Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[C:6]([Cl:9])[N:5]=[CH:4][N:3]=1.[N:10]1([NH2:19])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11]1.O>CN1CCCC1=O>[Cl:9][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:19][N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)[C:7]=1[NH2:8]
Reactant: Nc1c(Cl)ncnc1Cl
Reactant: Nn1ccc2ccccc21
Solvent: O
Solvent: CN1CCCC1=O
Product: Nc1c(Cl)ncnc1Nn1ccc2ccccc21
Yield: 78.9 %

Procedure:
A solution of 8 g of 4,6-dichloro-5-pyrimidinamine, and 7 g of 1H-indol-1-amine, in 100 ml N-methyl-2-pyrrolidone was stirred at 130°-135° for seven hours, then cooled, stirred with water and extracted with ether. The organic extract was washed with water and saturated sodium chloride, dried (anhy. MgSO4), filtered and evaporated to 16 g of a residue. This was purified by flash chromatography (silica, 5% ethyl acetate/DCM) to give 10 g solid. This was combined with product obtained from other condensations and purified by HPLC (silica 5% ethyl acetate/DCM) to give 7 g oil. This oil was crystallized from ether-petroleum ether to give 2.2 g solid, 6-Chloro-N4 -(1H-indol-1-yl)-4,5-pyrimidinediamine, m.p. 175°-176°C.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[N:11]2[N:12]=[C:13]([C:26]3[CH:31]=[CH:30][C:29]([N:32]=C(C4C=CC=CC=4)C4C=CC=CC=4)=[CH:28][CH:27]=3)[C:14]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:16]=3)=[C:10]2[CH:9]=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].Cl.CCOCC.C(=O)(O)[O-].[Na+]>O1CCCC1>[NH2:32][C:29]1[CH:28]=[CH:27][C:26]([C:13]2[C:14]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:16]=3)=[C:10]3[CH:9]=[CH:8][CH:7]=[C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:11]3[N:12]=2)=[CH:31][CH:30]=1
Reactant: CCCCNc1nccc(-c2c(-c3ccc(N=C(c4ccccc4)c4ccccc4)cc3)nn3c(NCCCC)cccc23)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCNc1nccc(-c2c(-c3ccc(N)cc3)nn3c(NCCCC)cccc23)n1

Procedure:
To a solution of N-butyl-3-[2-(butylamino)-4-pyrimidinyl]-2-{4-[(diphenylmethylene)-amino]phenyl}pyrazolo[1,5-a]pyridin-7-amine (1.0 g, 1.7 mmol) in tetrahydrofuran (50 mL) was added hydrochloric acid (10 mL, 4 N aqueous). The resultant solution was stirred at room temperature for 30 minutes. Ether was added and the solution was made basic by the slow addition of saturated aqueous sodium bicarbonate. The organic layer was washed with brine. The aqueous layer was extracted with ether and the combined organics dried over magnesium sulfate. Filtration and concentration followed by flash chromatography (1:1 hexanes:ethyl acetate) provided N-{4-[2-(4-aminophenyl)-7-(butylamino)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinyl}-N-butylamine as an orange oil. 1H NMR (CDCl3): δ 8.02 (d, 1 H), 7.81 (d, 1 H), 7.47 (d, 2 H), 7.31 (m, 1 H), 6.77 (d, 2 H), 6.42 (d, 1 H), 6.08 (m, 1 H), 6.00 (d, 1 H), 5.18 (broad, 1 H), 3.86 (broad, 2 H), 3.53 (m, 2 H), 3.39 (m, 2 H), 1.82–1.64 (m, 4 H), 1.58–1.46 (m, 4 H), 1.04–0.99 (m, 6 H); MS m/z430 (M+1). This material was treated with anhydrous hydrochloric acid in ether to provide the corresponding hydrochloride salt.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:9]=[C:10]([C:14]3[CH2:20][C:19](=[O:21])[NH:18][C:17]4[CH:22]=[C:23]([N:26]5[CH:30]=[CH:29][CH:28]=[CH:27]5)[CH:24]=[CH:25][C:16]=4[N:15]=3)[CH:11]=[CH:12][CH:13]=2)[S:6][CH:7]=1.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.[I-].[K+]>CO.O>[N:31]1([CH2:2][C:3]2[N:4]=[C:5]([C:8]3[CH:9]=[C:10]([C:14]4[CH2:20][C:19](=[O:21])[NH:18][C:17]5[CH:22]=[C:23]([N:26]6[CH:30]=[CH:29][CH:28]=[CH:27]6)[CH:24]=[CH:25][C:16]=5[N:15]=4)[CH:11]=[CH:12][CH:13]=3)[S:6][CH:7]=2)[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1
Reactant: O=C1CC(c2cccc(-c3nc(CCl)cs3)c2)=Nc2ccc(-n3cccc3)cc2N1
Reactant: C1COCCN1
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C1CC(c2cccc(-c3nc(CN4CCOCC4)cs3)c2)=Nc2ccc(-n3cccc3)cc2N1
Temperature: 40 °C

Procedure:
A mixture of 4-[3-(4-(chloromethyl)-thiazol-2-yl)-phenyl]-8-pyrrol-1-yl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (cf. Example 35) (65 mg, 0.15 mmol), morpholine (0.11 mL, 1.2 mmol) and potassium iodide (5 mg, 0.03 mmol) in methanol (1 mL) was heated to 40° C. for 1 h. The mixture was diluted with H2O and the precipitate formed was collected by filtration and chromatographed on silica gel using EtOAc/methanol (10:1) as eluent to give the title compound as a light-brown solid.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]=2[NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)=[CH:18][CH:17]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.C(O)(=O)C.C(O[C:35]1(O[Si](C)(C)C)[CH2:37][CH2:36]1)C.C([BH3-])#N.[Na+]>CO>[CH:1]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]=2[NH:15][C:16]2[CH:17]=[CH:18][C:19]([N:22]4[CH2:27][CH2:26][N:25]([CH:35]5[CH2:37][CH2:36]5)[CH2:24][CH2:23]4)=[CH:20][CH:21]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(Nc3ccc(N4CCNCC4)cc3)c3ccccc3nc2c1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: c1ccc2c(Nc3ccc(N4CCN(C5CC5)CC4)cc3)c3ccccc3nc2c1
Temperature: 25 °C
Yield: 2 %

Procedure:
35 mg (0.10 mmol) of 9-[4-(piperazin-1-yl)phenyl]aminoacridine (Example 16) was dissolved in 1 ml of methanol. 57 μl (1.0 mmol) of acetic acid, 22 μl (0.11 mmol) of (1-ethoxycyclopropyloxy)-trimethylsilane and a small amount of 3 Å molecular sieves were added. The reaction mixture was stirred at room temperature under nitrogen atmosphere. After 30 min 28 mg (0.45 mmol) of sodium cyanoborohydride was added and the reaction mixture was heated at 50° C. over night. The solvents were removed under vacuum, and the residue was purified by chromatography (silica gel column, eluent chloroform/methanol 6:1) to obtain 3.8 mg (10%, overall yield 2%) of the title compound.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH:17]1[C:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[O:7])=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: O=C(Cl)c1cccs1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCNCC1C(=O)c1cccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.1 %

Procedure:
2-Thiophenecarbonylchloride (2.04 g, 1.49 mL) was added to a solution of tert-butyl-1-piperazinecarboxylate (2.5 g, 13.4 mmol) and DMAP (20 mg) in pyridine (15 mL) at 0° C. under N2 atmosphere and stirred at room temperature for overnight. The mixture was poured into ice water, the precipitate was filtered, washed several times with water, and dried to yield white solids (3.5 g, 88%). M.P. 76° C. 1H NMR (DMSO-d6): δ 1.42 (s, 12H), 3.40 (m, 4H), 3.61 (m, 4H), 7.12 (m, 1H), 7.43 (d, J=4.1 Hz, 1H), 7.77 (d, J=4.8 Hz, 1H). EIMS m/z 297 (M+1), 319 (M+23). Anal. (C14H20N2O3S) C, H, N.
Reaction SMILES: [OH:1][N:2]=[C:3]1[S:7][C:6](=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[C:9]#[N:10])[CH:5]=[CH:4]1.[C:18]1([P:24](Cl)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C.O>C1COCC1>[C:18]1([P:24]([O:1][N:2]=[C:3]2[S:7][C:6](=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[CH3:17])[C:9]#[N:10])[CH:5]=[CH:4]2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:25])[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Cc1ccccc1C(C#N)=C1C=CC(=NO)S1
Reactant: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1ccccc1C(C#N)=C1C=CC(=NOP(=O)(c2ccccc2)c2ccccc2)S1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
4.7 g (20 mmol) of (5-Hydroxyimino-5H-thiophen-2-ylidene)-(2-methylphenyl)-acetonitrile, prepared as described in example 7.1, are dissolved in 50 ml of THF and cooled in an ice bath. After adding 5.1 g (21 mmol) of diphenylphosphinic chloride to the solution, 3.0 g (29 mmol) of triethylamine are added dropwise, keeping the temperature below 5° C. The reaction mixture is stirred at 5° C. for 30 min. The reaction mixture is poured into 50 ml of water, and filtered off. The yellow solid is washed with 50 ml of water and 50 ml of a mixture of water and CH3OH (10:1). The product is purified by the recrystallization from 2-PrOH to afford a yellow solid, mp 165-167° C.(Dec). The structure is confirmed by the 1H-NMR spectrum (CDCl3). δ [ppm]: 2.31 (s, 3H), 6.09 (d, 1H), 6.82 (d, 1H), 7.12-7.35 (m, 4H), 7.48-7.65 (m, 6H), 7.95-8.04 (m, 4H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([C:12]2[CH2:16][CH2:15][CH2:14][C:13]=2Br)[CH:6]=1)[CH3:2].[F:19][C:20]([F:40])([F:39])[C:21]1[CH:22]=[CH:23][C:24]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)=[C:25](B(O)O)[CH:26]=1>>[CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([C:12]2[CH2:16][CH2:15][CH2:14][C:13]=2[C:23]2[CH:22]=[C:21]([C:20]([F:40])([F:19])[F:39])[CH:26]=[CH:25][C:24]=2[O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[CH:6]=1)[CH3:2]
Reactant: OB(O)c1cc(C(F)(F)F)ccc1OCc1ccc(F)cc1
Reactant: CCOC(=O)c1cc(C)cc(C2=C(Br)CCC2)c1
Product: CCOC(=O)c1cc(C)cc(C2=C(c3cc(C(F)(F)F)ccc3OCc3ccc(F)cc3)CCC2)c1

Procedure:
Prepared by general procedure B(iii) but using 3-(2-bromocyclopent-1-enyl)-5-methylbenzoic acid ethyl ester instead of 3-(2-bromo-cyclopent-1-enyl)-6-methyl benzoic acid ethyl ester and using [5-trifluoromethyl-2-(4-fluorobenzyloxy)phenyl]boronic acid instead of (5-chloro-2-benzyloxyphenyl)boronic acid.
Reaction SMILES: [CH2:1]([S:8][CH2:9][C@H:10]([NH:16][C:17](=[O:80])[C@H:18]([CH2:76][CH:77]([CH3:79])[CH3:78])[NH:19][C:20](=[O:75])[C@H:21]([C:71]([CH3:74])([CH3:73])[CH3:72])[NH:22][C:23](=[O:70])[C@H:24]([CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][C:64]=1[CH3:69])[NH:25][C:26](=[O:61])[C@H:27]([CH2:52][CH2:53][C:54](=[O:60])[O:55]C(C)(C)C)[NH:28][C:29](=[O:51])[C@H:30]([CH2:43][C:44](=[O:50])[O:45]C(C)(C)C)[NH:31][C:32](=[O:42])[CH2:33][CH2:34][C:35]([O:37]C(C)(C)C)=[O:36])[CH:11](OC)[O:12]C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>FC(F)(F)C(O)=O.ClCCl.O>[CH2:1]([S:8][CH2:9][C@H:10]([NH:16][C:17](=[O:80])[C@H:18]([CH2:76][CH:77]([CH3:78])[CH3:79])[NH:19][C:20](=[O:75])[C@H:21]([C:71]([CH3:72])([CH3:73])[CH3:74])[NH:22][C:23](=[O:70])[C@H:24]([CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][C:64]=1[CH3:69])[NH:25][C:26](=[O:61])[C@H:27]([CH2:52][CH2:53][C:54](=[O:55])[OH:60])[NH:28][C:29](=[O:51])[C@H:30]([CH2:43][C:44](=[O:45])[OH:50])[NH:31][C:32](=[O:42])[CH2:33][CH2:34][C:35]([OH:37])=[O:36])[CH:11]=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(OC)[C@H](CSCc1ccccc1)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](Cc1ccccc1C)NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)CCC(=O)OC(C)(C)C)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: Cc1ccccc1C[C@H](NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)CCC(=O)O)C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C=O)CSCc1ccccc1)C(C)(C)C
Reaction time: 1.5 h
Yield: 88.1 %

Procedure:
56 mg (0.049 mmol) of N1-[2-(benzylthio)-1(R)-(dimethoxymethyl)ethyl]-N2-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-α-aspartyl]-O-tert-butyl-L-α-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucinamide were dissolved in 10 ml of trifluoroacetic acid/dichloromethane (1:1) containing 3 drops of water and the solution was stirred for 90 minutes. The solution was evaporated to dryness under a vacuum and the residue was re-evaporated twice with toluene. The solid was triturated with 10 ml of diethyl ether to give 40 mg of 3-(benzylthio)-2(R)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-α-aspartyl]-L-α-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]propionaldehyde as a white solid. MS: m/e 927.6 (M+H]+.
Reaction SMILES: [O:1]1CCCO[CH:2]1[C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=1[S:15]([CH2:18][CH3:19])(=[O:17])=[O:16].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O>CC(C)=O.O>[CH2:18]([S:15]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:7]=1[CH:2]=[O:1])[C:11]#[N:12])(=[O:16])=[O:17])[CH3:19]
Reactant: CCS(=O)(=O)c1cc(C#N)ccc1C1OCCCO1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CC(C)=O
Product: CCS(=O)(=O)c1cc(C#N)ccc1C=O
Temperature: 165 °C
Reaction time: 0.12 h

Procedure:
In an Emrys microwave, 4-(1,3-dioxan-2-yl)-3-(ethylsulfonyl)benzonitrile (1230 mg, 4.4 mmol) and pyridinium 4-toluenesulfonate (814 mg, 3.3 mmol; 0.75 eq.) in acetone/water (1:1, 20 ml) were heated with stirring at 165° C. for 7 min. The reaction mixture was then added to water (150 ml) and extracted with ethyl acetate (6×50 ml). The combined organic phases were then washed with saturated sodium chloride solution (30 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was subjected to flash chromatography on silica gel (mobile phase: cyclohexane→cyclohexane/ethyl acetate 3:2). The title compound was isolated as a solid (0.89 g, 90% of theory).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([C:9]([OH:11])=[O:10])[CH:6]=[CH:5][C:4]=1[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[S:19][CH:20]=[CH:21][C:22]=2[NH:23][S:24]([CH:27]([CH3:29])[CH3:28])(=[O:26])=[O:25])=[CH:14][CH:13]=1)#[N:2].[Cl:30]N1C(=O)CCC1=O>O1CCCC1>[Cl:30][C:20]1[S:19][C:18]([C:15]2[CH:14]=[CH:13][C:12]([C:4]3[CH:5]=[CH:6][C:7]([C:9]([OH:11])=[O:10])=[CH:8][C:3]=3[C:1]#[N:2])=[CH:17][CH:16]=2)=[C:22]([NH:23][S:24]([CH:27]([CH3:29])[CH3:28])(=[O:26])=[O:25])[CH:21]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)S(=O)(=O)Nc1ccsc1-c1ccc(-c2ccc(C(=O)O)cc2C#N)cc1
Solvent: C1CCOC1
Product: CC(C)S(=O)(=O)Nc1cc(Cl)sc1-c1ccc(-c2ccc(C(=O)O)cc2C#N)cc1
Reaction time: 72 h
Yield: 17.6 %

Procedure:
Dissolve 2-cyano-4′-[3-(propane-2-sulfonylamino)-thiophen-2-yl]-biphenyl-4-carboxylic acid (0.021 g) in dry tetrahydrofuran (0.5 mL) at 0° C. and add N-chlorosuccinimide (0.007 g). Allow the reaction mixture to reach RT and stir for 72 h. Add diethyl ether, concentrate in vacuo and purify by Strata® silica gel cartridges, eluting with dichloromethane-methanol gradient. Purify by reverse phase HPLC to give 0.004 g of the title compound as a white solid. MS (ES−) (m/z): 459 (M−1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:42])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([S:28]([CH:31]([CH3:33])[CH3:32])(=[O:30])=[O:29])[CH:25]=[C:24](Br)[CH:23]=2)[C:10]=1[CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH3:2].[C:43](=[O:46])([O-])[O-:44].[Cs+].[Cs+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([O:3][C:4](=[O:42])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([S:28]([CH:31]([CH3:33])[CH3:32])(=[O:30])=[O:29])[CH:25]=[C:24]([C:9]3[CH:14]=[CH:13][C:12]4[O:44][CH2:43][O:46][C:11]=4[CH:10]=3)[CH:23]=2)[C:10]=1[CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH3:2]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(S(=O)(=O)C(C)C)c2)c1CCC(=O)OCC
Reactant: O=C([O-])[O-]
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cs+]
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(-c3ccc4c(c3)OCO4)cc(S(=O)(=O)C(C)C)c2)c1CCC(=O)OCC
Yield: 159.1 %

Procedure:
A similar procedure as described in Example 41, step 1 was used, starting from 4-[3-{6-[3-bromo-5-(propane-2-sulfony)-phenoxy]-hexyl}-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (175 mg, 0.26 mmol), 3,4-(methylenedioxyphenyl)boronic acid (86.6 mg, 0.52 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (28.7 mg, 0.039 mmol), and cesium carbonate (171.8 mg, 0.52 mmol) to afford 4-[3-{6-[3-benzo[1,3]dioxol-5-yl-5-(propane-2-sulfonyl)-phenoxy]-hexyl}-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (147 mg, 79%) as a colorless viscous oil: ES(+)-HRMS m/e calcd for C39H50O10S (M+Na)+ 733.3017, found 733.3017.
Reaction SMILES: [NH2:1][C:2]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[OH:24])[C:15]2[CH:14]=[C:13]([Cl:16])[N:12]=[CH:11][C:10]=2[O:9][C:8]2[C:3]1=[CH:4][C:5]([Br:17])=[CH:6][CH:7]=2.C([O-])(=O)C.[K+].[N:30]#[C:31]Br.C(Cl)Cl>CO>[Br:17][C:5]1[CH:4]=[C:3]2[C:8](=[CH:7][CH:6]=1)[O:9][C:10]1[CH:11]=[N:12][C:13]([Cl:16])=[CH:14][C:15]=1[C:2]12[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][C:31]([NH2:30])=[N:1]1
Reactant: NC1(c2ccccc2O)c2cc(Br)ccc2Oc2cnc(Cl)cc21
Reactant: N#CBr
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: NC1=NC2(c3ccccc3O1)c1cc(Br)ccc1Oc1cnc(Cl)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(5-amino-7-bromo-3-chloro-5H-chromeno[2,3-c]pyridin-5-yl)phenol (0.406 g, 1.006 mmol) in MeOH 5 mL was added potassium acetate (0.126 mL, 2.012 mmol) followed by the dropwise addition of cyanogen bromide, 3.0M solution in DCM (0.402 mL, 1.207 mmol). The resulting mixture was stirred at RT overnight. The reaction mixture was concentrated, washed with sat. NaHCO3, extracted with DCM, dried over Na2SO4 and concentrated. The resulting product was dissolved in 1,2-dichloroethane followed by the addition of 4.0 M HCl in dioxane (15 mL) and stirred at RT for 1.5 h. The reaction mixture was concentrated, diluted with dichloromethane and washed with saturated NaHCO3 solution, brine, dried over Na2SO4, filtered, concentrated. The crude material was purified by chromatography on silica gel using gradient of 0-100% EtOAc/hexanes to give the desired product. MS m/z=429.8 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:16]2([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])=[C:24]([CH3:36])[CH:23]=3)[CH2:21][CH2:20]C[CH2:18][CH2:17]2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12].C1C=C(C2C=CC=C(O)C=2)C(O)=CC=1>>[CH3:36][C:24]1[CH:23]=[C:22]([C:16]([C:4]2[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[C:2]([CH3:1])[CH:3]=2)([CH2:17][CH3:18])[CH2:21][CH3:20])[CH:27]=[CH:26][C:25]=1[O:28][CH2:29][C:30](=[O:35])[C:31]([CH3:32])([CH3:33])[CH3:34]
Reactant: Cc1cc(C2(c3ccc(OCC(=O)C(C)(C)C)c(C)c3)CCCCC2)ccc1OCC(=O)C(C)(C)C
Agent: Oc1cccc(-c2ccccc2O)c1
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc(OCC(=O)C(C)(C)C)c(C)c1

Procedure:
Compound 7 was prepared analogously to Compound 4 except that the compound of Example 3 (6) was used instead of the compound of Example 1 (3). 1HNMR (CDCl3) δ: 6.89 (m, 4 H, Ar—H), 6.49 (d, J=8.3 Hz, 2 H, Ar—H), 4.82 (s, 4 H, CH2O), 2.23 (s, 6 H, Ar—CH3), 2.00 (q, J=7.3 Hz, 4 H, CH2CH3), 1.23 (s, 18 H, t-Bu), 0.58 (t, J=7.3 Hz, 6 H, CH2CH3).
Reaction SMILES: [CH:1]([C@:3]12[CH2:41][CH2:40][C@@H:39]([C:42]([CH3:44])=[CH2:43])[C@@H:4]1[C@@H:5]1[C@@:18]([CH3:21])([CH2:19][CH2:20]2)[C@@:17]2([CH3:22])[C@@H:8]([C@:9]3([CH3:38])[C@@H:14]([CH2:15][CH2:16]2)[C:13]([CH3:24])([CH3:23])[C:12]([C:25]2[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:27][CH:26]=2)=[CH:11][CH2:10]3)[CH2:7][CH2:6]1)=O.Cl.[NH2:46][OH:47].C(=O)([O-])[O-].[K+].[K+]>CCO>[OH:47]/[N:46]=[CH:1]/[C@:3]12[CH2:41][CH2:40][C@@H:39]([C:42]([CH3:44])=[CH2:43])[C@@H:4]1[C@@H:5]1[C@@:18]([CH3:21])([CH2:19][CH2:20]2)[C@@:17]2([CH3:22])[C@@H:8]([C@:9]3([CH3:38])[C@@H:14]([CH2:15][CH2:16]2)[C:13]([CH3:23])([CH3:24])[C:12]([C:25]2[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])=[CH:27][CH:26]=2)=[CH:11][CH2:10]3)[CH2:7][CH2:6]1
Reactant: NO
Reactant: C=C(C)[C@@H]1CC[C@]2(C=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: C=C(C)[C@@H]1CC[C@]2(/C=N/O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of tert-butyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-formyl-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (200 mg, 0.334 mmol) in EtOH (20 mL) was added hydroxylamine hydrochloride (186 mg, 2.67 mmol) and potassium carbonate (369 mg, 2.67 mmol) and the mixture was stirred overnight at room temperature. LC/MS showed the mass of the expected product. The mixture was diluted with 7 mL of sat. NaHCO3 and was extracted with dichloromethane (3×7 mL). The combined organic layers were dried with Na2SO4. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The crude product as an off white foam (˜100%) was used in the next step with no additional purification. LCMS: m/e 614.53 (MH+), 3.82 min (method 3). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.90 (2H, m, J=8.3 Hz), 7.60 (1H, s), 7.19 (2H, m, J=8.3 Hz), 5.23-5.35 (1H, m), 4.76 (1H, d, J=1.8 Hz), 4.64 (1H, s), 2.56 (1H, td, J=11.0, 5.4 Hz), 2.05-2.19 (1H, m), 1.92-2.05 (2H, m), 1.83-1.92 (2H, m), 1.64-1.82 (7H, m), 1.58-1.64 (9H, m), 1.38-1.57 (9H, m), 1.22-1.31 (2H, m), 1.10-1.20 (2H, m), 1.07 (3H, s), 1.04 (3H, s), 0.97-1.01 (3H, m), 0.85-0.97 (6H, m)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:32]=[CH:31][C:30]([Br:33])=[CH:29][C:10]=1[CH2:11][CH2:12][N:13]([C:16]1[CH:21]=[CH:20][C:19]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][N:17]=1)[CH2:14][CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:8][C:9]1[CH:32]=[CH:31][C:30]([Br:33])=[CH:29][C:10]=1[CH2:11][CH2:12][N:13]([C:16]1[CH:21]=[CH:20][C:19]([C:22]([OH:24])=[O:23])=[CH:18][N:17]=1)[CH2:14][CH3:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN(CCc1cc(Br)ccc1OCc1ccccc1)c1ccc(C(=O)OC(C)(C)C)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN(CCc1cc(Br)ccc1OCc1ccccc1)c1ccc(C(=O)O)cn1
Yield: 84.2 %

Procedure:
tert-Butyl 2-[N-(2-benzyloxy-5-bromophenethyl)-N-ethylamino]-5-pyridinecarboxylate (800 mg) and trifluoroacetic acid (20 ml) in dichloromethane (20 ml) was heated at reflux for 30 minutes. The solvent was evaporated and the residue crystallised from a mixture of dichloromethane and diethyl ether (1:2) to give the title compound (600 mg) mpt 214° C. (decomp).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][CH:23]=[CH:22][C:4]=1[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:21])[CH2:14][CH2:15][C:16]([O:18]CC)=[O:17])=[CH:9][CH:8]=1.[OH-].[Na+].Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:25]=[CH:24][CH:23]=[CH:22][C:4]=1[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([C:13](=[O:21])[CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:11][CH:12]=1
Reactant: CCOC(=O)CCC(=O)c1ccc(OCc2ccccc2OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccccc1COc1ccc(C(=O)CCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of Ethyl 4-(4-(2-methoxybenzyloxy)phenyl)-4-oxobutyrate (Step B, 1.49 g, 4.3 mmol) in abs ethanol (20 ml) was treated with 1N NaOH (6 ml). The reaction mixture was stirred at room temperature for 2 hours and then acidified with 1M HCl. The resulting white solid was filtered, washed with cold water and dried under vacuum to provide the title compound.