5 Hz, 3H); 13C-NMR (100 MHz, CDCl3) δ 175.7 (C), 171.8 (C), 171.7 (C), 170.9 (C), 169.9 (C), 168.2 (C), 130.2 (CH), 129.6 (CH), 82.6 (C), 69.4 (CH), 65.4 (CH), 57.6 (CH), 53.8 (CH), 42.4 (CH2), 40.0 (2×CH2), 38.6 (CH2), 34.1 (CH2), 33.1 (CH2), 28.2 (CH3), 27.4 (CH), 24.9 (CH2), 20.6 (CH3), 20.2 (CH3); LRMS (ES+) m/z 623 (90%, [M+Na]+), 601 (100%, [M+H]+).
Reaction SMILES: [OH-].[Na+].[C:3]1([CH2:13][CH2:14][OH:15])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.Cl.Cl[CH2:18][CH2:19][N:20]([CH2:23][CH3:24])[CH2:21][CH3:22].O>C1(C)C=CC=CC=1.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:19]([N:20]([CH2:23][CH3:24])[CH2:21][CH2:22][O:15][CH2:14][CH2:13][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1)[CH3:18]
Reactant: CCN(CC)CCCl
Reactant: OCCc1cccc2ccccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=S(=O)([O-])O
Solvent: Cc1ccccc1
Solvent: O
Product: CCN(CC)CCOCCc1cccc2ccccc12
Yield: 96.1 %

Procedure:
In a mixture of 1 mL of toluene and 3.5 ml of 50% (W/V) aqueous solution of sodium hydroxide is suspended 0.70 g of 2-(1-naphthyl)-1-ethanol, to which are added 1.00 g of N-(2-chloroethyl)-N,N-diethylamine hydrochloride and 0.14 g of tetra-n-butylammonium hydrogen sulfate. The mixture is heated under reflux for 2.5 hours. Water and toluene are added to the reaction mixture, and the organic layer is separated. The organic layer is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, and the residue is purified by column chromatography (eluent:chloroform:methanol=10:1). Thus, 1.06 g of N,N-diethyl-N-{2-[2-(1-naphthyl)ethoxy]ethyl}-amine is obtained as an oily product.
Reaction SMILES: [C:1]1([S:7][C:8]([C:11]([S:14](F)(=[O:16])=[O:15])([F:13])[F:12])([F:10])[F:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>ClCCCl>[CH2:18]([NH:25][S:14]([C:11]([F:13])([F:12])[C:8]([S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([F:10])[F:9])(=[O:16])=[O:15])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)Sc1ccccc1
Reactant: NCc1ccccc1
Agent: Cl
Solvent: ClCCCl
Product: O=S(=O)(NCc1ccccc1)C(F)(F)C(F)(F)Sc1ccccc1

Procedure:
Added to a solution of 1,2-dichloroethane (20 ml), containing the PhSCF2CF2SO2F (2.09 g, 7.2 mmol) obtained according to the method from example 3, was freshly distilled benzylamine (4 ml, 37 mmol). The mixture was stirred and heated at 50° C. for 20 h until the disappearance of PhSCF2CF2SO2F (monitored by TLC and 19F NMR/CDCl3). After returning to ambient temperature, an aqueous solution of HCl (10%) was added to the reaction medium. The aqueous and organic phases were separated and the aqueous phase was extracted with dichloromethane. The organic phases were combined and dried over MgSO4. After filtration and evaporation of the solvents, the residue was purified by chromatography over silica gel (pentane to pentane/AcOEt:4/1). The sulfonamide product was obtained in the form of a white solid (2.1 g, 77%).
Reaction SMILES: C1([CH2:4][N:5]([C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:24]=2F)[C:6]([C:8]2[C:9]([NH2:22])=[N:10][C:11]([N:14]3[CH2:18][C:17](C)(C)[NH:16][C:15]3=[O:21])=[N:12][CH:13]=2)=[O:7])CC1.[ClH:34]>>[ClH:34].[CH3:4][N:5]([C:23]1[CH:24]=[CH:25][CH:26]=[C:27]([C:29]([F:31])([F:30])[F:32])[CH:28]=1)[C:6]([C:8]1[C:9]([NH2:22])=[N:10][C:11]([N:14]2[CH2:18][CH2:17][NH:16][C:15]2=[O:21])=[N:12][CH:13]=1)=[O:7]
Reactant: CC1(C)CN(c2ncc(C(=O)N(CC3CC3)c3cc(C(F)(F)F)ccc3F)c(N)n2)C(=O)N1
Agent: Cl
Product: CN(C(=O)c1cnc(N2CCNC2=O)nc1N)c1cccc(C(F)(F)F)c1

Procedure:
2.853 g (7.5 mmol) of the compound I prepared as in Examples 62 and 63 were converted into the hydrochloride as in Example 6. 3.12 g of 4-amino-2-(2-oxo-1-imidazolidinyl)pyrimidine-5-carboxylic acid N-methyl-N-(3-trifluoromethylphenyl)amide hydrochloride were obtained, melting point 201°-202°.
Reaction SMILES: C([O:8][C@H:9]1[C@@H:15]2[C@@H:16]([O:17]CC3C=CC=CC=3)[C@@H:12]([C@H:13]([N:25]3[CH:33]=[C:31]([CH3:32])[C:29](=[O:30])[NH:28][C:26]3=[O:27])[O:14]2)[O:11][CH2:10]1)C1C=CC=CC=1>C(O)C.[OH-].[OH-].[Pd+2]>[OH:8][C@H:9]1[C@@H:15]2[C@@H:16]([OH:17])[C@@H:12]([C@H:13]([N:25]3[CH:33]=[C:31]([CH3:32])[C:29](=[O:30])[NH:28][C:26]3=[O:27])[O:14]2)[O:11][CH2:10]1
Reactant: Cc1cn([C@@H]2O[C@H]3[C@@H](OCc4ccccc4)[C@@H]2OC[C@H]3OCc2ccccc2)c(=O)[nH]c1=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: Cc1cn([C@@H]2O[C@H]3[C@@H](O)[C@@H]2OC[C@H]3O)c(=O)[nH]c1=O
Reaction time: 26 h

Procedure:
Nucleoside 18 (0.27 g, 0.60 mmol) was dissolved in absolute ethanol (20 cm3) and 20% palladium hydroxide on carbon (0.25 g) was added. The mixture was degassed and placed under an atmosphere of hydrogen. After stirring for 26 h the catalyst was filtered off (silica gel, washed with methanol, 400 cm3) and the filtrate was concentrated to dryness under reduced pressure. The residue was subjected to column chromatography on silica gel using dichloromethane/methanol (94:6, v/v) as eluent to give nucleoside 19 as white solid material (0.16 g, 98%) after evaporation of the solvents under reduced pressure.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[N:23]([CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])[N:22]=[CH:21]4)[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].[OH-].[Na+:35]>C(O)C>[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[N:23]([CH2:27][CH2:28][C:29]([O-:31])=[O:30])[N:22]=[CH:21]4)[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].[Na+:35]
Reactant: CCOC(=O)CCn1ncc2cc(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4c(cnn4CCC(=O)[O-])c3)no2)cc1C#N
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Ethyl 3-[5-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indazol-1-yl]propanoate (D58) (99 mg, 0.22 mmol) was dissolved in ethanol (2 ml) and 2M aq NaOH (0.55 ml) was added. The reaction was heated at 80° C. for 30 minutes and the reagents dissolved. The reaction mixture was cooled to room temperature and then left overnight. The resultant precipitate was filtered, washed with water and then ether, dried by heating in vacuo to afford the title compound (29.1 mg). δH (methanol-d4, 400 MHz) 1.46 (6H, d), 2.78, (2H, t), 4.71 (2H, t), 4.88-5.00 (estimate 1H [partially overlapping water peak], m). 7.43 (1H, d), 7.83 (1H, d), 8.10-8.17 (2H, m), 8.37-8.49 (2H, m), 8.56 (1H, s), MS (ES): C22H19N5O4 requires 417; found (MH+) 418.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH2:12][N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([C:22]3[N:27]=[C:26]([NH:28][C:29]4[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=4)[C:25]([O:35][CH3:36])=[CH:24][N:23]=3)=[N:14]2)=[C:10]([Cl:37])[CH:9]=[CH:8][C:3]=1[C:4](OC)=[O:5].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[Cl:1][C:2]1[C:11]([CH2:12][N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([C:22]3[N:27]=[C:26]([NH:28][C:29]4[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=4)[C:25]([O:35][CH3:36])=[CH:24][N:23]=3)=[N:14]2)=[C:10]([Cl:37])[CH:9]=[CH:8][C:3]=1[CH2:4][OH:5]
Reactant: COC(=O)c1ccc(Cl)c(Cn2nc(-c3ncc(OC)c(Nc4ccncc4)n3)c3ccccc32)c1Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cnc(-c2nn(Cc3c(Cl)ccc(CO)c3Cl)c3ccccc23)nc1Nc1ccncc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
80 mg of methyl 2,4-dichloro-3-({3-[5-methoxy-4-(pyridin-4-ylamino)pyrimidin-2-yl]-1H-indazol-1-yl}methyl)benzoate (2-16-1, 0.149 mmol, 1. eq.) was suspended in 2.4 ml of dry tetrahydrofuran under nitrogen atmosphere. The suspension was cooled with an ice bath to +3° C., upon which 254 μl of a 1 M lithium aluminium hydride solution in tetrahydrofuran (0.254 mmol, 1.7 eq.) were added dropwise. The ice bath was remove and the mixture was stirred at room temperature for 30 minutes. Then the mixture was acidified by 2 M sulfuric acid. The mixture formed a suspension which was filtered off and washed with water. The precipitate was dried in vacuo at 60° C. for 18 hours to yield 60 mg (0.11 mmol, 74.4%) of the analytically pure target compound.