Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:9](=[O:19])[NH:8][C:5]2=[N:6][CH:7]=1.C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][N:16]([S:28]([CH3:27])(=[O:30])=[O:29])[CH2:17][CH2:18]3)[C:9](=[O:19])[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=c1[nH]c2ncc(Br)cc2n1CCN1CCNCC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)N1CCN(CCn2c(=O)[nH]c3ncc(Br)cc32)CC1
Reaction time: 0.17 h

Procedure:
The compound obtained in Step 2 of Example 59 (100 mg) was dissolved in chloroform (10 ml). Triethylamine (0.128 ml) and methanesulfonyl chloride (0.036 ml) were added dropwise under ice-cooling, and the mixture was stirred at the same temperature for 10 minutes and then stirred at room temperature for 1.5 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (developed with methanol-chloroform) to give the title compound (82 mg) as a colorless solid.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([NH:12][C:13](=[O:15])[CH3:14])=[CH:10][CH:9]=[CH:8][C:7]=1[NH:16][C:17](=[O:19])[CH3:18])(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[C:13]([NH:12][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:16][C:17](=[O:19])[CH3:18])[C:6]=1[CH2:5][OH:4])(=[O:15])[CH3:14]
Reactant: CC(=O)Nc1cccc(NC(C)=O)c1COC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(=O)Nc1cccc(NC(C)=O)c1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.1 %

Procedure:
To a solution of 2,6-di(acetamido)benzyl acetate (0.97 g) in methanol (70 ml) was added an aqueous solution (1.8 ml) of potassium carbonate (608 mg) and the mixture was stirred at room temperature for 1 hour. After methanol was evaporated under reduced pressure, the resultant residue was subjected to column chromatography on silica gel (18 g) and eluted with a mixture of chloroform and methanol (20:1) to give 2,6-di(acetamido)benzyl alcohol (0.67 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=4[O:26][CH2:27][CH:28]4[CH2:30][CH2:29]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1.Cl[C:32]([O:34][CH2:35][CH3:36])=[O:33]>>[CH2:35]([O:34][C:32]([N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=4[O:26][CH2:27][CH:28]4[CH2:29][CH2:30]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:5][CH2:6]1)=[O:33])[CH3:36]
Reactant: CCOC(=O)Cl
Reactant: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCNCC4)c[nH]c23)c1
Product: CCOC(=O)N1CCC(NC(=O)c2c[nH]c3c(-c4cc(C)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-methyl-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide (example A172) and ethyl chloroformate the title compound is obtained as colorless solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:19]([C:21]3[O:22][C:23](=[O:38])[C:24]4[C:29]([C:30]=3[C:31]3[S:35][C:34]([CH:36]=[O:37])=[CH:33][CH:32]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH3:20])[N:9]=[C:10]([C:11]3[CH:16]=[C:15]([OH:17])[CH:14]=[C:13]([F:18])[CH:12]=3)[C:3]=12.CC(=CC)C.[O-:44]Cl=O.[Na+]>C(O)(C)(C)C.O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:19]([C:21]3[O:22][C:23](=[O:38])[C:24]4[C:29]([C:30]=3[C:31]3[S:35][C:34]([C:36]([OH:44])=[O:37])=[CH:33][CH:32]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH3:20])[N:9]=[C:10]([C:11]3[CH:16]=[C:15]([OH:17])[CH:14]=[C:13]([F:18])[CH:12]=3)[C:3]=12
Reactant: CC(c1oc(=O)c2ccccc2c1-c1ccc(C=O)s1)n1nc(-c2cc(O)cc(F)c2)c2c(N)ncnc21
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: CC(c1oc(=O)c2ccccc2c1-c1ccc(C(=O)O)s1)n1nc(-c2cc(O)cc(F)c2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.9 %

Procedure:
5-(3-(1-(4-amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-1-oxo-1H-isochromen-4-yl)thiophene-2-carbaldehyde (Intermediate F4, 19 mg, 0.036 mmol) was dissolved in 2-methyl-2-butene (300 μl, 2.83 mmol) and t-Butanol (0.5 ml), then a solution of NaClO2 (32.6 mg, 0.360 mmol) and K2H2PO4 (49.0 mg, 0.360 mmol) in 0.5 mL of water added and the mixture stirred at rt for 2 hrs. The reaction was quenched by the addition of 2M HClaqueous (1 ml) and the crude purified via reverse phase chromatography using a Biotage C18 30 g SNAP with a gradient of water and acetonitrile to give the title compound (8 mg, 40.9%) as white solid.
Reaction SMILES: C([NH:4][C:5]1[C:10]2[NH:11][C:12](=[O:21])[N:13]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:9]=2[CH:8]=[C:7]([CH:22]2[CH2:24][CH2:23]2)[N:6]=1)C=C.B(F)(F)F.CCOCC.C(Cl)Cl.CO>C(O)C.[Pd]>[NH2:4][C:5]1[C:10]2[NH:11][C:12](=[O:21])[N:13]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:9]=2[CH:8]=[C:7]([CH:22]2[CH2:23][CH2:24]2)[N:6]=1
Reactant: C=CCNc1nc(C2CC2)cc2c1[nH]c(=O)n2Cc1ccccc1
Agent: [Pd]
Agent: FB(F)F
Solvent: ClCCl
Solvent: CO
Solvent: CCOCC
Product: Nc1nc(C2CC2)cc2c1[nH]c(=O)n2Cc1ccccc1
Temperature: 25 °C
Yield: 30.3 %

Procedure:
4-Allylamino-1-Benzyl-6-cyclopropyl-1,3-dihydro-imidazo[4,5-c]pyridin-2-one (70 mg, 0.2 mmol) was dissolved in ethanol (2 mL) and 10% Pd—C (70 mg, w/w) was added followed by dropwise addition of BF3.OEt2 (27 □l, 0.2 mmol). The mixture was heated at reflux under N2 overnight. The mixture was allowed to cool to room temperature and filtered through arbocel, rinsing with fresh EtOH and the filtrate was concentrated in vacuo to give the crude (150 mg). Column chromatography through silica eluting with 98:2→95:5 DCM:MeOH gave the title compound (17 mg) as an off white solid.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[NH:18][C:17]3[CH:19]=[C:20]([C:23](=[O:32])[NH:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=4)[CH:21]=[CH:22][C:16]=3[N:15]=2)=[C:9]([CH3:33])[CH:8]=1)C>[Li+].[OH-].C1COCC1>[Cl:31][C:27]1[CH:26]=[C:25]([NH:24][C:23]([C:20]2[CH:21]=[CH:22][C:16]3[N:15]=[C:14]([C:10]4[C:9]([CH3:33])=[CH:8][C:7]([O:6][CH2:5][C:4]([OH:34])=[O:3])=[CH:12][C:11]=4[CH3:13])[NH:18][C:17]=3[CH:19]=2)=[O:32])[CH:30]=[CH:29][CH:28]=1
Reactant: CCOC(=O)COc1cc(C)c(-c2nc3ccc(C(=O)Nc4cccc(Cl)c4)cc3[nH]2)c(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(OCC(=O)O)cc(C)c1-c1nc2ccc(C(=O)Nc3cccc(Cl)c3)cc2[nH]1

Procedure:
A solution of {4-[6-(3-Chloro-phenylcarbamoyl)-1H-benzoimidazol-2-yl]-3,5-dimethyl-phenoxy}-acetic acid ethyl ester (71.7 mg) in 2N LiOH aqueous solution (1 mL) and THF (1 mL) was stirred at room temperature for 16 h. The mixture was washed with Et2O. The aqueous layer was acidified to pH 3 with 1N HCl aqueous solution, extracted with EtOAc, and the organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure to give {4-[6-(3-Chloro-phenylcarbamoyl)-1H-benzoimidazol-2-yl]-3,5-dimethyl-phenoxy}-acetic acid as white solid: MS (m/z) 444 (M+1); 1H NMR (MeOD, 400 MHz) δ 8.17 (s, 1H), 7.84 (d, 1H), 7.82 (s, 1H), 7.62 (d, 1H), 7.54 (d, 1H), 7.25 (t, 1H), 7.06 (dd, 1H), 6.70 (s, 2H), 4.59 (s, 2H), 2.06 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[N:10][C:11]2[N:12]([N:14]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:21][CH:20]=3)[C:16]=2[C:17]#[N:18])[CH:13]=1.[BH4-].[Na+].O>CO>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH2:9][NH:10][C:11]2[N:12]([N:14]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:21][CH:20]=3)[C:16]=2[C:17]#[N:18])[CH:13]=1
Reactant: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)nn2cc(-c3ccccc3N)cnc12
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCC(c1ccccc1N)=C2
Reaction time: 0.5 h
Yield: 74.9 %

Procedure:
To a solution of 6-(2-aminophenyl)-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (320 mg, 0.79 mmol) in MeOH (20 mL) was added NaBH4 (86 mg, 2.28 mmol). The solution was stirred at it for 30 min then was poured into water (50 mL) and extracted with EA (50 mL×3). The organic combined layers were dried over Na2SO4 and concentrated to give the crude product (240 mg, 75%) as a yellow solid. MS (ESI, m/e) [M+1]+ 406.0.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([CH:17]([C:19]2[CH:24]=[CH:23][C:22]([C@@H:25]([NH:27][C:28]3[N:33]=[C:32]([C:34]4[N:38]5[CH:39]=[CH:40][CH:41]=[C:42]([CH2:43][CH3:44])[C:37]5=[N:36][CH:35]=4)[C:31]([C:45]#[N:46])=[CH:30][N:29]=3)[CH3:26])=[CH:21][CH:20]=2)[OH:18])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>C(O)C.[OH-].[Pd+2].[OH-]>[CH2:43]([C:42]1[C:37]2[N:38]([C:34]([C:32]3[C:31]([C:45]#[N:46])=[CH:30][N:29]=[C:28]([NH:27][C@H:25]([C:22]4[CH:21]=[CH:20][C:19]([CH:17]([OH:18])[CH:14]5[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]5)=[CH:24][CH:23]=4)[CH3:26])[N:33]=3)=[CH:35][N:36]=2)[CH:39]=[CH:40][CH:41]=1)[CH3:44]
Reactant: CCc1cccn2c(-c3nc(N[C@@H](C)c4ccc(C(O)C5CCN(C(=O)OCc6ccccc6)CC5)cc4)ncc3C#N)cnc12
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCc1cccn2c(-c3nc(N[C@@H](C)c4ccc(C(O)C5CCNCC5)cc4)ncc3C#N)cnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.5 %

Procedure:
118 mg of the compound [25-2] was dissolved in 4 mL of ethanol, then 50 mg of a carbon catalyst of 20% palladium hydroxide was added thereto, and the mixture was stirred overnight at room temperature under hydrogen atmosphere. The catalyst was filtered through celite, the filtrate was concentrated under reduced pressure, and then the resulting residue was purified by preparative thin-layer chromatography, to obtain 66 mg of 4-(8-ethylimidazo[1,2-a]pyridin-3-yl)-2-[((1S)-1-{4-[hydroxy(piperidin-4-yl)methyl]phenyl}ethyl)amino]pyrimidine-5-carbonitrile [25-3] (hereinafter, referred to as the compound [25-3]).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6](I)[C:3]=1[C:4]#[N:5].[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1(C)C=CC=CC=1.CCO.O>COCCOC.O>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:3]=1[C:4]#[N:5]
Reactant: OB(O)c1ccccc1
Reactant: N#Cc1c(F)cccc1I
Solvent: COCCOC
Solvent: O
Solvent: Cc1ccccc1
Product: N#Cc1c(F)cccc1-c1ccccc1

Procedure:
The desired product was prepared by substituting 2-fluoro-6-iodobenzonitrile for Example 1A and phenylboronic acid for Example 1B in Example 1C. Additionally, toluene/EtOH/H2O (3:2:1) was substituted for DME/H2O as the solvent.
Reaction SMILES: [C:1](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.[CH3:16][N:17]1[CH:21]=[C:20]([C:22]2[CH:23]=[C:24]([C:28]3[N:33]=[CH:32][C:31]([C:34]4[CH:35]=[N:36][N:37]([CH:39]5[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]5)[CH:38]=4)=[CH:30][N:29]=3)[CH:25]=[CH:26][CH:27]=2)[CH:19]=[N:18]1.C=O.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>ClCCCl.C(Cl)Cl>[CH3:1][N:42]1[CH2:43][CH2:44][CH:39]([N:37]2[CH:38]=[C:34]([C:31]3[CH:30]=[N:29][C:28]([C:24]4[CH:25]=[CH:26][CH:27]=[C:22]([C:20]5[CH:19]=[N:18][N:17]([CH3:16])[CH:21]=5)[CH:23]=4)=[N:33][CH:32]=3)[CH:35]=[N:36]2)[CH2:40][CH2:41]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Cn1cc(-c2cccc(-c3ncc(-c4cnn(C5CCNCC5)c4)cn3)c2)cn1
Agent: C=O
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN1CCC(n2cc(-c3cnc(-c4cccc(-c5cnn(C)c5)c4)nc3)cn2)CC1
Temperature: 50 °C
Yield: 52.1 %

Procedure:
Sodium triacetoxyborohydride (50 mg; 0.24 mmol; 2.0 eq.) was added to a solution of 2-[3-(1-methyl-1H-pyrazol-4-yl)phenyl]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)pyrimidine (example 1, 50 mg; 0.12 mmol; 1.0 eq.), formaldehyde (16 μl of a 36% aq. solution; 0.21 mmol; 1.8 eq.) and DIEA (24 μl; 0.14 mmol; 1.2 eq.) in DCE (2 mL). The reaction mixture was heated at 50° C. for 1 hour. It was then diluted with DCM and poured into a saturated solution of NaHCO3. The organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated to give the title compound as a white solid (25 mg; 53%). 1H NMR (300 MHZ, DMSO-d6) δ 9.17 (s, 2H), 8.54-8.52 (m, 2H), 8.26 (s, 1H), 8.22 (dt, J=7.8 Hz, 1.5 Hz, 1H), 8.15 (s, 1H), 7.92 (d, J=1.5 Hz, 1H), 7.51 (dt, J=7.8 Hz, 1.5 Hz, 1H), 7.51 (t, J=7.8 Hz, 1H), 4.31-4.20 (m, 1H), 3.89 (s, 3H), 3.04-3.01 (m, 2H), 2.36-2.23 (m, 5H), 2.10-2.03 (m, 4H). HPLC (Condition A): Rt 2.48 min (purity 99.3%). MS (ESI+): 400.50.
Reaction SMILES: N#N.CCN(CC)CC.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH2:22][CH2:23][C:24]([OH:26])=O)[CH:15]=[C:16]([O:20][CH3:21])[C:17]=1[O:18][CH3:19].[CH3:27][O:28][C:29](=[O:44])[CH2:30][C:31]1[CH:32]=[C:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[NH2:43])[CH:34]=[CH:35][CH:36]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:27][O:28][C:29](=[O:44])[CH2:30][C:31]1[CH:32]=[C:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[NH:43][C:24](=[O:26])[CH2:23][CH2:22][C:14]2[CH:15]=[C:16]([O:20][CH3:21])[C:17]([O:18][CH3:19])=[C:12]([O:11][CH3:10])[CH:13]=2)[CH:34]=[CH:35][CH:36]=1
Reactant: COC(=O)Cc1cccc(-c2ccccc2N)c1
Reactant: COc1cc(CCC(=O)O)cc(OC)c1OC
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)Cc1cccc(-c2ccccc2NC(=O)CCc2cc(OC)c(OC)c(OC)c2)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 47.3 %

Procedure:
(The following reaction is done in an anhydrous N2 atmosphere.) Suspend EDCHCl (61 mg, 0.32 mmol) and Et3N (44 μL, 0.32 mmol) in anhydrous DCM (1.0 mL) and stir the resulting solution for 5 min at rt. Add 3-(3,4,5-Trimethoxy-phenyl)-propionic acid (55 mg, 0.23 mmol) and DMAP (2 mg, 0.02 mmol) and stir the resulting solution for 15 min. Add (2′-Amino-biphenyl-3-yl)-acetic acid methyl ester (71) (50 mg, 0.21 mmol) and stir the reaction solution overnight at rt. Quench reaction solution with water, separate layers and extract aqu. layer with DCM (3 times). Wash combined organic layer with brine and dry with Na2SO4. Purify the crude product by preparative radial chromatography (silica gel, EtOAc/CyH 1+1) to obtain {2′-[3-(3,4,5-Trimethoxy-phenyl)-propionylamino]-biphenyl-3-yl}-acetic acid methyl ester (72) (46 mg, 48%) as a yellow oil. 1H NMR (400 MHz, CDCl3): 2.50 (t, 2H, J=7.6 Hz); 2.90 (t, 2H, J=7.7 Hz); 3.64 (s, 2H); 3.65 (s, 3H); 3.77 (s, 6H); 3.78 (s, 3H); 6.38 (s, 2H); 7.09-7.18 (m, 3H); 7.19-7.28 (m, 3H); 7.34 (d, 1H, J=8.1 Hz); 7.38 (d, 1H, J=7.8 Hz); 8.31 (br.d, 1H, J=7.8 Hz).
Reaction SMILES: C[Si]([CH:5]=[N+:6]=[N-:7])(C)C.CN(C)C.[Br:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:21]=1[N:20]([CH3:22])[C:19]([C:23](Cl)=[O:24])=[CH:18]2.[Cl-].[NH4+]>O1CCCC1.C(#N)C>[Br:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:21]=1[N:20]([CH3:22])[C:19]([C:23](=[O:24])/[CH:5]=[N:6]/[NH2:7])=[CH:18]2
Reactant: Cn1c(C(=O)Cl)cc2cccc(Br)c21
Reactant: C[Si](C)(C)C=[N+]=[N-]
Agent: CN(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC#N
Product: Cn1c(C(=O)/C=N/N)cc2cccc(Br)c21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a dichloromethane (2 mL) solution of 7-bromo-1-methyl-1H-indole-2-carboxylic acid (200 mg), oxalyl dichloride (0.10 mL) and N,N-dimethylformamide (5 mL) were added and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, azeotroped twice with toluene to obtain a crude product of 7-bromo-1-methyl-1H-indole-2-carboxylic acid chloride. Separately, a solution was prepared by dissolving 2M trimethylsilyldiazomethane (0.60 mL) and trimethylamine (0.16 mL) in tetrahydrofuran (2 mL)-acetonitrile (2 mL) and a tetrahydrofuran (1 mL)acetonitrile (1 mL) solution of 7-bromo-1-methyl-1H-indole-2-carboxylic acid chloride was added thereto, and then the mixture was stirred at room temperature for 4 hours. To the reaction mixture, an aqueous saturated ammonium chloride solution was added, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate and then concentrated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=90:10 85:15) to obtain the titled compound having the following physical properties (72 mg).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][NH:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:7].[NH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>C(O)C>[N:15]1([CH2:2][CH2:3][CH2:4][NH:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:7])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1
Reactant: CCCCCCNC(=O)NCCCCl
Reactant: C1CNCCN1
Solvent: CCO
Product: CCCCCCNC(=O)NCCCN1CCNCC1
Yield: 39 %

Procedure:
A mixture of 1-(3-chloropropyl)-3-n-hexylurea (11.0 g; 50 mmole), piperazine (43.0 g; 500 mmole) and reagent ethanol (250 ml) was refluxed for 2 hours. The solvent was removed in vacuo, and the solid residue was dissolved in water. The resulting solution was extracted with methylene chloride, concentrated in vacuo, and the residue was chromatographed on silica gel to give 1-(3-piperazinylpropyl)-3-n-hexylurea as a light yellow oil (6.7 g; 39% yield).
Reaction SMILES: [CH2:1]([C:5]12[CH2:17][C:16]([CH3:19])([CH3:18])[C:15](=[O:20])[C:14]([CH3:21])=[C:13]1[C:12]1[C:7](=[CH:8][C:9]([O:22]COC)=[CH:10][CH:11]=1)[CH2:6]2)[CH2:2][CH2:3][CH3:4].Cl.C([O-])(O)=O.[Na+]>CO.CCOC(C)=O>[CH2:1]([C:5]12[CH2:17][C:16]([CH3:19])([CH3:18])[C:15](=[O:20])[C:14]([CH3:21])=[C:13]1[C:12]1[C:7](=[CH:8][C:9]([OH:22])=[CH:10][CH:11]=1)[CH2:6]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC12Cc3cc(OCOC)ccc3C1=C(C)C(=O)C(C)(C)C2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCC12Cc3cc(O)ccc3C1=C(C)C(=O)C(C)(C)C2
Temperature: 67.5 °C

Procedure:
A solution of 9a-butyl-7-methoxymethoxy-2,2,4-trimethyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one (28 mg, 0.08 mmol) in methanol (2 mL) was placed under a nitrogen atmosphere and treated with 2N aqueous HCl (0.12 mL, 0.24 mmol). The resulting yellow solution was stirred and heated in an oil bath at 55-80° C. for 45 minutes. After cooling to room temperature, the mixture was diluted with EtOAc (60 mL) and shaken with 5% aqueous NaHCO3. The aqueous portion was separated and extracted with EtOAc (40 mL). The combined organics were washed with water and brine, dried over MgSO4, filtered, and concentrated under vacuum to an oil. The crude product was purified by PLC on a 0.1×20×20 cm silica gel GF plate, developing twice with 4:1 hexanes-EtOAc. The band at Rf 0.34-0.43 was eluted with EtOAc and the eluant evaporated under vacuum to a residue which was lyophilized from benzene to afford 9a-butyl-7-hydroxy-2,2,4-trimethyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one as an amorphous solid.
Reaction SMILES: [CH2:1]([OH:24])[C@@H:2]([OH:23])[C@H:3]([OH:22])[C@H:4]([O:9][C@@H:10]1[O:15][C@H:14]([C:16]([OH:18])=[O:17])[C@@H:13]([OH:19])[C@H:12]([OH:20])[C@H:11]1[OH:21])[C@@H:5]([NH2:8])[CH:6]=[O:7].BrCC([C@H:29]1[CH2:46][CH2:45][C@@:44]2([CH3:47])[C:31](=[CH:32][CH2:33][C@@H:34]3[C@@H:43]2[CH2:42][CH2:41][C@@:39]2([CH3:40])[C@H:35]3[CH2:36][CH2:37][C:38]2=[O:48])[CH2:30]1)=O>CS(C)=O.[Ag]>[CH2:1]([OH:24])[C@@H:2]([OH:23])[C@H:3]([OH:22])[C@H:4]([O:9][C@@H:10]1[O:15][C@H:14]([C:16]([OH:18])=[O:17])[C@@H:13]([OH:19])[C@H:12]([OH:20])[C@H:11]1[OH:21])[C@@H:5]([NH2:8])[CH:6]=[O:7].[CH3:40][C@@:39]12[C:38](=[O:48])[CH2:37][CH2:36][C@H:35]1[C@@H:34]1[CH2:33][CH:32]=[C:31]3[CH2:30][C@@H:29]([OH:7])[CH2:46][CH2:45][C@:44]3([CH3:47])[C@H:43]1[CH2:42][CH2:41]2
Reactant: C[C@]12CC[C@H](C(=O)CBr)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: [Ag]
Agent: N[C@@H](C=O)[C@@H](O[C@@H]1O[C@H](C(=O)O)[C@@H](O)[C@H](O)[C@H]1O)[C@@H](O)[C@H](O)CO
Solvent: CS(C)=O
Product: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12

Procedure:
1.133 Grams (0.00245 mole) of silver salt of chondrosine was dissolved in 70 ml of DMSO (dimethylsulfoxide) and 0.84 g of the compound (1) was added to the solution to react them at room temperature for 2 days. After the reaction, AgBr was separated by a centrifugal separation and DMSO was distilled off from the resulting supernatant at 45° to 50° C. under a reduced pressure and then, 70 ml of ethanol was added to the residual solid and a floating insoluble material was separated and a filtrate was concentrated under a reduced pressure and poured into 2 ml of cold water to precipitate the product. The precipitate was dried and washed with ether and dried to obtain 0.36 g of a conjugate of chondrosine-dehydroepiandrosterone having the formula ##STR1##
Reaction SMILES: C1C2C3C=C4C(C=C5C(=C4)C=CC=C5)=CC=3SC=2C=CC=1.[CH:22]1[C:30]2[C:29]3[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=3[S:27][C:26]=2[CH:25]=[CH:24][CH:23]=1.[C:35]1(=O)[O:40][C:38](=[O:39])[C:37]2=[CH:41][CH:42]=[CH:43][CH:44]=[C:36]12.[Cl-].[Al+3].[Cl-].[Cl-].P(Cl)(Cl)(Cl)(Cl)Cl>>[CH:31]1[C:29]2[C:30]3[CH:22]=[C:23]4[C:24]([C:35](=[O:40])[C:36]5[CH:44]=[CH:43][CH:42]=[CH:41][C:37]=5[C:38]4=[O:39])=[CH:25][C:26]=3[S:27][C:28]=2[CH:34]=[CH:33][CH:32]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: c1ccc2c(c1)sc1ccccc12
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C1c2ccccc2C(=O)c2cc3c(cc21)sc1ccccc13

Procedure:
The synthesis of the anthra[2,3-b]benzo[d]thiophene unit with added trialkylsilylethynyl groups is shown in Scheme 1. Commercially available dibenzothiophene undertakes a Friedel-Crafts reaction with phthalic anhydride to give 2-(2′-carboxybenzoyl)dibenzothiaphene. The acid is then treated with aluminum chloride and phosphorus pentachloride to yield anthra[2,3-b]benzo[d]thiophene-7,12-dione. The dione is alkylated with the lithium salt of the trialkylsilylacetylene reagent followed by aromatisation utilising tin (II) chloride under acidic conditions to give 7,12-bis(trialkylsilylethynyl)anthra[2,3-b]benzo[d]thiophene.
Reaction SMILES: Cl[C:2]1[N:3]=[N+:4]([O-:16])[C:5]2[CH:14]=[C:13]3[C:9]([CH2:10][CH:11]([CH3:15])[CH2:12]3)=[CH:8][C:6]=2[N:7]=1.[CH3:17][N:18]([CH3:22])[CH2:19][CH2:20][NH2:21].CCN(CC)CC>COCCOC>[CH3:17][N:18]([CH3:22])[CH2:19][CH2:20][NH:21][C:2]1[N:3]=[N+:4]([O-:16])[C:5]2[CH:14]=[C:13]3[C:9]([CH2:10][CH:11]([CH3:15])[CH2:12]3)=[CH:8][C:6]=2[N:7]=1
Reactant: CC1Cc2cc3nc(Cl)n[n+]([O-])c3cc2C1
Reactant: CN(C)CCN
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: CC1Cc2cc3nc(NCCN(C)C)n[n+]([O-])c3cc2C1
Yield: 150.4 %

Procedure:
A solution of chloride 95 (240 mg, 0.9 mmol), N1,N1-dimethyl-1,2-ethanediamine (0.26 mL, 2.4 mmol) and Et3N (0.33 mL, 2.4 mmol) in DME (50 mL) was stirred at reflux temperature for 4 h. The solvent was evaporated and the residue partitioned between DCM (100 mL) and dilute aqueous NH3 solution (50 mL). The organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1-oxide 96 (389 mg, 86%) as a yellow solid: mp (MeOH/EtOAc) 119-121° C.; 1H NMR δ 8.03 (s, 1H, H-9), 7.35 (s, 1H, H-5), 5.82 (br s, 1H, NH), 3.52-3.58 (m, 2H, CH2N), 3.07-3.17 (m, 2H, CH2), 2.55-2.67 (m, 5H, CH, CH2, CH2N), 2.28 [s, 6H, N(CH3)2], 1.15 (d, J=6.1 Hz, 3H, CH3); 13C NMR δ 158.7, 154.2, 148.9, 142.9, 129.8, 120.7, 114.8, 57.6, 45.1 (2), 41.2, 40.4, 38.7, 34.9, 20.2. Anal. calcd for C15H21N5O: C, 62.7; H, 7.4; N, 24.4. Found: C, 62.4; H, 7.1; N, 24.1%.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21]O)[CH:17]=3)[N:12]([CH3:23])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.N1C(C)=CC(C)=CC=1C.CS([Cl:39])(=O)=O>CN(C1C=CN=CC=1)C.CN(C=O)C>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][Cl:39])[CH:17]=3)[N:12]([CH3:23])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CO)ccc21
Agent: CN(C)c1ccncc1
Solvent: Cc1cc(C)nc(C)c1
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCl)ccc21
Temperature: 25 °C
Yield: 90 %

Procedure:
A solution of N-(4-chlorobenzyl)-6-(hydroxymethyl)-1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide from Preparation No. 10 (1.0 g), collidine (0.44 mL), and DMAP (57.9 mg) in anhydrous DMF (48 mL) is cooled to 0° C. Methanesulfonyl chloride (0.24 mL) is added dropwise. The reaction is stirred at room temperature. The crude product is precipitated by addition of water and is filtered. The resulting solid is adsorbed onto silica and purified by chromatography (eluent 100% CH2Cl2 (1 L), 1% MeOH in CH2Cl2 (1 L)). Product-containing fractions were combined and concentrated to afford 948.8 mg (90%) of the title compound as a white solid.