Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[F:23].[CH2:24]([N:27]1[CH:31]=[CH:30][C:29]([C:32](O)=[O:33])=[N:28]1)[CH2:25][CH3:26]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:32]([C:29]2[CH:30]=[CH:31][N:27]([CH2:24][CH2:25][CH3:26])[N:28]=2)=[O:33])=[CH:18][C:17]=1[F:23]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Reactant: CCCn1ccc(C(=O)O)n1
Product: CCCn1ccc(C(=O)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)c(F)c2)n1
Yield: 17 %

Procedure:
C1 was prepared from A2 and 1-propylpyrazole-3-carboxylic acid following the general procedure reported in Preparative Example 11. The residue was purified by reverse phase RP-HPLC (column: C18), using H2O and ACN as eluents. The desired fractions were lyophilized to yield the title compound C1 (46 mg, 0.10 mmol, 17%) as a white powder. 1H NMR (400 MHz, d6-DMSO, 300K) δ 0.85 (t, J=7.3 Hz, 3H), 1.86 (sext., J=7.3 Hz, 2H), 3.94 (s, 6H), 4.18 (t, J=7.3 Hz, 2H), 6.45 (d, J=5.1 Hz, 1H), 6.79 (d, J=2.3 Hz, 1H), 7.39 (s, 1H), 7.42 (t, J=9.0 Hz, 1H), 7.52 (s, 1H), 7.78 (d, J=9.0 Hz, 1H), 7.90 (d, J=2.3 Hz, 1H), 8.05 (dd, J=13.4 Hz, J=2.3 Hz, 1H), 8.46 (d, J=5.2 Hz, 1H), 10.34 (s, 1H). MS (ES) C24H23FN4O4 requires: 450. Found: 451 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=[CH:5]2.C1(C)C=CC=CC=1.[CH3:24][C:25]1([CH3:38])[CH2:34][CH2:33][CH2:32][C:31]2[CH:30]=[C:29](B(O)O)[CH:28]=[CH:27][C:26]1=2.C(OCC)(=O)C>CO.C([O-])([O-])=O.[Na+].[Na+].CCCCCC>[CH2:15]([O:14][C:12]([C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([CH:33]3[CH2:32][C:31]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:25]([CH3:38])([CH3:24])[CH2:34]3)[CH:3]=2)[CH:8]=1)=[O:13])[CH3:16]
Reactant: CCOC(=O)c1ccc2cc(Br)ccc2c1
Reactant: CC1(C)CCCc2cc(B(O)O)ccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc2cc(C3Cc4ccccc4C(C)(C)C3)ccc2c1
Temperature: 80 °C

Procedure:
To a degassed solution of 0.39 g (1.4 mmol) of ethyl 6-bromo-naphthalene-2-carboxylate and 3.0 mL of toluene, was added sequentially 49 mg (0.04 mmol) of tetrakis-triphenylphosphine palladium(0), 2.0 mL (2.0 mmol) of 1M sodium carbonate and then a solution of 0.32 g (1.6 mmol) of (5,6,7,8-tetrahydro-5,5-dimethylnaphth-2-yl) boronic acid (Compound B13) in 3.0 mL of MeOH. The reaction was heated at 80° C. for 6 h, diluted with 2N Na2CO3, and extracted with CH2Cl2 (2×), the organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo to give an oil. Flash chromatography (silica, 5% ethyl acetate in hexane) of the crude material gave the title compound as a white solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH3:6])([OH:5])[CH3:4].Cl[C:8]1[CH:9]=[CH:10][C:11]2[N:12]([C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:27])([F:26])[F:25])[CH:18]=3)=[CH:15][N:16]=2)[N:13]=1.CCN(C(C)C)C(C)C.[F-].[Cs+]>CS(C)=O>[CH3:4][C:3]([OH:5])([CH3:6])[CH2:2][NH:1][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:25])([F:27])[F:26])[CH:18]=3)=[CH:15][N:16]=2)[N:13]=1
Reactant: FC(F)(F)Oc1cccc(-c2cnc3ccc(Cl)nn23)c1
Reactant: CC(C)(O)CN
Agent: [Cs+]
Agent: [F-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)(O)CNc1ccc2ncc(-c3cccc(OC(F)(F)F)c3)n2n1
Temperature: 120 °C
Reaction time: 5 h
Yield: 14.2 %

Procedure:
To the solution of compound 1-amino-2-methylpropan-2-ol (55 mg, 0.57 mmol) and compound 6-chloro-3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazine (150 mg, 0.48 mmol) in 3 mL DMSO was added DIEA (0.21 mL, 0.96 mmol) and 10 mg CsF, the solvent was stirred for 5 h at 120° C., Then the mixture was purified by HPLC to afford the compound 2-methyl-1-((3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazin-6-yl)amino)propan-2-ol (25 mg, 12%) as a white solid.
Reaction SMILES: CS(O[CH:6]([C:22]1[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=1)[CH2:7][CH2:8][CH:9](OS(C)(=O)=O)[C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=1)(=O)=O.[F:29][C:30]([F:39])([F:38])[C:31]1[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=1>CN(C=O)C>[Br:16][C:13]1[CH:14]=[CH:15][C:10]([C@@H:9]2[CH2:8][CH2:7][C@@H:6]([C:22]3[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=3)[N:35]2[C:34]2[CH:36]=[CH:37][C:31]([C:30]([F:29])([F:38])[F:39])=[CH:32][CH:33]=2)=[CH:11][CH:12]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: CS(=O)(=O)OC(CCC(OS(C)(=O)=O)c1ccc(Br)cc1)c1ccc(Br)cc1
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(N2[C@H](c3ccc(Br)cc3)CC[C@H]2c2ccc(Br)cc2)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
The product from Example 42B (11.13 g, 20.0 mmol) and 4-(trifluoromethyl)aniline (32.2 g, 200 mmol) were combined in DMF (50 mL). The mixture was stirred at 50° C. under nitrogen overnight. The reaction mixture was evaporated and the residue was diluted with ethyl acetate, treated with 1M HCl, stirred for 10 minutes, and filtered to remove the solid. The organic layer of filtrate was washed with brine, dried with sodium sulfate, filtered and evaporated. The residue was purified by chromatography on silica gel eluting with ethyl acetate/hexane (0 to 1%). The title compounds (500 mg, 5%) were eluted as the first of 2 stereoisomers and were obtained as a mixture of trans diastereomers.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[O:7][C:6]([C:8]2[CH:9]=[C:10]([CH2:16][CH3:17])[C:11](=[O:15])[NH:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.[C:18](Cl)(=[O:20])[CH3:19]>>[CH2:16]([C:10]1[C:11](=[O:15])[NH:12][C:13]([CH3:14])=[C:8]([C:6]2[O:7][C:3]([CH2:2][NH:1][C:18](=[O:20])[CH3:19])=[CH:4][CH:5]=2)[CH:9]=1)[CH3:17]
Reactant: CC(=O)Cl
Reactant: CCc1cc(-c2ccc(CN)o2)c(C)[nH]c1=O
Product: CCc1cc(-c2ccc(CNC(C)=O)o2)c(C)[nH]c1=O

Procedure:
Example 269 is substantially repeated except for utilizing 5-(5-aminomethylfuran-2-yl)-3-ethyl-6-methyl-1H-pyridin-2-one and acetyl chloride to afford the title compound. MS: m/e=275 (M+H). 1H NMR (D6-DMSO, δ ppm): 11.64 (s, 1H); 8.30 (t, 1H, J=5.3 Hz); 7.45 (s, 1H); 6.39 (d, 1H, J=3.2 Hz); 6.30 (d, 1H, J=3.2 Hz); 4.26 (d, 2H, J=5.3 Hz); 2.40 (q, 2H, J=7.4 Hz); 2.32 (s, 3H); 1.84 (s, 3H); 1.10 (t, 3H, J=7.4 Hz).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([Si:13]([CH2:18][CH3:19])([CH2:16][CH3:17])[CH2:14][CH3:15])[C:5]2[O:9][C:8]([F:11])([F:10])[O:7][C:6]=2[CH:12]=1.[C:20](=[O:22])=[O:21].[NH4+].[Cl-]>C(OCC)C>[F:10][C:8]1([F:11])[O:9][C:5]2[C:4]([Si:13]([CH2:18][CH3:19])([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:3][C:2]([C:20]([OH:22])=[O:21])=[CH:12][C:6]=2[O:7]1
Reactant: O=C=O
Reactant: CC[Si](CC)(CC)c1cc(Br)cc2c1OC(F)(F)O2
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC[Si](CC)(CC)c1cc(C(=O)O)cc2c1OC(F)(F)O2
Temperature: 35 °C
Reaction time: 0.5 h

Procedure:
200 ml of anhydrous diethyl ether were poured to 1.9 g of Mg turnings and 2.0 g of (6-bromo-2,2-difluoro-benzo[1,3]dioxol-4-yl)-triethyl-silane (Eur. J. Org. Chem. 2004, 1, 64) added. The mixture was then stirred at 35° C. for 30 minutes. Then, the heating was shut down and 23.4 g of (6-bromo-2,2-difluoro-benzo[1,3]dioxol-4-yl)-triethyl-silane was added dropwise to the stirred mixture at a rate that ensured gentle boiling. Stirring was continued at 35° C. for 2 h. Then, the mixture was intensly stirred at room temperature under an excess of anhydrous CO2 for 2 h. The reaction mixture was then poured into 300 ml of a saturated aqueous NH4Cl-solution, acidified to pH=3 using aqueous HClI-solution and the organic layer separated. The aqueous layer was then extracted using 200 ml of diethyl ether. The combined organic layer was dried using MgSO4 and evaporated to yield 22.0 g of the title compound that was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[N+]([C:14]1[CH:19]=[CH:18][N+:17]([O-:20])=[CH:16][CH:15]=1)([O-])=O.C([O-])([O-])=O.[Cs+].[Cs+].FC(F)(F)C(O)=O>CN(C)C=O.C(#N)C.O>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][O:5][C:14]1[CH:19]=[CH:18][N+:17]([O-:20])=[CH:16][CH:15]=1
Reactant: O=[N+]([O-])c1cc[n+]([O-])cc1
Reactant: OCc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Solvent: CN(C)C=O
Product: [O-][n+]1ccc(OCc2ccc(F)cc2F)cc1
Temperature: 80 °C
Yield: 96 %

Procedure:
2,4-difluorobenzyl alcohol (100. g, 0.694 mol) and 4-nitropyridine N-oxide (98. g, 0.700 mol)are combined with 250 g Cs2CO3 (1.1 eq) in 2.5 L anhydrous dimethylformamide and heated to 80° C. with stirring. The reaction was followed by 19F-NMR (crude reaction mixture with external D2O reference) and complete after 40 h. The mixture was filtered hot; product crystallized out on cooling. 90.21 g (55%) of white plates were collected by filtration and washed with diethyl ether. The mother liquor was diluted with 2.5 L diethyl ether and stored in the freezer overnight, yielding a second crop 68.76 g (41%, combined yield 96%). 1H-NMR (400 MHz, DMSO-d6) δ 8.06 (m, 2H), 7.61 (quartet, J=8.45 Hz, 1H), 7.30 (t, J=10.37 Hz, 1H), 7.12, (t, J=8.45 Hz, 1H), 7.09 (d, J=5.06 Hz, 2H), 5.14 (s, 2H). 19F-NMR (400 MHz, DMSO-d6) δ −109.43 (quintet, J=7.78 Hz, 1F), −113.82 (quartet, J=9.55 Hz, 1F). LC/MS tr=3.90 minutes (0-95% acetonitrile/water, 0.05% trifluoroacetic acid, over 6 minutes at 1 ml/min with detection at 215 nm, at 50° C.) ES-MS m/z 238 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[F:19].[CH3:20][N:21]([CH3:26])[S:22](Cl)(=[O:24])=[O:23].Cl>N1C=CC=CC=1>[F:19][C:13]1[CH:14]=[C:15]([F:18])[CH:16]=[CH:17][C:12]=1[O:11][C:3]1[CH:4]=[C:5]([C:8](=[O:10])[CH3:9])[CH:6]=[CH:7][C:2]=1[NH:1][S:22](=[O:24])(=[O:23])[N:21]([CH3:26])[CH3:20]
Reactant: CC(=O)c1ccc(N)c(Oc2ccc(F)cc2F)c1
Reactant: CN(C)S(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)c1ccc(NS(=O)(=O)N(C)C)c(Oc2ccc(F)cc2F)c1
Temperature: 80 °C
Reaction time: 11 h
Yield: 33.4 %

Procedure:
A mixture of 4'-amino-3'-(2,4-difluorophenoxy)acetophenone (2.0 g) and dimethylsulfamoyl chloride (11 g) in pyridine (20 ml) was stirred for 11 hours at 80° C. After cooling, the reaction mixture was poured into 2N aqueous solution of hydrochloric acid (200 ml) and extracted with ethyl acetate. The extract was washed with water, dried, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (100 g) eluting with a mixture of toluene and ethyl acetate (20:1), and recrystallized from a mixture of ethanol and water (2:1, 15 ml) to give prisms of 3'-(2,4-difluorophenoxy)-4'-(dimethylsulfamoylamino)acetophenone (0.94 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[C@@H:7]([N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][C:10]1=[O:18])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:20][C:21]1[C:29]2[C:28]([CH2:30]O)=[CH:27][S:26][C:25]=2[CH:24]=[CH:23][CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:19])[C@@H:7]([N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]([CH2:30][C:28]2[C:29]3[C:21]([CH3:20])=[CH:22][CH:23]=[CH:24][C:25]=3[S:26][CH:27]=2)[C:10]1=[O:18])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H](C(=O)OC(C)(C)C)n1c(=O)[nH]c2ccccc21
Reactant: Cc1cccc2scc(CO)c12
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Product: Cc1cccc2scc(Cn3c(=O)n([C@@H](C)C(=O)OC(C)(C)C)c4ccccc43)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.7 %

Procedure:
To a solution of (S)-2-(2-Oxo-2,3-dihydro-benzimidazol-1-yl)-propionic acid tert-butyl ester (0.3 g, 0.46 mmol), (4-Methyl-benzo[b]thiophen-3-yl)-methanol (0.12 g, 0.69 mmol), and triphenylphosphine (0.14 g, 0.55 mmol) was added dropwise DIAD (0.11 mL, 0.55 mmoL) at 0° C. The mixture was slowly warmed to room temperature and stirred for 2 h. The reaction mixture was diluted with ethyl acetate and washed with water (×2). The organic phase was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel prep TLC using 4:1 Hexanes:ethyl acetate as an eluent to afford 0.12 g (62%) of the desired product as a brownish oil. This product was not pure (˜70% pure by 1H-NMR), but was used for the next reaction without further purification.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:24])[CH2:15][NH:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:9][CH:8]=2)[N:6]=1.[CH:25]1([C:31]([OH:33])=O)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:24])[CH2:15][N:16]([CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:31]([CH:25]3[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]3)=[O:33])=[CH:9][CH:8]=2)[N:6]=1
Reactant: Nc1nc(-c2ccc(NC(=O)CNCc3ccccc3)cc2)cs1
Reactant: O=C(O)C1CCCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(-c2ccc(NC(=O)CN(Cc3ccccc3)C(=O)C3CCCCC3)cc2)cs1
Temperature: 25 °C
Reaction time: 6 h
Yield: 73.1 %

Procedure:
To a solution of N-{4-(2-amino-4-thiazolyl)phenyl)-2-{(phenylmethyl)amino}acetamide (352 mg, 1.04 mmol, described in example 2), cyclohexanecarboxylic acid (140 mg, 1.09 mmol) and DIPEA (269 mg, 2.08 mmol) in DMF (5.2 mL) was added TBTU (350 mg, 1.09 mmol). The mixture was stirred at room temperature for 6 h. The reaction mixture was diluted with EtOAc (125 mL). The resulting solution was washed with saturated aqueous NaHCO3 (40 mL), H2O (40 mL), and brine (40 mL), then dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, CHCl3: EtOH, 15:1) to yield the title compound (341 mg, 73% yield) as a white solid: M.p. 214.5-215.5°; 1H NMR (400 MHz, DMSO-d6) δ(2 rotamers, 1:1) 10.06, 9.92 (2 s, 1H), 7.73, 7.71 (2 d, J=8.5 Hz, 2H), 7.56, 7.55 (2 d, J=8.5 Hz, 2H), 7.20-7.41 (m, 5H), 7.01, 7.00 (2 s, 2H), 6.89, 6.88 (2 s, 1H), 4.70, 4.51 (2 s, 2H), 4.13, 4.02 (2 s, 2H), 2.64, 2.56 (2 broad t, J=10.5 Hz, 1H), 1.61-1.70 (m, 5H), 1.12-1.46 (m, 5H); MS (FAB) m/z 449 (MH)+; Anal. Calcd for C25H28N4O2S: C, 66.94; H, 6.29; N, 12.49. Found: C, 66.54; H, 6.29; N, 12.32.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]([OH:24])[CH:11]([C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=1)[CH2:12][CH2:13][CH2:14][OH:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CN=C1.[C:30]([Si:34]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)Cl)([CH3:33])([CH3:32])[CH3:31]>CN(C)C=O.C(OCC)(=O)C>[Si:1]([O:8][CH2:9][CH:10]([OH:24])[CH:11]([C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=1)[CH2:12][CH2:13][CH2:14][O:15][Si:34]([C:30]([CH3:33])([CH3:32])[CH3:31])([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCC(O)C(CCCO)C(=O)c1cccnc1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCC(O)C(CCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4.69 g (0.0133 mole) of 1-(t-butyldimethylsilyloxy)-3-nicotinoylhexan-2,6-diol, 2.18 g (0.032 mole) of imidazole in 12 ml of dimethylformamide is added at once 4.38 g (0.0159 mole) of t-butyldiphenylchlorosilane, the mixture is stirred at room temperature overnight, diluted with 30 ml of ethyl acetate and washed with water (2×10 ml) and brine, dried (MgSO4) and evaporated. The residue is purified by flash chromatography using ethyl acetate-methylene chloride (2:3) as eluent to give 1-(t-butyldimethylsilyloxy)-6-(t-butyldiphenylsilyloxy)-3-nicotinoylhexan-2-ol as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([OH:9])=[C:4]([CH2:10][CH3:11])[N:3]=1.O.[OH-].[Li+].[CH3:15][C:16]1[CH:25]=[C:24]([O:26][CH2:27][CH2:28][CH2:29]Br)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([O:9][CH2:29][CH2:28][CH2:27][O:26][C:24]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=[C:16]([CH3:15])[CH:25]=2)=[C:4]([CH2:10][CH3:11])[N:3]=1
Reactant: Cc1cc(OCCCBr)c2ccccc2n1
Reactant: CCc1nc(N)nc(N)c1O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nc(N)nc(N)c1OCCCOc1cc(C)nc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
A mixture of 2,4-diamino-6-ethyl-5-hydroxypyrimidine (0.539 g, 3.5 mmol) and lithium hydroxide monohydrate (0.294 g, 7.0 mmol) in DMF (10 mL) was stirred at 25° C. for 1 hour after that 3-(2-methylquinolin-4-yloxy)propyl bromide (0.980 g, 3.5 mmol) was added to the reaction mixture and the reaction mixture was left to stir at 25° C. overnight. Two thirds of the DMF was evaporated under vacuum and the reaction mixture was poured in water, solid was separated by filtration and dried in oven at 80° C. The crude product was purified by column chromatography on silica gel (4% MeOH: 96% CH2Cl2 as eluent) to obtain title compound as light yellow solid (0.5814 g, 47%). 1H NMR (400 MHz, DMSO-d6): 0.90 (3H, t, J=7.6 Hz), 2.30 (4H, m), 2.60 (3H, s), 3.86 (2H, t, J=5.9 Hz), 4.41 (2H, t, J=5.9 Hz), 5.59 (2H, s), 6.16 (2H, s), 6.97 (1H, s), 7.46 (1H, t, J=7.7 Hz), 7.67 (1H, t, J=7.7 Hz), 7.84 (1H, d, J=8.4 Hz), 8.09 (1H, d, J=8.2 Hz).
Reaction SMILES: [CH:1]1([C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[C:5]=2[C:6](=O)[C:7](=[O:14])[N:8]3[CH3:13])[CH2:3][CH2:2]1.O.NN>ClCCl.O>[CH:1]1([C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[C:5]=2[CH2:6][C:7](=[O:14])[N:8]3[CH3:13])[CH2:3][CH2:2]1
Reactant: CN1C(=O)C(=O)c2c(C3CC3)cccc21
Agent: NN
Solvent: ClCCl
Solvent: O
Product: CN1C(=O)Cc2c(C3CC3)cccc21
Temperature: 130 °C
Reaction time: 4 h

Procedure:
4-Cyclopropyl-1-methyl-1H-indole-2,3-dione (1.0 g, 4.2 mmol) was treated with hydrazine hydrate (7.0 mL, 225 mmol). The reaction was heated to 130° C. and stirred for 4 hours, at which time the reaction temperature was elevated to 150° C. for another 1.5 hours. The reaction was then placed at room temperature and cooled by the addition of ice. Once the reaction was cooled to room temperature it was diluted with dichloromethane and water and the layers were separated. The aqueous layer was extracted an additional two times with dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (ethyl acetate-heptane, 0 to 60%) to afford 4-cyclopropyl-1-methyl-1,3-dihydro-indol-2-one; MS: (ES+) ink 188.4 (M+H)+.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[O:24][C:25](=[O:27])[CH3:26])[CH2:6]1)(=[O:3])[CH3:2].CC1(C)N(Br)C(=O)N(Br)C1=O.C(=O)(O)[O-].[Na+]>CCCCCC>[C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH:9]=[C:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[O:24][C:25](=[O:27])[CH3:26])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H](OC(C)=O)[C@@]4(C)CC[C@@H]32)C1
Agent: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC=C3[C@@H]4CC[C@H](OC(C)=O)[C@@]4(C)CC[C@@H]32)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A mixture of androst-5-ene -3β,17β-diol diacetate (3.75 g, 10 mmol), dibromantin (2.03 g, 7 mmol), and sodium bicarbonate (4.54 g, 54 mmol) in hexane (200 ml) is heated under reflux for 0.5 hours. The mixture is then cooled and filtered and the filtrate evaporated to dryness. The residue is dissolved in 50 ml toluene and treated with lithium bromide (2 g) in 5 ml of acetone. The mixture is stirred at 0° C. for 2 hours and then treated with 2 ml triethylamine and 1.5 ml benzenethiol. After stirring at room temperature for 1.5 hours, 100 ml ethyl acetate is added and the organic solution is washed with 1N hydrochloric acid and water. The organic phase is dried and concentrated. The residue is then redissolved in 75 ml ethyl acetate, cooled to 0° C. and treated with 2.6 g of m chloroperbenzoic acid for 2 hours. The mixture is washed with 10% sodium bicarbonate solution and then concentrated. The residue is dissolved in 100 ml toluene, treated with triethylamine (3.6 ml), heated at 70° C. for 24 hours, cooled, and washed with water. The organic solution was concentrated and chromatographed to yield androst-5,7-diene-3β,17β-diol diacetate. The diacetate is treated with K2CO3 in a 10:1 methanol:water solution overnight to yield, after extractive workup, androst-5,7-diene-3β,17β-diol.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2].[Br:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][CH2:18][CH2:17]2.C(N(CC)CC)C>ClCCl>[Br:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[N:19]([S:9]([C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)(=[O:11])=[O:10])[CH2:18][CH2:17]2
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Brc1ccc2c(c1)CCN2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1ccc(S(=O)(=O)N2CCc3cc(Br)ccc32)cc1
Temperature: 25 °C

Procedure:
5.09 g of commercially available 4-cyano-benzenesulfonyl chloride were dissolved in 125 ml dichloromethane. Then 5.0 g 5-Bromo-2,3-dihydro-1H-indole were added followed by 12.2 ml triethylamine. The mixture was stirred at room temperature for thirty minutes. Then the solvent was removed in vacuo. The residue was diluted with 100 ml of ethyl acetate and the mixture washed with 100 ml water and 100 ml saturated NaHCO3 solution. The organic layer was then dried over MgSO4. The solvent was removed in vacuo. The resulting crude material was purified by chromatography on silica gel to obtain 5.46 g of 4-(5-Bromo-2,3-dihydro-indole-1-sulfonyl)-benzonitrile.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH2:6][C:5]2[S:8][C:9]([C:11]([O-:13])=O)=[N:10][C:4]=2[CH2:3]1.[Li+].Cl.[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([S:27]([N:30]1[CH2:35][CH2:34][NH:33][CH:32]([C:36](=[O:47])[NH:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[O:45][CH3:46])[CH2:31]1)(=[O:29])=[O:28])[CH:21]=[CH:20]2>>[ClH:16].[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([S:27]([N:30]1[CH2:35][CH2:34][N:33]([C:11]([C:9]3[S:8][C:5]4[CH2:6][NH:7][CH:2]([CH3:1])[CH2:3][C:4]=4[N:10]=3)=[O:13])[CH:32]([C:36](=[O:47])[NH:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[O:45][CH3:46])[CH2:31]1)(=[O:28])=[O:29])[CH:21]=[CH:20]2
Reactant: COc1ccccc1CNC(=O)C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1
Reactant: CC1Cc2nc(C(=O)[O-])sc2CN1
Agent: Cl
Agent: [Li+]
Product: COc1ccccc1CNC(=O)C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1C(=O)c1nc2c(s1)CNC(C)C2

Procedure:
Starting materials: lithium 6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate, 1-[(6-chloronaphthalen-2-yl)sulfonyl]-3-[[N-(2-methoxybenzyl)]carbamoyl]piperazine hydrochloride
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH2:10][CH:9]([CH:14]=[O:15])[CH2:8]2)([CH3:4])([CH3:3])[CH3:2].[CH2:16](O)[CH2:17][OH:18].C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>C1CCCCC1>[C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH2:10][CH:9]([CH:14]1[O:18][CH2:17][CH2:16][O:15]1)[CH2:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: OCCO
Reactant: CC(C)(C)c1ccc2c(c1)CC(C=O)C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCCCC1
Product: CC(C)(C)c1ccc2c(c1)CC(C1OCCO1)C2

Procedure:
A mixture of 5-tert-butyl-2-indancarbaldehyde (ex. 4; 9.8mmole), ethyleneglycol (6.1 g, 98 mmole) and p-toluenesulfonic acid (95 mg, 0.5 mmole) in cyclohexane (25 ml), was heated to reflux (80°) during 3 h with a Dean-Stark type trap. The cooled mixture was poured on ether and aq. sat. NaHCO3, and the organic phase was washed with aq. sat. NaHCO3, dried over K2CO3 and concentrated. After bulb-to-bulb distillation, the desired dioxolane was obtained.