Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH:6]=[O:7])[N:3]=[CH:2]1.[H-].[Na+].[CH3:10][CH2:11][CH2:12]Br.C1OCCOCCOCCOCCOCCOC1.[Cl-].[NH4+]>O1CCCC1>[CH2:10]([N:1]1[CH:5]=[C:4]([CH:6]=[O:7])[N:3]=[CH:2]1)[CH2:11][CH3:12]
Reactant: O=Cc1c[nH]cn1
Reactant: CCCBr
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: CCCn1cnc(C=O)c1
Reaction time: 0.75 h
Yield: 47 %

Procedure:
Imidazole-4-carboxaldehyde (30g, 0.31 mol) was added portionwise to a solution of sodium hydride (13.9 g, 60% dispersion in mineral oil, 0.348 mol) in tetrahydrofuran (450 ml), and the solution was stirred for 45 minutes. n-Propyl bromide (31.2 ml, 0.344 mol) was then added portionwise, followed by 18-crown-6 (150 mg), and the mixture was heated under reflux for 18 hours. Aqueous ammonium chloride solution was added to the cooled solution, and the mixture was extracted with ethyl acetate (2×) and dichloromethane (2×). The combined organic extracts were dried (MgSO4), filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with ethyl acetate:pentane (40:60), to give the title compound, 20.2 g, 47% yield. 1H-NMR (DMSO-d6, 400 MHz) δ: 0.80 (t, 3H), 1.76 (m, 2H), 3.98 (t, 2H), 7.84 (s, 1H), 8.04 (s, 1H), 9.70 (s, 1H). LRMS: m/z (TSP+) 277.3 [2M+H]+
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[S:8][C:9]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][N:11]=2)[CH2:3]1.[F:16][C:17]([F:26])([F:25])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[F:16][C:17]([F:26])([F:25])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[O:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[S:8][C:9]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][N:11]=2)[CH2:3]1
Reactant: COC(=O)c1cnc(N2CCC(O)C2)s1
Reactant: Oc1ccccc1C(F)(F)F
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cnc(N2CCC(Oc3ccccc3C(F)(F)F)C2)s1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of methyl 2-(3-hydroxypyrrolidin-1-yl)-1,3-thiazole-5-carboxylate (1 g, 4.4 mmol), 2-(trifluoromethyl)phenol (0.8 g, 4.9 mmol) and triphenylphosphine (1.5 g, 5.7 mmol) in THF at rt was added DEAD (900 μL, 5.7 mmol) over 5-10 min. The mixture was stirred at rt for 2 days. Solvent was evaporated. The residue was diluted with EtOAc and washed successively with 1 N aqueous NaOH and brine. The EtOAc layer was separated, dried (Na2SO4) and concentrated. CombiFlash chromatography (40 g, 30-70% EtOAc in hexanes in 20 min, 35 mL/min, 18 mL/fraction) gave a semi-solid which was triturated with hexanes-diethyl ether to give a white solid which was filtered off. Crystals appeared in the mother liquor after standing. These crystals were collected to give the title compound, contaminated with about 5-10% impurity. 1H NMR (400 MHz, acetone-d6): δ 7.84 (s, 1 H), 7.67 (m, 2 H), 7.41 (d, 1 H), 7.17 (t, 1H), 5.51 (s, 1H), 3.95 (m, 1H), 3.80-3.65 (m, 6H), 2.60-2.46 (m, 2H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20][C:21]1[CH:22]=[CH:23][C:24](I)=[C:25]([CH:34]=1)[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:27].[CH2:36]([N:39]1[C:43](=[O:44])[C:42]2=[CH:45][CH:46]=[CH:47][CH:48]=[C:41]2[C:40]1=[O:49])[C:37]#[CH:38]>[Pd](Cl)Cl.C(Cl)Cl>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([C:38]#[C:37][CH2:36][N:39]2[C:43](=[O:44])[C:42]3=[CH:45][CH:46]=[CH:47][CH:48]=[C:41]3[C:40]2=[O:49])=[C:25]([C:26](=[O:27])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:34]=1
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1I
Reactant: C#CCN1C(=O)c2ccccc2C1=O
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(c1ccccc1)c1cc(Cl)ccc1C#CCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C

Procedure:
A mixture of 0.71 g (4.0 mmole) of palladium chloride, 2.1 g (8.0 mmole) of triphenylphosphine, 0.80 g (4.2 mmole) of cuprous iodide, 68.8 g (0.20 mole) of 5-chloro-2-iodobenzophenone, 200 ml ofdiethylamine, and 400 ml of methylene chloride was stirred at room temperature under argon until complete solution was obtained. In one portion, 40.0 g (0.22 mole) of N-propargylphthalimide was added to the solution and the resulting mixture stirred for 20 hr. The volatiles were removed at reduced pressure and the residue was triturated with 200 ml of isopropanol. The resulting percipitate was collected by filtration to give crude end product. Recrystallization from acetone gave cream colored prisms, mp 148°-150° C.
Reaction SMILES: [P:1]([CH2:5][N:6](CC(O)=O)[CH2:7][C:8]([OH:10])=[O:9])([OH:4])([OH:3])=[O:2].O=O>[Pd].O>[P:1]([CH2:5][NH:6][CH2:7][C:8]([OH:10])=[O:9])([OH:4])([OH:3])=[O:2]
Reactant: O=C(O)CN(CC(=O)O)CP(=O)(O)O
Agent: [Pd]
Agent: O=O
Solvent: O
Product: O=C(O)CNCP(=O)(O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
A mixture of 10 g. of N-(phosphonomethyl) iminodiacetic acid, 170 mls. of water and 0.6 g. of commercial 5% palladium on carbon catalyst was placed in a pressure vessel and oxygen admitted to a pressure of 30 pounds per square inch. The mixture was continuously shaken at this pressure for 3 hours while maintaining the temperature at 90°-100°C. After cooling to room temperature, excess oxygen was vented, the catalyst removed by filtration and the filtrate concentrated to dryness at reduced pressure. The yield of 97% pure N-phosphonomethyl glycine was 7.3 g. (96% yield).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[N:16]=[N:17][C:18]([CH2:36][CH2:37][CH2:38][CH3:39])=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[C:23]([C:34]#[N:35])[CH:22]=3)[CH:20]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(Cl)[Cl:41]>Cl.O1CCOCC1>[ClH:41].[ClH:41].[CH2:36]([C:18]1[N:17]=[N:16][C:15]([O:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:20][C:19]=1[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[C:23]([CH:22]=1)[C:34]#[N:35])[CH2:37][CH2:38][CH3:39]
Reactant: CCCCc1nnc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1-c1ccc(OC2CCCCC2)c(C#N)c1
Reactant: ClCCl
Agent: Cl
Solvent: C1COCCO1
Product: CCCCc1nnc(OC2CCNCC2)cc1-c1ccc(OC2CCCCC2)c(C#N)c1
Reaction time: 0.5 h

Procedure:
To a stirring solution of 4-[6-butyl-5-(3-cyano-4-cyclohexyloxy-phenyl)-pyridazin-3-yloxy]-piperidine-1-carboxylic acid tert-butyl ester (0.025 g, 0.046 mmol) in DCM (2.0 mL), 4.0 M HCl in dioxane (2.0 mL) was added and stirring continued for 30 min. Solvent evaporated, resulting solid was washed with ether, dried to get 5-[3-Butyl-6-(piperidin-4-yloxy)-pyridazin-4-yl]-2-cyclohexyloxy-benzonitrile dihydrochloride (22 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.[Cl:21][C:22]1[C:27]2[NH:28][C:29]([CH3:31])=[N:30][C:26]=2[CH:25]=[C:24]([O:32][C:33]2[CH:38]=[C:37](Cl)[N:36]=[CH:35][N:34]=2)[CH:23]=1.CCN(C(C)C)C(C)C.O>CN(C=O)C>[Cl:21][C:22]1[C:27]2[NH:28][C:29]([CH3:31])=[N:30][C:26]=2[CH:25]=[C:24]([O:32][C:33]2[N:34]=[CH:35][N:36]=[C:37]([N:17]3[CH2:18][CH2:19][CH:14]([N:10]4[CH2:9][CH2:8][C:7]5[CH:20]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=5[NH:12][C:11]4=[O:13])[CH2:15][CH2:16]3)[CH:38]=2)[CH:23]=1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Reactant: Cc1nc2cc(Oc3cc(Cl)ncn3)cc(Cl)c2[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(Oc4cc(Cl)c5[nH]c(C)nc5c4)ncn3)CC1)C(=O)N2

Procedure:
100 mg (0.36 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 110 mg (0.37 mmol) 7-chloro-5-(6-chloropyrimidin-4-yloxy)-2-methyl-1H-benzo[d]-imidazole and 0.14 mL (0.81 mmol) DIPEA in 2.0 mL DMF were stirred for 3 h at RT and 4 h at 40° C. The reaction mixture was mixed with water. The precipitate formed was suction filtered, washed and dried. The substance was purified by preparative HPLC-MS. The fractions containing product were combined and freeze-dried.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[NH:12][NH:11][C:10]2=[O:15])[CH:5]=[CH:6][C:7]=1[Cl:8].[OH-].[Na+].[Cl:18][C:19]([Cl:23])([Cl:22])[S:20]Cl>O>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:10](=[O:15])[N:11]([S:20][C:19]([Cl:23])([Cl:22])[Cl:18])[N:12]([S:20][C:19]([Cl:23])([Cl:22])[Cl:18])[C:13]2=[O:14])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=c1[nH][nH]c(=O)n1-c1ccc(Cl)c(Cl)c1
Reactant: ClSC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=c1n(-c2ccc(Cl)c(Cl)c2)c(=O)n(SC(Cl)(Cl)Cl)n1SC(Cl)(Cl)Cl

Procedure:
To a solution of 24.6g (0.1 mole) 4-(3,4-dichlorophenyl)urazole in 100 ml water was added a solution of 8g (0.2 mole) sodium hydroxide in 10 ml water. A mixture of 37.2g (0.2 mole) trichloromethylsulfenyl chloride and 1.5g of an emulsifier solution (as in example 1) in 25 ml water was added dropwise to the above basic solution while keeping the reaction mixture at 0° C. The precipitate that formed was filtered and the filter cake was washed with water. After drying and recrystallizing from benzene there was obtained 48g (87%) of 4-(3,4-dichlorophenyl)-1,2-bis(trichloromethylthio)urazole having a melting point of 167° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:20]([CH3:22])=[O:21])[C:3]=1[CH3:23].[O:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:31]=[C:32]([NH2:36])[CH:33]=[N:34][CH:35]=2)[CH2:26][CH2:25]1>C1(C)C=CC=CC=1>[F:12][C:10]1[CH:9]=[C:8]([F:13])[CH:7]=[C:6]2[C:11]=1[C:2]([NH:36][C:32]1[CH:33]=[N:34][CH:35]=[C:30]([N:27]3[CH2:28][CH2:29][O:24][CH2:25][CH2:26]3)[CH:31]=1)=[C:3]([CH3:23])[C:4]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20]([CH3:22])=[O:21])=[N:5]2
Reactant: Cc1c(-c2ccccc2S(C)=O)nc2cc(F)cc(F)c2c1Cl
Reactant: Nc1cncc(N2CCOCC2)c1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccc2S(C)=O)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1

Procedure:
Essentially prepared according to Procedure H using (+/−)-4-chloro-5,7-difluoro-3-methyl-2-(2-(methylsulfinyl)phenyl)quinoline (30.0 mg, 0.085 mmol) and 5-morpholinopyridin-3-amine in toluene to give 5,7-difluoro-3-methyl-2-(2-(methylsulfinyl)phenyl)-N-(5-morpholinopyridin-3-yl)quinolin-4-amine. 1H NMR (CDCl3) δ ppm 8.22 (1H, dd, J=7.9, 1.1 Hz), 7.96 (1H, d, J=2.3 Hz), 7.81 (1H, d, J=2.2 Hz), 7.73 (1H, td, J=7.7, 1.3 Hz), 7.63 (1H, td, J=7.5, 1.3 Hz), 7.50 (1H, ddd, J=9.2, 2.5, 1.4 Hz), 7.39 (1H, dd, J=7.6, 1.2 Hz), 7.20 (1H, d, J=14.1 Hz), 7.08 (1H, ddd, J=13.9, 8.4, 2.5 Hz), 6.60 (1H, t, J=2.2 Hz), 3.80-3.93 (4H, m), 3.12-3.28 (4H, m), 2.87 (3H, s), 1.98 (3H, s). Mass Spectrum (ESI) m/e=495.2 (M+1).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([CH:20]=[O:21])[C:6]2[CH:7]=[CH:8][N:9]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:10]=2[CH:11]=1.[BH4-].[Na+]>CO>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][N:9]2[CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:17])([CH3:18])[CH3:19])=[C:5]([CH2:20][OH:21])[CH:4]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(C=O)cc(C(F)(F)F)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C[Si](C)(C)CCOCn1ccc2c(CO)cc(C(F)(F)F)cc21
Reaction time: 1 h

Procedure:
A solution of 6-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-4-carbaldehyde (0.95 g, 2.77 mmol) in methanol (20 ml) at 25° C. was treated with sodium borohydride (0.209 g, 5.53 mmol) and stirred for 1 h. The resulting solution was concentrated in vacuo, taken up in ethyl acetate, washed with brine, dried over sodium sulfate and re-concentrated to a light yellow oil. Column chromatography (ethyl acetate/hexanes gradient elution) afforded 0.91 g (95%) as a colorless oil. 1H-NMR (CDCl3, 500 MHz) δ ppm 7.74 (s, 1H), 7.41 (m, 2H), 6.73 (m, 1H), 5.46 (s, 2H), 5.10 (s, 2H), 3.46 (m, 2H), 0.88 (m, 2H), −0.07 (s, 9H). Mass spec.: 346.17 (MH)+.
Reaction SMILES: [S:1]1[C:5](B(O)O)=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.Br[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1>>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:5]2[S:1][C:2]3[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=3[CH:4]=2)=[CH:15][CH:16]=1
Reactant: OB(O)c1cc2ccccc2s1
Reactant: COc1ccc(Br)cc1
Product: COc1ccc(-c2cc3ccccc3s2)cc1
Yield: 91 %

Procedure:
The title compound was prepared in 91% yield from benzo[b]thiophene-2-boronic acid and 4-bromoanisole by using a coupling procedure similar to that described below in Example 14-A.
Reaction SMILES: [Si]([O:8][C@H:9]([C@H:44]1[CH2:48][C@@H:47]([O:49][CH2:50][CH2:51][CH3:52])[CH2:46][N:45]1C(OC(C)(C)C)=O)[C@@H:10](NC(=O)C1C=C(C2OC=CN=2)C=C(C(N2CCC[C@@H]2COC)=O)C=1)[CH2:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=1)(C(C)(C)C)(C)C.[Si](O[C@H:68]([C@H]1C[C@@H](OCCC)CN1C(OC(C)(C)C)=O)[C@@H:69]([NH:79][C:80](=[O:90])[C:81]1[CH:86]=[CH:85][CH:84]=[C:83]([C:87](=[O:89])[NH2:88])[CH:82]=1)[CH2:70][C:71]1[CH:76]=[C:75]([F:77])[CH:74]=[C:73](F)C=1)(C(C)(C)C)(C)C.C(OC(N1C[C@H](OCCC)C[C@@H]1[C@@H](O[Si](C(C)(C)C)(C)C)[C@@H](NC(C1C=C(C=CC=1)C(O)=O)=O)CC1C=C(F)C=C(F)C=1)=O)(C)(C)C.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.FC1C=CC(C(N)C)=CC=1>ClCCl>[F:19][C:14]1[CH:13]=[C:12]([CH2:11][C@H:10]([NH:88][C:87](=[O:89])[C:83]2[CH:84]=[CH:85][CH:86]=[C:81]([C:80]([NH:79][CH:69]([C:70]3[CH:71]=[CH:76][C:75]([F:77])=[CH:74][CH:73]=3)[CH3:68])=[O:90])[CH:82]=2)[C@H:9]([OH:8])[C@H:44]2[CH2:48][C@@H:47]([O:49][CH2:50][CH2:51][CH3:52])[CH2:46][NH:45]2)[CH:17]=[C:16]([F:18])[CH:15]=1
Reactant: CCCO[C@@H]1C[C@H]([C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cc(C(=O)N3CCC[C@@H]3COC)cc(-c3ncco3)c2)N(C(=O)OC(C)(C)C)C1
Reactant: CCCO[C@@H]1C[C@H]([C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cccc(C(N)=O)c2)N(C(=O)OC(C)(C)C)C1
Agent: CC(N)c1ccc(F)cc1
Agent: CCCO[C@@H]1C[C@H]([C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cccc(C(=O)O)c2)N(C(=O)OC(C)(C)C)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCO[C@H]1CN[C@@H]([C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cccc(C(=O)NC(C)c3ccc(F)cc3)c2)C1
Reaction time: 0.33 h
Yield: 84 %

Procedure:
Step 16 (A): (2R,4R)-tert-Butyl 2-((1S,2S)-1-(tert-butyldimethylsilyloxy)-2-(3-(carbamoyl)benzamido)-3-(3,5-difluorophenyl)propyl)-4-propoxypyrrolidine-1-carboxylate. To a solution of 3-(((1S,2S)-1-((2R,4R)-1-(tert-butoxycarbonyl)-4-propoxypyrrolidin-2-yl)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)propan-2-yl)carbamoyl)benzoic acid (Step 1 (C), 40 mg, 0.06 mmol) in dichloromethane (1.5 mL) was added Hunig's base (24 mg, 0.18 mmol) to make a clear solution and HATU (28 mg, 0.072 mmol) was then added. After stirring for 20 min, the reaction mixture was added 1-(4-fluorophenyl)ethanamine (17 mg, 0.12 mmol) and the reaction mixture was stirred at rt overnight. The reaction mixture was concentrated under vacuum and purified by silica gel Flash Chromatography (0% to 15% to 30% EtOAc/Hexane step gradient) to give 38 mg of the title compound (84% yield): 1H NMR (CDCl3, 500 MHz) δ 0.02 (3H, s), 0.05 (3H, s), 0.84 (9H, s), 0.89 (3H, m), 1.47 (9H, s), 1.50 (2H, m), 1.58 (3H, d, J=5 Hz), 2.00-2.05 (1H, m), 2.22 (1H, m), 2.64 (1H, m), 2.86-2.92 (1H, m), 3.28-3.37 (3H, m), 3.76 (1H, m), 4.00 (1H, m), 4.07-4.12 (2H, m), 4.61 (1H, m), 5.31 (1H, m), 6.51-6.52 (1H, m), 6.60 (1H, m), 6.77 (2H, d, J=10 Hz), 7.00 (2H, m), 7.34 (2H, dd, J=5, 10 Hz), 7.49 (1H, m), 7.99-8.02 (2H, m), 8.20 (1H, s), 8.33 (1H, m). MS (ESI) (M+H)+ 798.46.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:22]=[CH:21][C:20]2[C@:19]3([OH:23])[C@H:10]([C@H:11]4[C@@:15]([CH2:17][C@@H:18]3[OH:24])([CH3:16])[C:14](=[O:25])[CH2:13][CH2:12]4)[CH2:9][CH2:8][C:7]=2[CH:6]=1)(=[O:3])[CH3:2].[Cr](O)(O)(=O)=O.CO.O>CC(C)=O>[C:1]([O:4][C:5]1[CH:22]=[CH:21][C:20]2[C@:19]3([OH:23])[C@H:10]([C@H:11]4[C@@:15]([CH2:17][C:18]3=[O:24])([CH3:16])[C:14](=[O:25])[CH2:13][CH2:12]4)[CH2:9][CH2:8][C:7]=2[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc2c(c1)CC[C@H]1[C@@H]3CCC(=O)[C@@]3(C)C[C@H](O)[C@]21O
Agent: O=[Cr](=O)(O)O
Solvent: CO
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)Oc1ccc2c(c1)CC[C@H]1[C@@H]3CCC(=O)[C@@]3(C)CC(=O)[C@]21O
Reaction time: 0.08 h
Yield: 36 %

Procedure:
3-Acetoxy-9α,11β -dihydroxy-oestra-1,3,5(10)-trien-17-one (690 mg.) in acetone (30 ml) at 5° was treated dropwise with stirring with 8N chromic acid (1.0 ml). The solution was stirred for 5 mins. then methanol (1 ml), and water (30 ml) were added. The organic solvents were distilled off in vacuo and the steroid extracted into ethyl acetate. The organic solution was washed with dilute hydrochloric acid, then water, dried and the solvent was evaporated. The resulting gum was crystallised from methanol to give the title compound (247 mg, 36%), m.p. 247°-8°, [α]D + 297° (c. 1.0 in dioxan).
Reaction SMILES: [CH2:1]([N:7]1[C:18](=[O:19])[C:17]2[N:15]([CH3:16])[CH:14]=[N:13][C:12]=2[N:10](C)[C:8]1=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH-].[Na+]>C(Cl)(Cl)Cl.C(O)C>[CH2:1]([NH:7][C:18]([C:17]1[N:15]([CH3:16])[CH:14]=[N:13][C:12]=1[NH:10][CH3:8])=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CCCCCCNC(=O)c1c(NC)ncn1C
Temperature: 25 °C
Yield: 38.4 %

Procedure:
Hexyltheobromine (7.5 g) was added to 60 ml of 3N sodium hydroxide, and the mixture was refluxed at elevated temperatures for 6 hours. After the reaction mixture was cooled to ambient temperature, it was extracted with chloroform and the extract was dried and concentrated under reduced pressure to give the residue which in turn was subjected to silica gel column chromatography using a chloroform/ethanol (25:2(v/v)) eluent, thereby yielding 2.6 g (38%) of 5-hexylaminocarbonyl-1-methyl-4-methylaminoimidazole as an oil. A portion of this product was then treated with an ethanolic solution of picric acid to give its picrate.
Reaction SMILES: [CH:1]([C@H:14]1[O:19][CH2:18][C@@H:17]([NH2:20])[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1.C(O)(=O)C.[BH3-]C#N.[Na+]>ClCCCl.CO>[CH:1]([C@H:14]1[O:19][CH2:18][C@@H:17]([NH:20][CH2:26][C:25]2[CH:28]=[CH:29][C:22]([F:21])=[CH:23][CH:24]=2)[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@H]1CC[C@@H](C(c2ccccc2)c2ccccc2)OC1
Reactant: O=Cc1ccc(F)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: ClCCCl
Product: Fc1ccc(CN[C@H]2CC[C@@H](C(c3ccccc3)c3ccccc3)OC2)cc1
Yield: 80.9 %

Procedure:
Trans-5-amino-2-diphenylmethyl-tetrahydropyran 15 (0.21 g, 0.79 mmol) was reacted with 4-fluorobenzaldehyde (0.098 g, 0.79 mmol) in the presence of glacial acetic acid (0.047 g, 0.79 mmol) in 1,2-dichloroethane (20 ml), and then reduced by NaCNBH3 (0.059 g, 0.95 mmol) in methanol (5 ml) (Procedure D) to give compound 16b (0.24 g, 82%).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[F:16][C:17]1[CH:28]=[CH:27][C:20]([CH2:21][CH:22]([C:24]([OH:26])=[O:25])[NH2:23])=[CH:19][CH:18]=1>>[C:24]([CH:22]([NH:23][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:21][C:20]1[CH:27]=[CH:28][C:17]([F:16])=[CH:18][CH:19]=1)([OH:26])=[O:25]
Reactant: NC(Cc1ccc(F)cc1)C(=O)O
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Product: O=C(O)c1cc2cc(Cl)ccc2nc1NC(Cc1ccc(F)cc1)C(=O)O
Yield: 80 %

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with 4-fluoro-DL-phenylalanine to provide the title compound in 80% yield as yellow needles.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([CH2:13]O)[CH:10]([CH2:15][OH:16])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.S(Cl)(C1C=CC(C)=CC=1)(=O)=O>C1(C)C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH2:1]([N:8]1[CH2:9][CH:10]2[CH2:15][O:16][CH2:13][CH:11]2[CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCC1CN(Cc2ccccc2)CC1CO
Agent: CN(C)c1ccncc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: c1ccc(CN2CC3COCC3C2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 38.6 %

Procedure:
To a solution of (1-benzylpyrrolidine-3,4-diyl)dimethanol (1.44 g) in toluene (60 mL) was added Et3N (1.72 mL), TsCl (1.75 g) and DMAP (40 mg). The reaction mixture was stirred at room temperature for 12 h under N2, washed with water once, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was used for next step. To a solution of the above product in toluene (20 mL) was added Et3N (0.85 mL). The reaction mixture was heated to reflux for 4 h and cooled to room temperature. The reaction mixture was washed with water followed by brine, dried over anhydrous Na2SO4 and filtrated. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (eluting agent: 20:1 (v/v) CH2Cl2/CH3OH) to afford the title compound (0.51 g, 62.30%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 204.3 (M+1); 1H NMR (400 MHz, CDCl3) δ: 2.31-2.35 (m, 2H), 2.71 (m, 2H), 2.79-2.81 (m, 2H), 3.57-3.60 (m, 4H), 3.76-3.80 (m, 2H), 7.24-7.34 (m, 5H) ppm.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][C:3]=1[O:11][CH3:12]>CCO.[Pd]>[CH3:12][O:11][C:3]1[C:2]([CH3:1])=[C:7]([CH:6]=[CH:5][CH:4]=1)[NH2:8]
Reactant: COc1cccc([N+](=O)[O-])c1C
Agent: [Pd]
Solvent: CCO
Product: COc1cccc(N)c1C
Reaction time: 8 h
Yield: 97.5 %

Procedure:
To 2-methyl-3-nitroanisole (5.02 g, 29.9 mmol) in EtOH (300 mL) was added Pd/C (0.50 g). The reaction was stirred under a H2 balloon overnight then filtered through celite to afford 3-methoxy-2-methylaniline (4.00 g, 98%). LCMS found 138.0 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([S:8](Cl)(=[O:10])=[O:9])[N:5]=[CH:4]1)[CH3:2].[OH2:12]>>[CH2:1]([N:3]1[CH:7]=[C:6]([S:8]([OH:10])(=[O:12])=[O:9])[N:5]=[CH:4]1)[CH3:2]
Reactant: CCn1cnc(S(=O)(=O)Cl)c1
Reactant: O
Product: CCn1cnc(S(=O)(=O)O)c1

Procedure:
5.6 g (29 mmol) of 1-ethyl-4-imidazolesulfonyl chloride from Example C-2 are suspended in 70 ml of water at room temperature until a clear solution is formed. After evaporating in vacuo, the residue is recrystallized from ethanol/water in order to give the title compound of melting point 278° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]=1[CH3:14].CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.Br[CH2:35][C:36]1[CH:41]=[CH:40][C:39]([S:42]([CH2:45][CH3:46])(=[O:44])=[O:43])=[CH:38][C:37]=1[C:47]([F:50])([F:49])[F:48]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:35][C:36]2[CH:41]=[CH:40][C:39]([S:42]([CH2:45][CH3:46])(=[O:44])=[O:43])=[CH:38][C:37]=2[C:47]([F:49])([F:50])[F:48])[C:6]=1[CH3:14]
Reactant: COC(=O)Cc1c(C)[nH]c2ncccc12
Reactant: CCS(=O)(=O)c1ccc(CBr)c(C(F)(F)F)c1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CN(C)C=O
Product: CCS(=O)(=O)c1ccc(Cn2c(C)c(CC(=O)OC)c3cccnc32)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of (2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester ((0.77 g, 3.78 mmol) in dry DMF (12 ml) under an inert atmosphere of Argon is added dropwise, BEMP (1.75 ml, 6.04 mmol). The mixture was allowed to stir at room temperature for 1 hour and then treated with 1-bromomethyl-4-ethanesulfonyl-2-trifluoromethyl-benzene (2 g, 6.04 mmol). Stirring continues for a further 2 hours after which time, the reaction mixture is partitioned between ethyl acetate/diethyl ether (80 ml of a 1:1 mixture) and water (100 ml). The organic portion is separated and washed with brine and concentrated in vacuo. Purification of the crude by chromatography on silica eluting with iso-hexane/ethyl acetate (3:1 increasing to 2:1) yields the titled product. (MH+ 455)