Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:6]([NH:8][C@H:9]([C:11]([O:13][CH3:14])=[O:12])[CH3:10])=[O:7])[CH:3]([CH3:5])[CH3:4].[CH2:25]([N:32]=[C:33]=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CO.C(Cl)(Cl)Cl.[Pd]>[C:26]1([CH2:25][NH:32][C:33]([NH:1][C@H:2]([C:6]([NH:8][C@H:9]([C:11]([O:13][CH3:14])=[O:12])[CH3:10])=[O:7])[CH:3]([CH3:5])[CH3:4])=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C=NCc1ccccc1
Reactant: COC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Agent: [Pd]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)NCc1ccccc1)C(C)C
Reaction time: 1 h
Yield: 59 %

Procedure:
CBZValAlaOCH3 (1.35 g, 4.00 mmole) was hydrogenated at 3 arm. over 10% Pd on carbon (150 mg) in CH3OH (40 mL) at room temperature. After 1 hour, the catalyst was removed by filtration through a nylon filter. The filtrate was evaporated in vacuo giving a white solid which was slurried in CHCl3 (40 mL) and treated with benzyl isocyanate (586 mg, 4.4 mmole). After 1 hour at room temperature, the reaction mixture was washed three times with 1N HCl, dried over MgSO4, filtered and concentrated in vacuo giving 791 mg (61%) of the desired product as a white powder. Recrystallization of a portion from ethyl acetate/CH3OH gave an analytical sample: mp 227°-228° C.; 1H NMR (DMSO-d6) δ 0.80 (d, J=6.8 Hz, 3H), 0.86 (d, J=6.7 Hz, 3H), 1.26 (d, J=7.3 Hz, 3H), 1.85-1.95 (m, 1H), 3.59 (s, 3H), 4.10 (dd, J=5.9, 9.2 Hz, 1H), 4.15-4.3 (m, 3H), 6.08 (d, J=9.3 Hz, 1H), 6.53 (t, J=6.0 Hz, 1H), 7.15-7.35 (m, 5H), 8.39 (d, J=6.7 Hz, 1H); MS (LSIMS) m/e 336 (100, M+ +1), 233 (62), 203 (76); [α]D20 +6.1° (c=1.0, DMF); Analysis calculated for C17H25N3O4 ; C, 60.88; H, 7.51; N, 12.53; found: C, 60.98; H, 7.30; N, 12.34.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:13]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)[N:12]=2)[CH:10]=1)CCC.Br[C:40]1[CH:41]=[C:42]([S:46]([NH2:49])(=[O:48])=[O:47])[CH:43]=[N:44][CH:45]=1.CCCCCCC>C1(C)C=CC=CC=1>[F:20][C:17]([F:18])([F:19])[C:15]1[CH:14]=[C:13]([C:21]2[CH:22]=[CH:23][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:25][CH:26]=2)[N:12]=[C:11]([N:9]2[CH:10]=[C:6]([C:40]3[CH:41]=[C:42]([S:46]([NH2:49])(=[O:48])=[O:47])[CH:43]=[N:44][CH:45]=3)[N:7]=[CH:8]2)[CH:16]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2cc(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)n2)cn1
Reactant: NS(=O)(=O)c1cncc(Br)c1
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Product: NS(=O)(=O)c1cncc(-c2cn(-c3cc(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)n3)cn2)c1
Temperature: 25 °C
Yield: 71.8 %

Procedure:
A stirred mixture of 2-(4-tributylstannanyl-imidazol-1-yl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyridine (Example G.11) (0.503 g, 0.7 mmol), commercially available 5-bromo-pyridine-3-sulfonic acid amide (0.183 g, 0.77 mmol), tetrakis(triphenyl-phosphine)palladium (0.040 g, 0.030 mmol) in toluene (5 mL) was heated under reflux conditions for 18 h. Cooled to rt, some precipitate occurred, diluted with toluene (˜5 mL), added heptane, filtered the precipitate off, washed with toluene/heptane, dried in HV to give the title compound as a white solid (258 mg, 72%). MS (ISP) 514.2 [(M+H)+]; mp>250° C.
Reaction SMILES: [C:1]([Mg]Br)#[CH:2].CON(C)[C:8](=[O:18])[CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1.CCOCC>C1COCC1>[F:17][C:14]1[CH:13]=[CH:12][C:11]([O:10][CH2:9][C:8](=[O:18])[C:1]#[CH:2])=[CH:16][CH:15]=1
Reactant: C#C[Mg]Br
Reactant: CON(C)C(=O)COc1ccc(F)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: C#CC(=O)COc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 209.7 %

Procedure:
A solution of ethynylmagnesium bromide (0.5 M in THF, 508 mL, 254 mmol), was added slowly, as a stream down the side of the flask, to an ice water cooled solution of N-methoxy-N-methyl-2-(4-fluorophenoxy)ethanamide (20.00 g, 74 mmol) in THF (100 mL). After an additional 30 minutes at 0° C., the reaction mixture was poured into a vigorously stirred mixture of 1M NaH2SO4 (1700 mL) and ether (1 L). The layers were separated and the aqueous layer then extracted with ether (700 mL). The combined organic phases were washed with brine and dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by eluting through a plug of silica gel (10 cm×3 cm) with 1:4 ether:pet. ether to afford 27.65 g (91% yield) of 4-(4-fluorophenoxy)-1-butyn-3-one, a compound of formula (AA), as a low melting solid; 1H NMR (CDCl3) δ3.40 (s, 1H), 4.70 (s, 2H), 6.85 (m, 2H), 7.0 (t, 2H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:14])[CH:11]=NO)[CH:5]=[CH:6][C:7]=1[F:8].S(=O)(=O)(O)[OH:16]>>[F:8][C:7]1[CH:6]=[C:5]2[C:4](=[CH:3][C:2]=1[F:1])[NH:9][C:10](=[O:14])[C:11]2=[O:16]
Reactant: O=C(C=NO)Nc1ccc(F)c(F)c1
Reactant: O=S(=O)(O)O
Product: O=C1Nc2cc(F)c(F)cc2C1=O

Procedure:
In accordance with the above reaction scheme, an aqueous solution of 3,4-difluoroaniline (I) and hydroxylamine hydrochloride containing hydrochloric acid is reacted with an aqueous solution of chloral hydrate and sodium sulfate at the reflux, then filtered while hot, giving N-(3,4-difluorophenyl)-2-(hydroxyimino)-acetamide (II). The compound (II) is reacted with concentrated sulfuric acid with heat, then added to cracked ice, giving 5,6-difluoro-1H-indole-2,3-dione (III). A basic aqueous solution of compound (III) is treated with hydrogen peroxide and heat, then cooled and acidified, giving 2-amino-4,5-difluorobenzoic acid (IV). The compound (IV) is added to a mixture of anhydrous copper(II) chloride, t-butyl nitrite and anhydrous acetonitrile at 0°-5° C., then added to a dilute mineral acid, giving 2-chloro-4,5-difluorobenzoic acid (V).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([C:8]2[C:17](=[O:18])[NH:16][C:11]3=[N:12][CH:13]=[CH:14][N:15]=[C:10]3[C:9]=2[OH:19])=[C:5]([CH3:7])[N:6]=1.[C:20](Cl)(=[O:24])[CH:21]([CH3:23])[CH3:22].N1C=CC=CC=1>ClCCl>[Cl:1][C:2]1[S:3][C:4]([C:8]2[C:17](=[O:18])[NH:16][C:11]3=[N:12][CH:13]=[CH:14][N:15]=[C:10]3[C:9]=2[O:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])=[C:5]([CH3:7])[N:6]=1
Reactant: CC(C)C(=O)Cl
Reactant: Cc1nc(Cl)sc1-c1c(O)c2nccnc2[nH]c1=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1nc(Cl)sc1-c1c(OC(=O)C(C)C)c2nccnc2[nH]c1=O

Procedure:
7-(2-Chloro-4-methyl-thiazol-5-yl)-8-hydroxy-5H-pyrido[2,3-b]pyrazin-6-one (Example 2.3) (0.30 g), isobutyryl chloride (0.13 ml), and pyridine (0.10 ml) were stirred in dichloromethane (15 ml) at ambient temperature for 2 hours. The reaction mixture was washed successively with aqueous hydrochloric acid (1M), aqueous sodium hydrogen carbonate (saturated) and water. The organic fraction was dried over magnesium sulfate and concentrated to give Compound No. B9 of Table B (0.220 g).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:9])[NH:4][CH:5]=[C:6]([Br:8])[N:7]=1.[OH-].[Na+].C(=O)([O-])[O-].[Na+].[Na+].S(OCC)(O[CH2:22][CH3:23])(=O)=O>O>[CH2:22]([N:4]1[CH:5]=[C:6]([Br:8])[N:7]=[C:2]([Br:1])[C:3]1=[O:9])[CH3:23]
Reactant: CCOS(=O)(=O)OCC
Reactant: O=c1[nH]cc(Br)nc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCn1cc(Br)nc(Br)c1=O
Reaction time: 15 h
Yield: 66.8 %

Procedure:
6.2 g of 3,5-dibromo-pyrazin-2-one are suspended in a mixture of 38 ml of water, 11.1 ml of 2N sodium hydroxide solution and 0.5 g of sodium carbonate. 4.3 g of diethyl sulfate are then added dropwise at 20°-25° C. and the mixture is subsequently stirred at the same temperature for 15 hours. The product is filtered off at 0° C., washed with ice-water and dried to give 4.6 g of 1-ethyl-3,5-dibromo-pyrazin-2-one.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12]2[O:13][C@H:14]3[C:23]4([O:27][CH2:26][CH2:25][O:24]4)[CH2:22][CH2:21][C@@H:20]4[C@@:15]53[CH2:16][CH2:17][N:18]([CH3:29])[C@@H:19]4[CH2:28][C:10]([C:11]=25)=[CH:9][CH:8]=1)(=O)=O.[CH3:32][N:33](C)C=O>C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C-]#N.[Zn+2].[C-]#N>[CH3:29][N:18]1[CH2:17][CH2:16][C@@:15]23[C:11]4[C:10]5[CH2:28][C@@H:19]1[C@@H:20]2[CH2:21][CH2:22][C:23]1([C@@H:14]3[O:13][C:12]=4[C:7]([C:32]#[N:33])=[CH:8][CH:9]=5)[O:24][CH2:25][CH2:26][O:27]1
Reactant: CN(C)C=O
Reactant: CN1CC[C@]23c4c5ccc(OS(=O)(=O)C(F)(F)F)c4O[C@H]2C2(CC[C@H]3[C@H]1C5)OCCO2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: CN1CC[C@]23c4c5ccc(C#N)c4O[C@H]2C2(CC[C@H]3[C@H]1C5)OCCO2
Temperature: 40 °C
Yield: 63 %

Procedure:
To a solution of (4R,4aR,7aR,12bS)-3-methyl-1,2,3,4,4a,5,6,7a-octahydrospiro[4,12-methanobenzofuro[3,2-e]isoquinoline-7,2′-[1,3]dioxolan]-9-yl trifluoromethanesulfonate (20.77 g, 45.0 mmol) in degassed dimethylformamide (400 mL) was added tetrakis(triphenylphosphine)palladium(0) (5.21 g, 4.50 mmol). After heating to 40° C., zinc cyanide (3.18 g, 27.0 mmol) was added and the reaction mixture heated at 110° C. for 6 hours. The reaction mixture was cooled to room to temperature and diluted with ethyl acetate and filtered through a pad of celite. The filtrate was diluted further with ethyl acetate and washed with water (3×500 mL). The aqueous phase was basified with sodium hydrogen carbonate solution and re-extracted with ethyl acetate and the combined organics dried (MgSO4), filtered and concentrated under reduced pressure. Purification by silica chromatography (100% dichloromethane to 5% NH3/methanol in dichloromethane) gave (4R,4aR,7aR,12bS)-3-methyl-1,2,3,4,4a,5,6,7a-octahydrospiro[4,12-methanobenzofuro[3,2-e]isoquinoline-7,2′-[1,3]dioxolane]-9-carbonitrile (10.0 g, 91% pure LCMS, 63% yield over three steps); [M+H]+339.1.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([N+:15]([O-])=O)=[CH:13][N:12]=[C:11]([O:18][C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:28])[CH3:27])[CH:22]=[CH:23][CH:24]=3)[CH:10]=2)=[CH:4][CH:3]=1.[H][H]>CO.[Pd]>[NH2:15][C:14]1[C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=2)=[CH:10][C:11]([O:18][C:19]2[CH:20]=[C:21]([NH:25][C:26](=[O:28])[CH3:27])[CH:22]=[CH:23][CH:24]=2)=[N:12][CH:13]=1
Reactant: CC(=O)Nc1cccc(Oc2cc(Nc3ccc(O)cc3)c([N+](=O)[O-])cn2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(=O)Nc1cccc(Oc2cc(Nc3ccc(O)cc3)c(N)cn2)c1
Yield: 78.9 %

Procedure:
The product of Step 2 (2.9 g, 7.6 mmol) was hydrogenated in methanol (50 mL) in the presense of 5% Pd/C (250 mg) with a balloon of hydrogen overnight. The reaction mixture was filtered through Celite and concentrated to give the title compound (2.1 g, 79%) as a dark orange solid. MS (ES+) m/e 351 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([C:12](=[O:15])[CH2:13]Br)[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[CH:23]1[C:28]([OH:29])=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:30]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([C:12](=[O:15])[CH2:13][O:29][C:28]2[CH:23]=[C:24]([CH3:30])[CH:25]=[CH:26][CH:27]=2)[CH:5]=1
Reactant: Cc1cccc(O)c1
Reactant: COC(=O)c1ccc(OC)c(C(=O)CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC)c(C(=O)COc2cccc(C)c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.8 %

Procedure:
The compound of step 1 (1.18 g, 4.12 mmol) and potassium carbonate (1.72 g, 12.4 mmol) were suspended in DMF (10 ml), m-cresol (450 mg, 4.12 mmol) was added, and the mixture was stirred at room temperature for 2 h. The volatiles were evaporated in vacuo, the residue was partitioned between EA and water, and the aqueous phase extracted with EA. The combined organic extracts were washed with a sodium chloride solution, dried over sodium sulfate, filtered and evaporated to dryness. The residue was purified by preparative RP HPLC (water/ACN gradient) to give 0.49 g of the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH2:9])[N:3]=1.[NH:10]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C(N(CC)CC)C>CO>[Cl:8][C:6]1[CH:7]=[C:2]([N:10]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[N:3]=[C:4]([NH2:9])[N:5]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: C1CCCNCC1
Solvent: CCN(CC)CC
Solvent: CO
Product: Nc1nc(Cl)cc(N2CCCCCC2)n1
Temperature: 50 °C
Reaction time: 5 h
Yield: 86.8 %

Procedure:
In a 25 mL sealable tube under nitrogen were combined 4,6-dichloro-2-pyrimidinamine (0.50 g, 3.05 mmol) and hexahydro-1H-azepine (0.34 mL, 3.05 mmol) in CH3OH (10 mL). Triethylamine (0.47 mL, 3.35 mmol) was added, the vial was sealed, and the reaction mixture was stirred for 5 hours at 50° C. The reaction was cooled to room temperature and concentrated. The resulting yellow solid was partitioned between EtOAc and water. The organic layer was separated, dried (MgSO4), filtered and concentrated to afford the title compound (600 mg, 82%) as a yellow solid. LC-MS (ES) m/z=227 [M+H]+.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[N:8]1[CH:13]=[CH:12][C:11](CCO)=[CH:10][CH:9]=1.C(N(CC)CC)C>C(Cl)Cl.CN(C1C=CC=CN=1)C>[C:5]([O:4][CH2:1][CH2:2][C:11]1[CH:12]=[CH:13][N:8]=[CH:9][CH:10]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: OCCc1ccncc1
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCCc1ccncc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of 11.3 ml of acetic anhydride in 100 ml of methylene chloride was added approximately 125 mg of dimethylaminopyridine, and the solution was cooled to 0° C. In a separate container 12.2 g (0.099 mol) of 4-pyridineethanol was suspended in 80 ml of methylene chloride and 12.14 g (0.120 mol, 16.7 ml) of triethylamine was added. This mixture was added to the acetic anhydride solution slowly by pipet. The resulting mixture was stirred at room temperature for approximately 90 minutes and quenched with about 100 ml of water. The mixture was placed in a separatory funnel and the organic layer was isolated and washed two times with 100 ml portions of water. The aqueous layers were combined and extracted two times with methylene chloride and one time with diethyl ether. The organic extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to provide 16.2 g of the desired compound. Purification by high pressure liquid chromatography provided 11.19 g of 4-pyridineethanol acetate.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6]C(C)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[OH-].[K+].CC[O:16][C:17]([CH3:19])=[O:18]>N1C=CC=CC=1.CO>[I:1][C:2]1[CH:7]=[CH:6][C:19]([C:17]([OH:16])=[O:18])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: Cc1ccc(I)cc1[N+](=O)[O-]
Reactant: CCOC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: CO
Product: O=C(O)c1ccc(I)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
In a 1 L three-neck round-bottom flask equipped with an internal thermometer, a reflux condenser, and an addition funnel, Bu4N+MnO4− (124 g, 343 mmol) was dissolved in pyridine (200 mL). The solution was heated to 60° C., and then the heating source was removed. A solution of 4-iodo-2-nitrotoluene (43.0 g, 163 mmol) in pyridine (60 mL) was added through the additional funnel over 2 h. The reaction temperature was maintained at 60° C. by adjusting the addition rate. When the addition was complete, the reaction mixture was cooled to rt. The solution was concentrated, diluted with EtOAc (300 mL) and water (200 mL), and stirred at rt for 30 min. The precipitated brown solid was filtered off and washed with EtOAc. The clear organic layer was washed with 5% aq. H2SO4 (200 mL) and brine (200 mL), dried (MgSO4), and concentrated to afford a thick, brown oil. The crude product was dissolved in EtOAc (200 mL) and then a solution of KOH (9.1 g, 163 mmol) in MeOH (ca. 30 mL) was added dropwise. The mixture was stirred at rt for 1 h, and the precipitated solid was collected by filtration and washed with EtOAc. The filtrate was concentrated and the precipitation was repeated with KOH in MeOH. The two crops were combined and dissolved in water (ca. 250 mL) and acidified with conc. HCl to pH<2. The precipitated white solid was collected by filtration and dried under vacuum to give the desired product (40 g, 136 mmol, 83%, >98% purity by HPLC). 1H NMR (400 MHz, CD3OD): 8.13 (d, J=1.6, 1H), 8.01 (dd, J=8.1, 1.6, 1H), 7.50 (d, J=8.1, 1H).
Reaction SMILES: C1(O[C:8](=[O:30])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[C:19]([F:25])[C:18]=3[F:26])[C:11]=2[C:27](=[O:29])[NH2:28])C=CC=CC=1.[CH3:31][NH:32][CH2:33][CH2:34][CH2:35][NH2:36]>>[CH3:31][NH:32][CH2:33][CH2:34][CH2:35][NH:36][C:8](=[O:30])[NH:9][C:10]1[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]2[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[C:19]([F:25])[C:18]=2[F:26])[C:11]=1[C:27]([NH2:28])=[O:29]
Reactant: CNCCCN
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)c(F)c1F
Product: CNCCCNC(=O)Nc1snc(OCc2c(F)cc(C)c(F)c2F)c1C(N)=O

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and N-methyl-propane-1,3-diamine by the procedure analogous to Example 1. MS (APCI, m/z): 432 [M+H]+.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15]([CH2:16][C@@H:17]([OH:28])[C@@H:18]4[O:27][C@@H:19]42)=[CH:14][CH:13]=3)[CH2:10][CH2:9]1)[CH3:7].CC1(C)COC(C([C@@H]2[C@]3(C)[C@H](C4[C@H](CC3)[C@]3(C)C(C[C@@H](O)[C@@H]5O[C@@H]53)=CC=4)CC2)C)OC1>>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15]([CH2:16][C@@H:17]([OH:28])[CH2:18][C@@H:19]2[OH:27])=[CH:14][CH:13]=3)[CH2:10][CH2:9]1)[CH3:7]
Reactant: CC(C1OCCO1)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Agent: CC(C1OCC(C)(C)CO1)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Product: CC(C1OCCO1)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Yield: 78.3 %

Procedure:
The procedure of Example 24 was repeated except that 3.4 mg (0.00887 mmole) of 20-(1,3-dioxolan-2-yl)-1α,2α-epoxypregna-5,7-dien-3β-ol was used in lieu of 3.8 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxypregna-5,7-dien-3β-ol to give 2.7 mg of 20-(1,3-dioxolan-2-yl)pregna-5,7-diene-1α,3β-diol (yield: 78% ).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[C:6]([OH:12])[CH:5]=1.CCN(CC)CC.[O:21](S(C(F)(F)F)(=O)=O)[S:22]([C:25]([F:28])([F:27])[F:26])(=O)=[O:23].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[C:6]([O:12][S:22]([C:25]([F:28])([F:27])[F:26])(=[O:23])=[O:21])[CH:5]=1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1ccc(C#N)c(O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C#N)c(OS(=O)(=O)C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
4-cyano-3-hydroxybenzoic acid methyl ester, Example 34, Step 3 (2 g, 11.3 mmol) was dissolved in CH2Cl2 (57 ml) and cooled to 0° C. in an ice bath. The mixture was treated with Et3N (3 ml, 22.6 mmol) followed by the addition of Tf2O (1.9 ml, 11.3 mmol). The reaction mixture was warmed to room temp. and stirred for 4 hours. Saturated NaHCO3 (10 mL) was added and the mixture was extracted with EtOAc (2×10 mL). The organic layers were combined and dried (MgSO4), filtered, and concentrated. The residue was then purified by flash chromatography (15% EtOAc/Hexane) to yield the desired product.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[C:7]([CH2:18]O)=[N:8][CH:9]=[CH:10][C:11]=1[N:12]([CH3:17])[CH2:13][CH2:14][CH2:15][OH:16]>ClCCl>[Cl:5][C:6]1[C:7]([CH2:18][Cl:3])=[N:8][CH:9]=[CH:10][C:11]=1[N:12]([CH3:17])[CH2:13][CH2:14][CH2:15][OH:16]
Reactant: CN(CCCO)c1ccnc(CO)c1Cl
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CN(CCCO)c1ccnc(CCl)c1Cl
Reaction time: 1 h

Procedure:
Thionyl chloride (3.5 ml, 47.6 mmol), dissolved in dichloromethane (25 ml), is added dropwise at 4° C. to a solution of 3-[(3-chloro-2-hydroxymethyl-pyridin-4-yl)-methyl-amino]-propanol (5.0 g, 21.6 mmol) in dichloromethane (75 ml). The solution is stirred for 1 h at this temperature, triturated with ice water and neutralized with saturated sodium bicarbonate solution. After separation of the organic layer the aqueous phase is extracted with dichloromethane. The combined organic extracts are washed with water, dried over magnesium sulfate and evaporated in vacua. The residue is employed without additional purification for the synthesis described in step b).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH2:6]P(OCC)(OCC)=O)=[O:5].[H-].[Na+].[CH3:17][N:18]1[CH2:25][CH:24]2[C:26](=O)[CH:20]([C@H:21]([CH3:29])[CH2:22][C@H:23]2[CH3:28])[CH2:19]1.C(OCC)(=O)C>O1CCCC1>[CH3:17][N:18]1[CH2:25][CH:24]2[C:26](=[CH:6][C:4]([O:3][CH2:2][CH3:1])=[O:5])[CH:20]([C@H:21]([CH3:29])[CH2:22][C@H:23]2[CH3:28])[CH2:19]1
Reactant: C[C@@H]1C[C@@H](C)C2CN(C)CC1C2=O
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C=C1C2CN(C)CC1[C@H](C)C[C@H]2C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 32.5 %

Procedure:
To a solution of 130 g of triethyl phosphono acetate in tetrahydrofuran (600 ml) was added 25 g of sodium hydride (oily: 60% or above) under ice-cooling and the resulting mixture was stirred at room temperature for 10 minutes. Then a solution of 70 g of the crude (6R*,8R*)-3,6,8-trimethyl-3-azabicyclo[3.3.1]nonan-9-one in tetrahydrofuran (300 ml) was added thereto and the reaction mixture was heated under reflux for 2 hours. After adding ethyl acetate, the reaction mixture was washed twice with a saturated aqueous solution of sodium chloride and the organic layer was dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluted with n-hexane/ethyl acetate) to thereby give 31.5 g of the title compound as a pale yellow oily substance.
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].[C:32]1([N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)Cl>[C:2]([O:4][C@H:5]1[C:14]2[C@:15]3([CH3:30])[C:16](/[C:17](=[CH:18]\[N:41]4[CH2:42][CH2:43][N:38]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)[CH2:39][CH2:40]4)/[C:23](=[O:24])[O:25][C@@H:26]3[CH2:27][O:28][CH3:29])=[C:20]([OH:19])[C:21](=[O:22])[C:13]=2[CH:8]2[C@@:7]([CH3:31])([C@@H:11]([OH:12])[CH2:10][CH2:9]2)[CH2:6]1)(=[O:3])[CH3:1]
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: ClCCl
Product: COC[C@H]1OC(=O)/C(=C/N2CCN(c3ccccc3)CC2)C2=C(O)C(=O)C3=C([C@H](OC(C)=O)C[C@@]4(C)C3CC[C@@H]4O)[C@]21C
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.5 %

Procedure:
To a solution of 50 mg (0.12 mmol) 17-hydroxywortmannin in 0.5 mL CH2Cl2 is added 38.9 mg (0.24 mmol) 1-phenylpiperazine. The reaction mixture is stirred at room temperature overnight. CH2Cl2 is removed in vacuo. The residue is triturated with Et2O to give 16 mg (22.5%) product as an orange powder. MS (ESI) m/z 593.3 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([CH3:20])([CH3:19])[CH2:13][C:12]2=[N:21]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N>C1COCC1.CO.[Ni]>[NH2:21][CH:12]1[C:11]2[C:16](=[CH:17][CH:18]=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:10]=2)[O:15][C:14]([CH3:20])([CH3:19])[CH2:13]1
Reactant: CC1(C)CC(=NO)c2cc(OCc3ccccc3)ccc2O1
Agent: [Ni]
Agent: N
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)CC(N)c2cc(OCc3ccccc3)ccc2O1

Procedure:
30 g of 6-benzyloxy-2,2-dimethylchroman-4-one oxime were dissolved in 900 ml of THF/methanol (1:1), treated with 25 ml of aqueous ammonia and hydrogenated in a shaking duck using Raney Ni. The catalyst was then filtered off with suction, the filtrate was concentrated in vacuo, the residue was dissolved in EA, dried and concentrated, and the residue was crystallized using petroleum ether, 22.9 g, m.p. 86-88° C.