Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=2[CH3:18])[C:12](O)=[O:13])[C:5]([CH3:19])=[N:4][C:3]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[F:29].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[CH3:45][C@@H:46]([NH2:49])[CH2:47][OH:48]>CC(N(C)C)=O.ClCCl>[Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=2[CH3:18])[C:12]([NH:49][C@H:46]([CH3:45])[CH2:47][OH:48])=[O:13])[C:5]([CH3:19])=[N:4][C:3]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[F:29]
Reactant: C[C@@H](N)CO
Reactant: Cc1ccc(C(=O)O)cc1-n1c(C)nc(OCc2ccc(F)cc2F)c(Br)c1=O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: Cc1ccc(C(=O)N[C@H](C)CO)cc1-n1c(C)nc(OCc2ccc(F)cc2F)c(Br)c1=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 49 %

Procedure:
To a solution of 3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-1(6H)-yl]-4-methylbenzoic acid (4.0 g, 0.0086 mol) in dimethylacetamide (10.0 mL) at −20° C. was added N-methylmorpholine (1.2 g, 0.012 mol), followed by the dropwise addition of a solution of isobutylchloroformate (1.58 g, 0.012 mmol) in dichloromethane (5.0 mL). The reaction mixture was stirred for 10 min. under argon atmosphere after which it was stirred at room temperature for 20 min. The reaction mixture was then cooled to 0° C., and added R-2-amino-1-propanol (0.97 g, 1.01 mol). The resulting mixture was stirred at room temperature for 1.5 h, concentrated in vacuo, and the residue was purified by reverse-phase HPLC using 10-90% CH3CN/Water gradient (40 min) at a flow rate of 80 mL/min. The appropriate fractions (MH+, m/z=522) were combined, and freeze-dried to give a white solid. This was dissolved in dichloromethane (20 mL), washed successively with 5% sodium bicarbonate (2×15 mL), water (2×20 mL), dried (Na2SO4), and concentrated to dryness to afford the racemic title compound (2.2 g, 49%) as a white amorphous substance: 1H NMR (CD3OD/400 MHz) δ 7.91 (dd, 1H, J=1.6 Hz, & 6.4 Hz), 7.68 (d, 1H, J=1.6 Hz), 7.60 (m, 1H), 7.53 (d, 1H, J=8.4 Hz), 7.01 (m, 2H), 5.57 (abq, 2H), 4.18 (m, 1H), 3.56 (m, 2H), 2.17 (s, 3H), 2.13 (s, 3H), and 1.22 (d, 3H, J=6.8 Hz); ES-HRMS m/z 522.0860 (M+H calcd for C23H23N3O4F2 Br requires 522.0835). 19F NMR (CD3OD/400 MHz) −111.85 (m) and −115.90 (m).
Reaction SMILES: C[O:2][C:3](=[O:25])[C@@H:4]([N:9]1[CH2:13][C:12]2=[CH:14][C:15]3[C:16]([O:22][CH3:23])=[CH:17][CH:18]=[CH:19][C:20]=3[O:21][CH:11]2[C:10]1=[O:24])[CH2:5][CH:6]([CH3:8])[CH3:7].O.[OH-].[Li+]>O1CCCC1.O>[CH3:23][O:22][C:16]1[C:15]2[CH2:14][C:12]3[CH2:13][N:9]([C@@H:4]([CH2:5][CH:6]([CH3:8])[CH3:7])[C:3]([OH:25])=[O:2])[C:10](=[O:24])[C:11]=3[O:21][C:20]=2[CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)[C@H](CC(C)C)N1CC2=Cc3c(OC)cccc3OC2C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc2c1CC1=C(O2)C(=O)N([C@@H](CC(C)C)C(=O)O)C1
Yield: 72.3 %

Procedure:
A solution of (S)-2-(8-methoxy-3-oxo-3,3a-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-4-methyl-pentanoic acid methyl ester (0.75 g, 2.17 mmol) and lithium hydroxide monohydrate (0.12 g, 2.82 mmol) was stirred at 25° C. for 2 hours in tetrahydrofuran-water (3:1) mixture (30 mL). The reaction mixture was concentrated in vacuo to remove tetrahydrofuran, and the residue was acidified with 2N hydrochloric acid, and diluted with water. The resulting solution was extracted with ethyl acetate (3×). The combined organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed in vacuo to afford (S)-2-(8-methoxy-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-4-methyl-pentanoic acid (0.52 g, 72.3%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:11]=2[C:12]([O:14][CH3:15])=[O:13])=[C:5]([N+:21]([O-:23])=[O:22])[CH:4]=1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>C1(C)C=CC=CC=1>[Cl:20][C:18]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([CH2:2][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[CH:4][C:5]=2[N+:21]([O-:23])=[O:22])[CH:19]=1
Reactant: C1COCCN1
Reactant: COC(=O)c1ccc(Cl)cc1Nc1ccc(CBr)cc1[N+](=O)[O-]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(Cl)cc1Nc1ccc(CN2CCOCC2)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 93.6 %

Procedure:
A mixture of Example 570A (80 mg, 0.2 mmol) and morpholine (35 mg, 0.4 mmol) in 4 mL of toluene was heated under reflux for two hours. After the reaction mixture was cooled to room temperature, it was loaded onto silica gel for purification that yielded 76 mg of the desired product (94%). MS (DCI) m/e 406 (M+H)+; 1H NMR (300 MHz, DMSO-d6) □ 10.61 (s, 1H), 8.04 (d, J=1.87 Hz, 1H), 7.95 (d, J=8.73 Hz, 1H,) 7.65-7.66 (m, 1H), 7.61 (dd, J=8.73, 1.87 Hz, 1H), 7.46 (d, J=1.87 Hz, 1H), 7.10 (dd, J=8.58, 2.03 Hz, 1H), 3.88 (s, 3H), 3.57-3.59 (m, 4H), 3.39 (s, 2H), 2.28-2.90 (m, 4H).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][C:5]([C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[C:22]([O:30][CH3:31])[CH:21]=4)[N:18]=3)[NH:13][CH:12]=2)=[O:10])([CH3:8])[CH2:4][CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:51](O)=[O:52].N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:8][C:5]1([C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[C:22]([O:30][CH3:31])[C:23]([O:28][CH3:29])=[C:24]([O:26][CH3:27])[CH:25]=4)[N:18]=3)[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3][CH:2]([O:1][CH:51]=[O:52])[CH2:7][CH2:6]1
Reactant: COc1cc(-c2cnc3[nH]cc(C(=O)C4(C)CCC(O)CC4)c3n2)cc(OC)c1OC
Reactant: O=CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc(-c2cnc3[nH]cc(C(=O)C4(C)CCC(OC=O)CC4)c3n2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 58.8 %

Procedure:
A solution of (4-hydroxy-1-methyl-cyclohexyl)-[2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-methanone (19 mg, 0.045 mmol), triphenyl phosphine (23 mg, 0.088 mmol), and formic acid (0.003 ml, 0.087 mmol), in THF (0.4 ml), was treated with diethyl azodicarboxylate (0.01 ml, 0.092 mmol). After stirring at room temperature for 2 days, the reaction mixture was purified by preparative thin layer chromatography using 70% EtOAc in Hexanes as eluant providing 12 mg (59%) of formic acid 4-methyl-4-[2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbonyl]-cyclohexyl ester as a white solid. M+H=454.
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[N:4][N:3]1[C:25](=[S:27])[NH2:26].Br[CH2:29][C:30](OC)=[O:31].CN(C)C=O>O>[O:31]=[C:30]1[CH2:29][S:27][C:25]([N:3]2[CH:2]([CH3:1])[CH2:8][C:7]3[CH:9]=[C:10]4[O:15][CH2:14][O:13][C:11]4=[CH:12][C:6]=3[C:5]([C:16]3[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=3)=[N:4]2)=[N:26]1
Reactant: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1C(N)=S)OCO3
Reactant: COC(=O)CBr
Solvent: CN(C)C=O
Solvent: O
Product: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1C1=NC(=O)CS1)OCO3
Temperature: 85 °C
Reaction time: 1 h
Yield: 90.6 %

Procedure:
A mixture of 1.00 g (2.6 mmol) of the starting material I, 1.19 g (7.78 mmol) of methyl bromoacetate and 10 ml of dimethylformamide was stirred at 80-90° C. for 1 h. After diluting with water the obtained crude product was purified by refluxing in methanol to yield 1.00 g (91%) of the title compound; Mp.: 218-220° C.
Reaction SMILES: [O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]34[CH2:21][CH2:20][C:17]([O:22][P:23](=[O:40])([O:32]CC5C=CC=CC=5)[O:24]CC5C=CC=CC=5)([CH2:18][CH2:19]3)[CH2:16][CH2:15]4)[NH:6][C:5]=2[C:4](=[O:41])[N:3]1[CH2:42][CH2:43][CH3:44]>CO.C1COCC1.[Pd]>[O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]34[CH2:19][CH2:18][C:17]([O:22][P:23](=[O:24])([OH:32])[OH:40])([CH2:16][CH2:15]3)[CH2:20][CH2:21]4)[NH:6][C:5]=2[C:4](=[O:41])[N:3]1[CH2:42][CH2:43][CH3:44]
Reactant: CCCn1c(=O)c2[nH]c(C34CCC(OP(=O)(OCc5ccccc5)OCc5ccccc5)(CC3)CC4)nc2n(CCC)c1=O
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CCCn1c(=O)c2[nH]c(C34CCC(OP(=O)(O)O)(CC3)CC4)nc2n(CCC)c1=O
Yield: 86 %

Procedure:
Phosphoric acid dibenzyl ester 4-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl ester was dissolved in a mixture of 15 ml methanol and 10 ml of THF, Pd/C (10%, 50 mg) was added to the mixture. Hydrogenation was taken place at 50 psi for 8 h. Pd/C was filtered off and solvent was evaporated off. The residue was recrystallized in a mixture of methanol and ethyl acetate to get 190 mg title product (yield 86%). MS (M+1, 441)
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:34]2[CH:39]=[CH:38][C:37]([O:40]CC3C=CC=CC=3)=[CH:36][CH:35]=2)=[C:4]([O:22][C:23]2[CH:28]=[CH:27][C:26](/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32])=[CH:25][CH:24]=2)[C:5]2[C:10]([C:11]=1[O:12][CH3:13])=[CH:9][C:8]([O:14]CC1C=CC=CC=1)=[CH:7][CH:6]=2>C(Cl)(Cl)Cl.CO>[OH:14][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[C:4]([O:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[CH:27][CH:28]=1)=[C:3]([C:34]1[CH:35]=[CH:36][C:37]([OH:40])=[CH:38][CH:39]=1)[C:2]([CH3:1])=[C:11]2[O:12][CH3:13]
Reactant: COc1c(C)c(-c2ccc(OCc3ccccc3)cc2)c(Oc2ccc(/C=C/C(=O)O)cc2)c2ccc(OCc3ccccc3)cc12
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1c(C)c(-c2ccc(O)cc2)c(Oc2ccc(CCC(=O)O)cc2)c2ccc(O)cc12

Procedure:
Synthesized in manner similar to that employed for Example 46 (Step 8) using (2E)-3-{4-[(3-methyl-4-(methyloxy)-6-[(phenylmethyl)oxy]-2-{4-[(phenylmethyl)oxy]phenyl}-1-naphthalenyl)oxy]phenyl}-2-propenoic acid (258). 1H NMR (CD3OD, 400 MHz) δ 7.61 (d, J=9.1 Hz, 1H), 7.35 (d, J=2.4 Hz, 1H), 6.94-6.89 (m, 5H), 6.66 (d, J=8.4 Hz, 2H), 6.42 (d, J=8.4 Hz, 2H), 3.88 (s, 3H), 2.77-2.73 (m, 2H), 2.38 (bs, 2H), 2.12 (s, 3H). LRMS (ES−) m/z 443 (M−1)−. TLC (90:10; CHCl3/MeOH): Rf=0.07.
Reaction SMILES: C([O:3][P:4]([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])C.[CH3:11][O:12][CH2:13]Br>>[CH3:11][O:12][CH2:13][P:4](=[O:3])([O:5][CH2:6][CH3:7])[O:8][CH2:9][CH3:10]
Reactant: CCOP(OCC)OCC
Reactant: COCBr
Product: CCOP(=O)(COC)OCC
Temperature: 25 °C
Reaction time: 24 h
Yield: 85.6 %

Procedure:
To a sample of 17.90 mL (0.104 mol) of triethylphosphite at -78° C. under argon was added dropwise 8.50 mL (0.104 mol) of bromomethyl methyl ether. The mixture slowly warmed to RT and stirred for 24 h, when it was fractionally distilled (bp 100° C., 5 mm) to provide 16.22 g (98%) of title compound as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:12][CH2:13][CH2:14][CH2:15][C@H:16]1[O:20][C:19](=[O:21])[N:18]([C:22]2[CH:23]=[CH:24][C:25]3[S:30][CH2:29][C:28](=[O:31])[NH:27][C:26]=3[CH:32]=2)[CH2:17]1>>[NH2:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:12][CH2:13][CH2:14][CH2:15][C@H:16]1[O:20][C:19](=[O:21])[N:18]([C:22]2[CH:23]=[CH:24][C:25]3[S:30][CH2:29][C:28](=[O:31])[NH:27][C:26]=3[CH:32]=2)[CH2:17]1)=[O:6]
Reactant: Cc1ccc(C(=O)O)c(N)c1
Reactant: NCCC[C@@H]1CN(c2ccc3c(c2)NC(=O)CS3)C(=O)O1
Product: Cc1ccc(C(=O)NCCC[C@@H]2CN(c3ccc4c(c3)NC(=O)CS4)C(=O)O2)c(N)c1
Yield: 82 %

Procedure:
Starting from 2-amino-4-methylbenzoic acid and 6-[(R)-5-(3-amino-propyl)-2-oxo-oxazolidin-3-yl]-4H-benzo[1,4]thiazin-3-one (described in WO 2010/041219) and using Procedure D, the title compound was obtained as a beige solid (116 mg; 82% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][C:15]([OH:17])=O)[N:13]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:20]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([N:27]1[CH2:32][CH2:31][N:30]([C:15](=[O:17])[CH2:14][C:12]2[N:13]=[C:9]([NH:8][C:6](=[O:7])[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:19][CH:18]=3)[S:10][CH:11]=2)[CH2:29][CH2:28]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: O=C(O)Cc1csc(NC(=O)c2ccc(Cl)cc2)n1
Product: O=C(Nc1nc(CC(=O)N2CCN(Cc3ccccc3)CC2)cs1)c1ccc(Cl)cc1

Procedure:
In analogy to example 1.3, [2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetic acid (example 1.2) was coupled with 1-benzyl-piperazine to give N-{4-[2-(4-benzyl-piperazin-1-yl)-2-oxo-ethyl]-thiazol-2-yl}-4-chloro-benzamide, using general method A. Orange solid. MS 455.4 ([M+H]+)
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:21])[N:4]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][C:19]=2[CH3:20])[C:13]([O:15]C)=[O:14])[C:5]([CH3:9])=[CH:6][C:7]=1[OH:8].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[OH-].[Na+].Cl>>[Br:1][C:2]1[C:3](=[O:21])[N:4]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][C:19]=2[CH3:20])[C:13]([OH:15])=[O:14])[C:5]([CH3:9])=[CH:6][C:7]=1[OH:8]
Reactant: COC(=O)c1ccc(C)c(-n2c(C)cc(O)c(Br)c2=O)c1
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: Cc1ccc(C(=O)O)cc1-n1c(C)cc(O)c(Br)c1=O
Temperature: 25 °C
Reaction time: 42.5 h

Procedure:
(+/−)Methyl 3-(3-bromo-4-hydroxy-6-methyl-2-oxopyridin-1(2H)-yl)-4-methylbenzoate (4) (1 kg, 2.84 moles) was mixed with 1M dibasic potassium phosphate buffer solution (dibasic potassium phosphate (3.05 kg, 17.5 moles) and water (16.4 L)) and warmed to 25° C. The pH of the solution was adjusted to 9.1 with 10% NaOH solution (about 4.2 L) followed by the addition of Savinase® enzyme (Novozyme, Bagsvaerd, Denmark) and warmed to 30° C. After stirring for about 40-45 hours, the pH of the solution was adjusted to 6.0 using 6N HCl (2.3 L) and stirred for 30 minutes. The resulting precipitate was the unreacted enantiomer of the ester methyl (+)3-(3-bromo-4-hydroxy-6-methyl-2-oxopyridin-1(2H)-yl)-4-methylbenzoate (423 gm), which was isolated by filtration and washed with water. The aqueous filtrate was washed with 5.0 L methylene chloride. It was then further acidified to pH 3.6 with 2.1 L of 6N HCl to precipitate and isolate the optically enriched acid (−)3-(3-bromo-4-hydroxy-6-methyl-2-oxopyridin-1(2H)-yl)-4-methylbenzoic acid (10) by filtration. 1.3 kg (80% of theory) of product was obtained after drying.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]([CH:19]([CH3:21])[CH3:20])=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([OH:22])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:29][O:30][CH2:31]Cl>C(#N)C>[CH2:1]([O:8][C:9]1[C:18]([CH:19]([CH3:20])[CH3:21])=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([O:22][CH2:29][O:30][CH3:31])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCCl
Reactant: COC(=O)c1cc(C(C)C)c(OCc2ccccc2)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCOc1cc(OCc2ccccc2)c(C(C)C)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of methyl 4-benzyloxy-2-hydroxy-5-isopropylbenzoate (900 mg, 3.0 mmol) and anhydrous potassium carbonate (994 mg, 7.2 mmol) in acetonitrile (20 ml) was treated with chloromethyl methyl ether (0.24 ml, 6.6 mmol) and the mixture was stirred and held at 50° C. for 24 hours whereupon further anhydrous potassium carbonate (994 mg, 7.2 mmol) and chloromethyl methyl ether (0.96 ml, 26.4 mmol) were added and the mixture was stirred and held at 50° C. for a further 4 days. Upon cooling to room temperature the solvent was removed in vacuo and the residue treated with water (30 ml). The organic material was extracted with dichloromethane (2×20 ml) and the combined organic extracts were evaporated in vacuo to afford crude methyl 4-benzyloxy-5-isopropyl-2-(methoxymethyloxy)benzoate as a pale yellow oil that was used in the next step without further purification. 1H NMR (DMSO-d6) 7.57 (1H, s), 7.48 (2H, d), 7.44 (2H, t), 7.38 (1H, t), 6.90 (1H, s), 5.23 (4H, s), 3.78 (3H, s), 3.39 (3H, s), 3.21 (1H, m), 1.17 (6H, d). MS: [M+Na]+ 367.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH2:9])[CH:3]=1.[C:10]1(=O)[C:23]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[CH:13]=[CH:12][C:11]1=O>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[N:8]=[C:22]1[C:21]([C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:23]=31)=[N:9]2
Reactant: Nc1ccc(Cl)cc1N
Reactant: O=C1C=Cc2c(ccc3ccccc23)C1=O
Product: Clc1ccc2nc3c4ccccc4c4ccccc4c3nc2c1
Yield: 83 %

Procedure:
When one tenth mole each of 4-chloro-o-phenylendiamine and phenanthrenequinone were reacted by the method of Example 7(A), 26 g. (83 percent yield) of 11-chlorodibenzo[a,c]phenazine, mp = 241-242° C. were obtained.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]2[C:10](=[C:11]3[C:16]=1[CH:15]=[C:14]([F:17])[CH:13]=[CH:12]3)[CH:9]=[CH:8][CH:7]=[CH:6]2)[CH3:2].[BH4-].[Na+].FC(F)(F)C(O)=O.C1C=CC2C3C=CC=CC=3NCC=2C=1.C(N(CC)CC)C.[CH3:48][O:49][C:50]1[CH:55]=[CH:54][C:53]([S:56](Cl)(=[O:58])=[O:57])=[CH:52][C:51]=1[CH3:60]>O1CCCC1.ClCCl>[CH:14]1[CH:13]=[CH:12][C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[NH:4][CH2:3][C:16]=2[CH:15]=1.[CH2:1]([CH:3]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]1[S:56]([C:53]1[CH:54]=[CH:55][C:50]([O:49][CH3:48])=[C:51]([CH3:60])[CH:52]=1)(=[O:58])=[O:57])[CH3:2]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1C
Reactant: CCc1nc2ccccc2c2ccc(F)cc12
Agent: [BH4-]
Agent: [Na+]
Agent: c1ccc2c(c1)CNc1ccccc1-2
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CCC1c2cc(F)ccc2-c2ccccc2N1S(=O)(=O)c1ccc(OC)c(C)c1

Procedure:
The intermediate dihydrophenanthridine was prepared from 6-ethyl-8-fluoro-phenanthridine, (Example 40, Step b, 0.79 g, 3.48 mmol), by treatment with sodium borohydride (0.79 g, 21 mmol) and trifluoroacetic acid (1.1 mL, 14 mmol) in tetrahydrofuran (18 mL). In a separate, second step, the dihydrophenanthridine was treated with triethylamine (0.8 mL, 6 mmol) and 4-methoxy-3-methylbenzenesulfonyl chloride (0.66 g, 3.0 mmol, 2 equivalents) in dichloromethane (5 mL) according to the procedure and in the same manner as described in Example 32, Method A, Step d. The crude product was purified by flash column chromatography on silica gel, eluting with a mixture of ethyl acetate-hexane (1:19 to 3:7 gradient), to yield 6-ethyl-8-fluoro-5-[(4-methoxy-3-methylphenyl)sulfonyl]-5,6-dihydrophenanthridine as a homogeneous, white solid (0.57 g, 92% from the dihydrophenanthridine), m.p. 140° C.;
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[CH:17]=[C:18]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([O:35]CC)=[O:34])=[CH:29][CH:28]=3)[CH:19]=[CH:20][C:21]=2[CH2:22][CH:23]([OH:26])[CH2:24][OH:25])[CH:8]=[CH:9][C:10]=1[N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].C(C1C=C(C2C=C(C3C=CC(C(O)=O)=CC=3)C=CC=2CCCO)C=CC=1N(CC)CC)(C)(C)C>>[C:1]([C:5]1[CH:6]=[C:7]([C:16]2[CH:17]=[C:18]([C:27]3[CH:28]=[CH:29][C:30]([C:33]([OH:35])=[O:34])=[CH:31][CH:32]=3)[CH:19]=[CH:20][C:21]=2[CH2:22][CH:23]([OH:26])[CH2:24][OH:25])[CH:8]=[CH:9][C:10]=1[N:11]([CH2:12][CH3:13])[CH2:14][CH3:15])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(=O)c1ccc(-c2ccc(CC(O)CO)c(-c3ccc(N(CC)CC)c(C(C)(C)C)c3)c2)cc1
Agent: CCN(CC)c1ccc(-c2cc(-c3ccc(C(=O)O)cc3)ccc2CCCO)cc1C(C)(C)C
Agent: [Na+]
Agent: [OH-]
Product: CCN(CC)c1ccc(-c2cc(-c3ccc(C(=O)O)cc3)ccc2CC(O)CO)cc1C(C)(C)C
Yield: 86 %

Procedure:
In a manner similar to that of Example 3, by reacting 70 mg of ethyl 3″-tert-butyl-4″-diethylamino-4′-(2,3-dihydroxypropyl)-[1,1′;3′,1″]terphenyl-4-carboxylate (0.14 mmol) with 0.2 mL of 1N sodium hydroxide solution, 58 mg of 3″-tert-butyl-4″-diethylamino-4′-(3-hydroxypropyl)-[1,1′;3′,1″]terphenyl-4-carboxylic acid are obtained (yield=86%) in the form of a white solid (m.p.=130° C.).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][O:6][C:7]=1[CH3:8])#[CH:2].[NH2:15][C:16]1[CH:21]=[N:20][C:19](Br)=[CH:18][N:17]=1>>[CH3:8][C:7]1[O:6][N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]=1[C:1]#[C:2][C:19]1[N:20]=[CH:21][C:16]([NH2:15])=[N:17][CH:18]=1
Reactant: Nc1cnc(Br)cn1
Reactant: C#Cc1c(-c2ccccc2)noc1C
Product: Cc1onc(-c2ccccc2)c1C#Cc1cnc(N)cn1
Yield: 25 %

Procedure:
As described for example 11c, 4-ethynyl-5-methyl-3-phenyl-isoxazole (92 mg, 0.50 mmol) was converted (using 2-amino-5-bromopyrazine instead of 2-chloro-4-iodopyridine) to the title compound (SiO2, heptane:ethyl acetate=95:5 to 0:100, 35 mg, 25%) which was obtained as a brown solid. MS: m/e=277.2 [M+H]+.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.Br[CH2:9][C:10]1[CH:22]=[CH:21][C:13]([CH:14]=[CH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:12][CH:11]=1>C(#N)C>[NH:3]1[CH:7]=[CH:6][N:5]=[C:4]1[CH2:9][C:10]1[CH:22]=[CH:21][C:13]([CH:14]=[CH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:12][CH:11]=1
Reactant: CCOC(=O)C=Cc1ccc(CBr)cc1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)C=Cc1ccc(Cc2ncc[nH]2)cc1
Reaction time: 0.5 h
Yield: 69.5 %

Procedure:
To a suspension of 0.96 g of 50% sodium hydride in 50 ml of dry acetonitrile was added 1.3 g of imidazole at room temperature, and then the mixture was stirred for 30 min. A solution of 5.38 g of ethyl p-bromomethylcinnamate in 20 ml of dry acetonitrile was added to the mixture at room temperature for 10 min, and then the mixture was stirred at the same temperature for 1 hr. After concentration under reduced pressure, the residue was dissolved in 100 ml of benzene and washed with water and dried. The solvent was evaporated and the residual oil was chromatographed on silica gel using chloroform, and the resulting crystals were recrystallized from diethyl ether to give 3.4 g of ethyl 4-(1-imidazolylmethyl)cinnamate. This compound was added to 30 ml of 80% aqueous ethanol containing 0.8 g of sodium hydroxide and the mixture was stirred for 4 hr at room temperature. After concentration and reduced pressure, 25 ml of water was added to the residue and the mixture was washed with diethyl ether. The mixture was adjusted to pH 1 to 2 by an addition of concentrated hydrochloric acid and the acidic solution was concentrated under reduced pressure. To the residue, 30 ml of 2-methyl-2-propanol was added and the mixture was evaporated again, and the residue was dissolved in 80 ml of ethanol and the insoluble materials were filtered off. The filtrate was evaporated to obtain 3.4 g of crude 4-(1-imidazolylmethyl)cinnamic acid hydrochloride.
Reaction SMILES: CN(C)C=O.[OH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[CH:10]2.N1C=CN=C1.[C:21]([Si:25]([CH3:28])([CH3:27])Cl)([CH3:24])([CH3:23])[CH3:22]>O>[Si:25]([O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[CH:10]2)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:28])[CH3:27]
Reactant: Oc1ccc2[nH]ncc2c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc2[nH]ncc2c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Charge a 10 L reaction vessel with N,N-dimethylformamide (DMF, 2.50 L), 5-hydroxyindazole (150.20 g, 1.12 mol) and 1H-imidazole (114.35 g, 1.68 mol). Cool the mixture to 0° C. and add tert-butyldimethylchlorosilane (253.16 g, 1.68 mol) over 0.5 hours. Stir the mixture at 18° C. for 3 hours. Add water (2.5 L) to the reaction slowly with an ice bath at 5° C. to maintain an internal temperature at around 20° C. Transfer the mixture to a separating funnel and extract with EA (2×2.5 L). Combine the extracts and wash with water (3×2.5 L) and brine. Dry the organic solutions over anhydrous sodium sulfate, filter, and evaporate to a red oil. Pass the oil through a silica gel pad and elute with eluent (0% to 30% EA in hexane) to afford the title compound as an orange oil which crystallizes. Yield: 300 g (100%). MS (ES) m/z 249 [M+1]+.