Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH:10]1[CH:14]=[C:13]([CH2:15][OH:16])[N:12]=[CH:11]1.[C:17]1([C:23](Cl)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CC#N>[C:17]1([C:23]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:10]2[CH:14]=[C:13]([CH2:15][OH:16])[N:12]=[CH:11]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCc1c[nH]cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: OCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.3 %

Procedure:
Diisopropylethylamine (14 mL, 80 mmol) was added dropwise to a suspension of 4-imidazole methanol (5.4 g, 40 mmol) in CH3CN (15 mL) at 0° C. A homogeneous yellow solution was formed. To this solution was added triphenylmethyl chloride (11.2 g, 40 mmol). The reaction mixture was stirred at room temperature for 2 h. The resultant white precipitate was filtered and washed successively with saturated NaHCO3 aqueous solution (2×20 mL) and water (2×20 mL), then dried in a vacuum oven (45° C.) for 12 h to afford a white solid 11.2 g (82%) which was used in next step without further purification.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][CH:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[CH2:15][CH2:14]2)=[CH:8][CH:7]=1)(=[O:4])=[O:3].I([O-])(=O)(=O)=[O:28].[Na+].Cl.[OH-].[Na+]>CO>[CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([CH:13]2[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[CH2:17][CH2:18]2)=[O:28])=[CH:8][CH:7]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Nc1ccc(SC2CCN(CCc3cccnc3)CC2)cc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CS(=O)(=O)Nc1ccc(S(=O)C2CCN(CCc3cccnc3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.2 %

Procedure:
A mixture of 0.50 g (1.28 mmol) of 4-(4-methylsulfonylaminophenylthio)-1-[2-(3-pyridyl)ethyl]piperidine, 0.33 g (1.53 mmol) of sodium periodate, 5 ml of 1N hydrochloric acid and 5 ml of methanol was stirred at room temperature for 1 h. About 5 ml of a 1N sodium hydroxide solution was added thereto to adjust the pH to about 7. After extraction with chloroform, the organic layer was concentrated and the residue was purified by silica gel column chromatography (CHCl3 :CH3OH:NH4OH=95:5:0.5). The fraction containing the intended compound was concentrated to give a solid residue, which was recrystallized from ethyl acetate to give a 0.34 g (yield: 64%) of the compound.
Reaction SMILES: [NH2:1][CH:2]([CH2:4][CH2:5][CH2:6][C:7]([C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([NH2:17])=[C:12]([CH3:18])[CH:11]=1)([CH3:9])[CH3:8])[CH3:3].[H][H]>C(O)(C)(C)C>[NH2:1][CH:2]([CH2:4][CH2:5][CH2:6][C:7]([CH:10]1[CH2:15][CH:14]([CH3:16])[CH:13]([NH2:17])[CH:12]([CH3:18])[CH2:11]1)([CH3:9])[CH3:8])[CH3:3]
Reactant: Cc1cc(C(C)(C)CCCC(C)N)cc(C)c1N
Reactant: [H][H]
Solvent: CC(C)(C)O
Product: CC(N)CCCC(C)(C)C1CC(C)C(N)C(C)C1

Procedure:
58 Parts of 2-amino-6-(4-amino-3,5-dimethylphenyl)-6-methylheptane, 640 parts of tert-butanol, and 12 parts of 5% Rh/Al2O2 were heated in an autoclave at 150°-60° C. with hydrogen at a pressure of 200 bar. After 15 hours hydrogen uptake was complete and the reaction mixture was then filtered free of catalyst. Distillation of the filtrate after removal of the tert-butanol gave 47 parts of 2-amino-6-(4-amino-3,5-dimethylcyclohexyl)-6-methylheptane b0.2 116°-8° C.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[NH:14][C:15](=O)[CH3:16].C([O-])(=O)C.[NH4+:23].C(O)(=O)C>O>[CH3:11][O:10][C:8]1[CH:9]=[C:4]2[C:5](=[CH:6][C:7]=1[O:12][CH3:13])[N:14]=[C:15]([CH3:16])[N:23]=[C:3]2[OH:2]
Reactant: COC(=O)c1cc(OC)c(OC)cc1NC(C)=O
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Solvent: O
Product: COc1cc2nc(C)nc(O)c2cc1OC
Temperature: 25 °C

Procedure:
To the crude 2-acetylamino-4,5-dimethoxy-benzoic acid methyl ester obtained above was added ammonium acetate (7.98 g, 0.104 mol) and acetic acid (10 mL). The mixture was heated at reflux in a pressure tube until the formation of the desired cyclization product, as indicated by LC/MS: m/z 221 (M+H). After cooling to RT, the reaction mixture was diluted with water, and extracted with EtOAc 3 times. The combined organic phase was basified with aq. NaOH solution, and washed 3 times with EtOAc. The aqueous layer was then acidified with aq. HCl and extracted three times with EtOAc. The combined organic extract was dired over Na2SO4 and concentrated in vacuo, affording 6,7-dimethoxy-2-methyl-quinazolin-4-ol (0.15 g), which was used without further purification. LC/MS: m/z 221 (M+H).
Reaction SMILES: C(OC([N:8]1[CH2:12][C@H:11]([S:13]([CH3:16])(=[O:15])=[O:14])[CH2:10][C@H:9]1[C:17](=[O:24])[NH:18][C:19]1([C:22]#[N:23])[CH2:21][CH2:20]1)=O)(C)(C)C.[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28]>ClCCl>[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28].[C:22]([C:19]1([NH:18][C:17]([C@@H:9]2[CH2:10][C@@H:11]([S:13]([CH3:16])(=[O:15])=[O:14])[CH2:12][NH:8]2)=[O:24])[CH2:20][CH2:21]1)#[N:23]
Reactant: CC(C)(C)OC(=O)N1C[C@H](S(C)(=O)=O)C[C@H]1C(=O)NC1(C#N)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)[C@H]1CN[C@H](C(=O)NC2(C#N)CC2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
To a solution of (2S,4R)-2-(1-cyano-cyclopropylcarbamoyl)-4-methanesulfonyl-pyrrolidine-1-carboxylic acid tert-butyl ester (500 mg, 1.39 mmol) in dichloromethane was added trifluoroacetic acid (0.5 ml, 6.99 mmol) at 0° C. The resulting mixture was stirred at 25° C. for 16 h. After complete consumption of starting material, the reaction mixture was evaporated in vacuo to get the crude title compound (500 mg, 1.39 mmol; quant.) which was used in next step without further purification. MS: m/z=258.0 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[CH:19]=[CH:18][C:6]([CH2:7][NH:8][C:9]2[CH:17]=[CH:16][C:12]3[N:13]=[CH:14][NH:15][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1)[CH3:2].[F:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([F:30])[C:28]=1[F:29])[CH2:24]Br.C([O-])([O-])=O.[K+].[K+]>>[F:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([F:30])[C:28]=1[F:29])[CH2:24][N:8]([CH2:7][C:6]1[CH:18]=[CH:19][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=1)[C:9]1[CH:17]=[CH:16][C:12]2[NH:13][CH:14]=[N:15][C:11]=2[CH:10]=1
Reactant: Fc1cc(CBr)cc(F)c1F
Reactant: CCc1ccc(CNc2ccc3nc[nH]c3c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCc1ccc(CN(Cc2cc(F)c(F)c(F)c2)c2ccc3[nH]cnc3c2)cc1

Procedure:
The compound was synthesized starting from N-(4-ethylbenzyl)benzimidazol-5-amine (251 mg; 1 mmol; 1 eq.), 3,4,5-trifluorobenzylbromide (248 mg; 1.1 mmol; 1.1 eq.) and K2CO3 (152 mg; 1.1 mmol; 1.1 eq.) according to method 6; Yield: 0.078 g (19.7%); MS m/z: 396.2 [M+H]+; 1H-NMR (500 MHz, DMSO d6): δ 1.14 (t, 3H, 3J=7.6 Hz); 2.55 (q, 2H, 3J=7.6 Hz); 4.64 (s, 2H); 4.66 (s, 2H); 6.71-6.74 (m, 2H); 7.13-7.20 (m, 6H); 7.35 (d, 1H, 3J=8.2 Hz); 7.94 (s, 1H); 12.03 (br s, 1H); HPLC (METHOD [A]): rt 18.63 min (92.1%)
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[O:6][CH:5]([CH2:7][O:8][CH2:9][CH:10]2[O:14][CH:13]([CH2:15][OH:16])[CH2:12][CH2:11]2)[CH2:4][O:3]1.Cl[CH2:19][C:20]([N:22]([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])=[O:21].[H-].[Na+].O>CS(C)=O>[CH3:1][C:2]1([CH3:17])[O:6][CH:5]([CH2:7][O:8][CH2:9][CH:10]2[O:14][CH:13]([CH2:15][O:16][CH2:19][C:20]([N:22]([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])=[O:21])[CH2:12][CH2:11]2)[CH2:4][O:3]1
Reactant: CCCN(CCC)C(=O)CCl
Reactant: CC1(C)OCC(COCC2CCC(CO)O2)O1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCCN(CCC)C(=O)COCC1CCC(COCC2COC(C)(C)O2)O1
Temperature: 25 °C
Yield: 62.7 %

Procedure:
A mixture of 4.93 g of 5-[[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]methyl]tetrahydro-2-furan-methanol (0.02 mole) and 3.55 g of 2-chloro-N,N-dipropylacetamide (0.02 mole) are dissolved in 125 ml of dry dimethyl sulfoxide and the mixture stirred at room temperature under nitrogen. Slowly 0.50 g of sodium hydride (0.02 mole) is added to the dimethyl sulfoxide mixture and the reaction allowed to stir at ambient temperature (23°). After stirring for 10 minutes an exothermic reaction begins to take place and an ice-bath is used to maintain the reaction temperature below 30°. After stirring for 1 hour the ice-bath is removed and the reaction allowed to stir at room temperature for 18 hours. The excess NaH is destroyed by adding 5 ml of methanol and the entire reaction mixture is then poured into 400 ml of water. The product is extracted with 3×125 ml portions of chloroform. The CHCl3 extracts are combined and washed with 4× 300 ml portions of water. The CHCl3 layer is separated and dried over anhydrous Na2SO4 overnight. The CHCl3 is then removed in vacuo yielding a pale yellow oil which is vacuum distilled through a 10 cm vigreux column and the fraction distilling at 91°-94° @ 0.4 mm is collected, yielding 4.86 g (63%) of the above compound.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][CH2:7][C@@H:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1.CC(C)([O-])C.[Na+].Cl[CH2:23][C:24]1[O:25][C:26]([CH2:29][CH3:30])=[N:27][N:28]=1>CS(C)=O.CCOC(C)=O>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:23][C:24]3[O:25][C:26]([CH2:29][CH3:30])=[N:27][N:28]=3)[CH2:7][C@@H:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1
Reactant: Clc1ncc2c(n1)N1CCOC[C@H]1CN2
Reactant: CCc1nnc(CCl)o1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCc1nnc(CN2C[C@@H]3COCCN3c3nc(Cl)ncc32)o1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 55.5 %

Procedure:
To a 50 mL round-bottom flask was added (R)-2-chloro-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x3, 200 mg, 0.882 mmol) in DMSO (8 mL) followed by sodium tert-butoxide (102 mg, 1.059 mmol). The reaction mixture was stirred at room temperature for 10 minutes. 2-(Chloromethyl)-5-ethyl-1,3,4-oxadiazole (155 mg, 1.059 mmol) was then added to give an orange solution. After 1 hour, LC/MS indicated the reaction was complete. The reaction mixture was subsequently diluted with EtOAc and washed with aqueous saturated NH4Cl (3×). The combined organic layers were dried over MgSO4, filtered, and concentrated. The product was purified by column chromatography (12 g SiO2 column, EtOAc (20-80%)/hexane gradient) to give the title compound as a pale yellow solid (165 mg, 56%). 1H NMR (400 MHz, DMSO-d6) δ 1.24 (t, J=7.58 Hz, 3H), 2.83 (d, J=7.33 Hz, 2H), 2.93-3.03 (m, 1H), 3.04-3.21 (m, 2H), 3.36-3.51 (m, 2H), 3.59-3.71 (m, 1H), 3.85-3.98 (m, 2H), 4.20-4.29 (m, 1H), 4.57-4.67 (m, 1H), 4.84-4.94 (m, 1H), 7.57 (s, 1H). ESI-MS m/z [M+H]+ calc'd for C14H17ClN6O2, 337.78. found 337.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([OH:13])=O)[NH:8][C:5]2=[N:6][CH:7]=1.Cl.[NH2:15][C@@H:16]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)[C:17]([N:19]1[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]1)=[O:18].C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-].CN1CCOCC1>C(O)C>[F:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][C@H:16]([NH:15][C:11]([C:9]2[NH:8][C:5]3=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=[C:4]3[CH:10]=2)=[O:13])[C:17]([N:19]2[CH2:20][CH2:21][CH:22]([OH:25])[CH2:23][CH2:24]2)=[O:18])=[CH:28][CH:29]=1
Reactant: O=C(O)c1cc2cc(Cl)cnc2[nH]1
Reactant: N[C@@H](Cc1ccc(F)cc1)C(=O)N1CCC(O)CC1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: CN1CCOCC1
Solvent: CCO
Product: O=C(N[C@@H](Cc1ccc(F)cc1)C(=O)N1CCC(O)CC1)c1cc2cc(Cl)cnc2[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5-Chloro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (Preparation 57, 50 mg, 0.25 mmol), 2-(S)-amino-3-(4-fluorophenyl)-1-(4-hydroxypiperidin-1-yl)propan-1-one hydrochloride (85 mg, 0.25 mmol) and DMTMM (85 mg, 0.31 mmol) were dissolved in ethanol (5 ml) and 4-methylmorpholine (31 μl, 0.28 mmol). The reaction mixture was stirred at rt for 16 h. The solvent was removed in vacuo and the residue partitioned between water (30 ml) and EtOAc (3×25 ml). The combined organics were dried (MgSO4), concentrated in vacuo and purified by chromatography on silica gel eluting with methanol:dichloromethane (1:19) to give the title compound as a beige solid. m/z (ES+)=445 [M+H]+; RT=3.31 min.
Reaction SMILES: [N:1](=[C:3]([C:9]([CH3:11])=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5])O.[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH2:18])=[CH:15][CH:14]=1>CC#N>[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]2[NH:1][C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:9]([CH3:11])[N:18]=2)=[CH:15][CH:14]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)C(=NO)C(C)=O
Solvent: CC#N
Product: CCOC(=O)c1[nH]c(-c2ccc(Cl)cc2)nc1C
Yield: 40.8 %

Procedure:
A solution of ethyl 2-oximinoacetoacetate (6 g, 38 mmol; obtained according to Org.Synth. 1941, 21, 67) in MeCN (75 mL) was treated with 4-chlorobenzylamine (5.6 g, 40 mmol) at reflux for 18 h. Next, the reaction mixture was allowed to cool and the yellow solid formed was collected by filtration to give ethyl 2-(4-chlorophenyl)-5-methyl-3H-imidazole-4-carboxylate as a white solid (4.1 g, 40%): mp 237°-238° C.; 1H NMR (300 MHz, DMSO--d6) δ (DMSO) 7.96 (d, J=8, 2H, arom), 7.57 (d, J=8, 2H, arom), 4.27 (q, J=7, 2H, OCH2), 2.54 (s, 3H, Me-imidazole), 1.33 (t, J=7, 3H, OCH2CH3). Analysis calculated for C13H13ClN2O2 : C 58.99; H 4.95; N 10.58. Found: C 59.20; H 4.95; N 10.59.
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)=[CH:10][C:9]([CH2:19][CH2:20][CH:21]=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:23][C:24]1[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:23][C:24]1[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=1[N:31]1[CH2:32][CH2:33][N:34]([CH2:21][CH2:20][CH2:19][C:9]2[CH:10]=[C:11]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)[N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=2)[CH2:35][CH2:36]1
Reactant: Cc1cccc(N2CCNCC2)c1C
Reactant: Cc1ccc(-c2cc(CCC=O)nn2-c2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(CCCN3CCN(c4cccc(C)c4C)CC3)nn2-c2ccccc2)cc1

Procedure:
104 mg (75%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-phenyl-5-p-tolyl-1H-pyrazol-3-yl)propanal (80 mg, 0.276 mmol), 1-(2,3-dimethylphenyl)piperazine (53 mg, 0.276 mmol), DIPEA (0.072 mL, 0.414 mmol) and NaBH(OAc)3 (175 mg, 0.828 mmol).
Reaction SMILES: C([O:8][C:9]([C@@H:11]1[CH2:14][C@H:13]([C:15]([O:17][C@H:18]2[CH2:35][CH2:34][C@@:33]3([CH3:36])[C@@H:20]([CH2:21][CH2:22][C@:23]4([CH3:47])[C@@H:32]3[CH2:31][CH2:30][C@H:29]3[C@@:24]4([CH3:46])[CH2:25][CH2:26][C@@:27]4([C:43]([OH:45])=[O:44])[CH2:39][CH2:38][C@@H:37]([C:40]([CH3:42])=[CH2:41])[C@@H:28]43)[C:19]2([CH3:49])[CH3:48])=[O:16])[C:12]1([CH3:51])[CH3:50])=[O:10])C1C=CC=CC=1.[SiH](CC)(CC)CC>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:9]([C@@H:11]1[CH2:14][C@H:13]([C:15]([O:17][C@H:18]2[CH2:35][CH2:34][C@@:33]3([CH3:36])[C@@H:20]([CH2:21][CH2:22][C@:23]4([CH3:47])[C@@H:32]3[CH2:31][CH2:30][C@H:29]3[C@@:24]4([CH3:46])[CH2:25][CH2:26][C@@:27]4([C:43]([OH:45])=[O:44])[CH2:39][CH2:38][C@@H:37]([C:40]([CH3:42])=[CH2:41])[C@@H:28]43)[C:19]2([CH3:49])[CH3:48])=[O:16])[C:12]1([CH3:51])[CH3:50])([OH:10])=[O:8]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)[C@H]6C[C@@H](C(=O)OCc7ccccc7)C6(C)C)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)[C@H]6C[C@@H](C(=O)O)C6(C)C)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 36.7 %

Procedure:
To a stirred solution of (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-((1S,3R)-3-(benzyloxycarbonyl)-2,2-dimethylcyclobutanecarbonyloxy)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carboxylic acid (Example 18, 0.25 g) in dry DCM (10 ml) Et3N (5.77 ml) and Et3SiH (0.057 g) were added at about 0° C. then Pd(OAc)2 (0.005 g) was added under nitrogen conditions and the reaction mixture was stirred at reflux temperatures for over night. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM, and concentrated under reduced pressure, purified by column chromatography to afford the title compound (80 mg, 36.86% Yield). 1H NMR (300 MHz, CDCl3): δ 4.73 (1H, s), 4.54 (1H, s), 4.4-4.36 (1H, m), 3.0-2.90 (1H, m), 2.80-2.65 (2H, m), 2.6 (2H, m), 2.3-2.1 (3H, m), 2.0-1.88 (4H, m), 1.64 (5H, m), 1.61 (2H, m), 1.6-1.4 (4H, m), 1.39-1.3 (4H, m), 1.32 (6H, s), 1.3-1.02 (4H, m), 1.00 (3H, s),0.91 (3H, s), 0.89 (3H, s), 0.809 (3H, s), 0.790 (3H, s), 0.751 (3H, s); Mass: [M+Na]+ 633 (75%); 1R (KBr, cm−1): 3400, 2949, 1732, 1703, 1459, 1389, 1364, 1264, 1211, 1139, 1126, 1106, 1020, 942, 889. Melting Range: 308-310° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][C:3]=1[CH3:17]>C(OCC)(=O)C.CCCCCC.[C].[Pd]>[NH2:8][C:7]1[CH:6]=[C:5]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:4]=[C:3]([CH3:17])[C:2]=1[NH2:1]
Reactant: Cc1cc(-c2ccccc2)cc([N+](=O)[O-])c1N
Agent: [Pd]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1cc(-c2ccccc2)cc(N)c1N
Yield: 99.7 %

Procedure:
[step 3] 4-Amino-3-methyl-5-nitrobiphenyl (100 mg, 0.44 mmol) obtained in step 2 was dissolved in ethanol-ethyl acetate (1/1, 4 mL), and the mixture was stirred in the presence of 10% palladium carbon (10 mg) under a hydrogen atmosphere at room temperature for 20 hr. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give 3,4-diamino-5-methylbiphenyl (87 mg, 100%).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[C:13](=[O:15])[CH3:14].C([O-])([O-])=O.[K+].[K+].Br[CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27]>CC#N>[C:29]([O:28][C:26](=[O:27])[CH2:25][N:9]1[C:10]2[C:6](=[CH:5][C:4]([O:3][C:2]([F:1])([F:16])[F:17])=[CH:12][CH:11]=2)[C:7]([C:13](=[O:15])[CH3:14])=[CH:8]1)([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(=O)c1c[nH]c2ccc(OC(F)(F)F)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)c1cn(CC(=O)OC(C)(C)C)c2ccc(OC(F)(F)F)cc12
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(5-trifluoromethoxy-1H-indol-3-yl)-ethanone (0.50 g, 2.06 mmol) in CH3CN (10 mL) was added K2CO3 (0.313 g, 2.26 mmol) and tert-butyl 2-bromoacetate (0.334 mL, 2.26 mmol). The reaction mixture was stirred at 90° C. overnight. The reaction mixture was filtered, and the filtrate was diluted with CH2Cl2. The organics were washed with 1M aqueous HCl solution (5 mL) and saturated aqueous NaHCO3 solution (5 mL). The organic layer was dried (phase separator) and evaporated in vacuo to afford the title compound as a yellowish oil: MS: 358.0 [M+H]+; tR (HPLC conditions c): 5.66 min. The material thus obtained was used directly in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](=[O:12])[NH:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[H-].[Na+].[CH3:15][Si:16]([CH3:23])([CH3:22])[CH2:17][CH2:18][O:19][CH2:20]Cl>CN(C)C=O>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](=[O:12])[N:7]([CH2:20][O:19][CH2:18][CH2:17][Si:16]([CH3:23])([CH3:22])[CH3:15])[CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: O=c1[nH]cnc2cc(Cl)ncc12
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cnc2cc(Cl)ncc2c1=O
Temperature: 0 °C

Procedure:
In a dried round bottom flask under N2 atmosphere was added 7-chloro-3H-pyrido[4,3-d]pyrimidin-4-one (3, 9.0 g, 49.56 mmol) to dimethylformamide (50 mL). The solution was stirred at 0° C. and sodium hydride (1.78 g, 74.35 mmol) was added portion-wise over 10 min. The anionic suspension was stirred for 1 h at 0° C. followed by the addition of 2-(trimethylsilyl)ethoxymethyl chloride (12.4 g, 74.35 mmol) at 0° C. The reaction mixture was stirred at room temperature for 5 h. After consumption of starting materials as indicated by TLC, the reaction mixture was quenched with ice. A solid precipitates. It was filtered and washed with excess n-pentane. The solid was dried under vacuum to afford 7-chloro-3-(2-trimethylsilylethoxymethyl)pyrido[4,3-d]pyrimidin-4-one (4) as a brown solid. Yield: 9.1 g, 59%; 1H NMR (400 MHz, DMSO-d6) δ 9.17 (s, 1H), 8.72 (s, 1H), 7.79 (s, 1H), 5.49 (s, 2H), 3.65 (t, J=16 Hz, 2H), 0.90 (t, J=16 Hz, 2H), −0.03 (s, 9H).
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][C:5]=1[CH3:12].[C:13]([C:16]1[CH:36]=[CH:35][C:19]([O:20][CH2:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]2)=[CH:18][C:17]=1[CH3:37])(=[O:15])[CH3:14]>CCO>[OH:3][C:4]1[CH:11]=[CH:10][C:7](/[CH:8]=[CH:14]/[C:13]([C:16]2[CH:36]=[CH:35][C:19]([O:20][CH2:21][CH:22]3[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])[CH2:26][CH2:27]3)=[CH:18][C:17]=2[CH3:37])=[O:15])=[CH:6][C:5]=1[CH3:12]
Reactant: CC(=O)c1ccc(OCC2CCN(C(=O)OC(C)(C)C)CC2)cc1C
Reactant: Cc1cc(C=O)ccc1O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(/C=C/C(=O)c2ccc(OCC3CCN(C(=O)OC(C)(C)C)CC3)cc2C)ccc1O
Temperature: 80 °C
Yield: 47.5 %

Procedure:
To a round bottomed flask was added EtOH (10 mL) and potassium hydroxide (507 mg, 9.05 mmol). The mixture was stirred until homogeneous before adding commercially available 4-hydroxy-3-methyl benzaldehyde (247 mg, 1.81 mmol) and tert-butyl 4-((4-acetyl-3-methylphenoxy)methyl)piperidine-1-carboxylate (630 mg, 1.81 mmol). The reaction was heated to 80° C. for 5 h, cooled to rt, and concentrated via rotary evaporation. The product was dry-loaded onto a silica gel column and purified through flash chromatography (1:1 EtOAc:Hexanes) to afford (E)-tert-butyl 4-((4-(3-(4-hydroxy-3-methylphenyl)acryloyl)-3-methylphenoxy)methyl)piperidine-1-carboxylate (400 mg, 47% yield).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:9]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][N:20]=1)[P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]>[Pd].C(O)C>[CH2:12]([O:11][P:10]([CH:9]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][N:20]=1)[P:4](=[O:8])([O:3][CH2:1][CH3:2])[O:5][CH2:6][CH3:7])(=[O:17])[O:14][CH2:15][CH3:16])[CH3:13]
Reactant: CCOP(=O)(OCC)C(Nc1ccc([N+](=O)[O-])cn1)P(=O)(OCC)OCC
Agent: [Pd]
Solvent: CCO
Product: CCOP(=O)(OCC)C(Nc1ccc(N)cn1)P(=O)(OCC)OCC

Procedure:
[(5-Nitro-2-pyridinyl)aminomethylene]bis[phosphonic acid] tetraethyl ester (5.29 9, 12.4 mmol), absolute ethanol (100 ml) and 10% palladium on charcoal (1.3 g) are placed in a 500 ml Parr hydrogenation flask and hydrogenated for 4 hours at 40 psi. The reaction mixture is filtered through celite then concentrated under reduced pressure. The resultant solid is carried on without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:17])[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[CH:11][C:10]([OH:16])=[CH:9][CH:8]=3.[CH3:18]OS(OC)(=O)=O>O.C(O)C>[OH:16][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[C:6](=[O:17])[C:5]1[CH:4]=[CH:3][C:2]([O:1][CH3:18])=[CH:15][C:14]=1[O:13]2
Reactant: COS(=O)(=O)OC
Reactant: O=c1c2ccc(O)cc2oc2cc(O)ccc12
Solvent: O
Solvent: CCO
Product: COc1ccc2c(=O)c3ccc(O)cc3oc2c1
Yield: 50 %

Procedure:
7.0 g (30.7 mmol) of 3,6-dihydroxyxanthone is dissolved in aq. NAOH (2.5 g(62.5 mmol) in 200 mls H2O). 3.2 mls (33.6 mmol) of dimethylsulfate is added dropwise with stirring, and solid forms immediately upon completion. Stirred further 1 hour and heated to reflux for 15 minutes. Additional base is added to insure complete solubility of phenols. The solution is acidified with HCl, and filtration yields a mixture of staring material and the target compound. Solid is heated to reflux in about 200 mls ethanol for 15 minutes to dissolve starting material, and solid is filtered out, washing with ethanol and water. This may have to be repeated several times to obtain pure compound in about 50% yield; mp=303-306-C.NMR (200 MHZ in d-DMSO) s 3.89 (3H,s), 6.82 (1H,d,J=2.24 Hz), 6.87 (1H,m), 6.99 (1H,dd,J=8.78 Hz, 2.20 Hz),, 7.09 (1H,d,J=2.26 Hz), 7.99 (1H,d,J=8.52 Hz), 8.03 (1H,d,J=8.78 Hz).