Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.CO.C(=O)=O>>[F:20][C:2]([F:1])([F:19])[C:3]1[CH:4]=[CH:5][C:6]([C@@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10]2)=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1ccc(C2NCCc3ccccc32)cc1
Agent: O=C=O
Solvent: CO
Product: FC(F)(F)c1ccc([C@H]2NCCc3ccccc32)cc1

Procedure:
Enantiomers of 1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (2.120 g, 7.46 mmol, racemic mixture) were separated using chiral SFC (Chiralcel AD-H (250×21 Mm), 45% methanol/CO2 (100 bar), 65 mL/min, 220 nm) to give the title compound as a light yellow solid. MS (ESI, positive ion) m/z: 278 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4](Cl)[N:3]=1.[CH:15]1([CH2:18][NH2:19])[CH2:17][CH2:16]1>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:19][CH2:18][CH:15]2[CH2:17][CH2:16]2)[N:3]=1
Reactant: NCC1CC1
Reactant: CC(C)n1cnc2c(Cl)nc(Cl)nc21
Solvent: CCN(CC)CC
Product: CC(C)n1cnc2c(NCC3CC3)nc(Cl)nc21

Procedure:
2-Chloro-6-[(cyclopropyl)methylamino]-9-(2-propyl)purine is prepared from 2,6-dichloro-9-(2-propyl)purine (See Example 15 for preparation), cyclopropylmethylamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C:2]([C:5]([NH:7][C@@H:8]([C:19]([N:21]1[CH2:28][CH2:27][CH2:26][C@@H:22]1[C:23]([OH:25])=[O:24])=[O:20])[CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)=[O:6])([CH3:4])[CH3:3].[NH:36]1[CH2:41][CH2:40][CH2:39][CH:38]([C:42](N)=O)[CH2:37]1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:1][C:2]([C:5]([NH:7][C@@H:8]([C:19]([N:21]1[CH2:28][CH2:27][CH2:26][C@@H:22]1[C:23]([OH:25])=[O:24])=[O:20])[CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)=[O:6])([CH3:3])[CH3:4].[CH3:42][CH:38]1[CH2:39][CH2:40][CH2:41][N:36]([C:5]([NH2:7])=[O:6])[CH2:37]1
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)N1CCC[C@@H]1C(=O)O
Reactant: NC(=O)C1CCCNC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(N)C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)N1CCC[C@@H]1C(=O)O
Product: CC1CCCN(C(N)=O)C1
Yield: 84.8 %

Procedure:
Under N2 atmosphere, the Boc-Aib-DTrp-DPro-3-piperidinamide was dissolved in 25 ml of CH2Cl2 and 10 ml of trifluoracetic acid was added while being stirred. The reaction mixture was stirred for 30 min. All volatiles were removed under vacuum and the residue was dissolved in 30 ml of CH2Cl2 and washed with 10 ml saturated NaCHO3 aqueous solution. The organic layer was removed and the aqueous layer was extracted with CH2Cl2 (3×10 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and the solvent removed in vacuum. The residue was further purified by column chromatography (SiO2, CHCl3/MeOH, 85:15) to afford 0.28 mmol (84.8%) of compound (YL-111) which was characterized by TLC and mass spectra M+=468.6.
Reaction SMILES: C(#N)C.[CH:4]1([C:7]2[N:11]([C:12]3[CH:21]=[CH:20][CH:19]=[C:18]4[C:13]=3[CH:14]=[CH:15][CH:16]=[N:17]4)[N:10]=[CH:9][C:8]=2[C:22](Cl)=[O:23])[CH2:6][CH2:5]1.C1(C2N(C3C=CC=C4C=3C=CC=N4)N=CC=2C(Cl)=O)CC1.[NH2:46][C:47]([NH2:49])=[NH:48].O1CCCC1>Cl.NC(N)=N.O.[OH-].[Na+]>[CH:4]1([C:7]2[N:11]([C:12]3[CH:21]=[CH:20][CH:19]=[C:18]4[C:13]=3[CH:14]=[CH:15][CH:16]=[N:17]4)[N:10]=[CH:9][C:8]=2[C:22]([NH:48][C:47]([NH2:49])=[NH:46])=[O:23])[CH2:6][CH2:5]1
Reactant: O=C(Cl)c1cnn(-c2cccc3ncccc23)c1C1CC1
Reactant: N=C(N)N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC#N
Solvent: O
Product: N=C(N)NC(=O)c1cnn(-c2cccc3ncccc23)c1C1CC1
Temperature: 52.5 °C
Reaction time: 2 h

Procedure:
In a reaction flask, guanidine HCl (35.1 g) was dissolved in water (268 ml) and 50% NaOH (114.6 g). The acetonitrile/5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carbonyl chloride mixture of Example 4, was added in three equal portions to the flask containing the guanidine solution while maintaining the reaction temperature below 15° C. throughout the addition. The reaction mixture was brought to room temperature and stirred under nitrogen atmosphere for two hours. The reaction was confirmed to be complete by HPLC. A distillation head and condensor were then attached to the reaction vessel. The product mixture was atmospherically distilled at 85° C. resulting in a slurry having a volume of 400-450 ml. Tetrahydrofuran (THF) (720 ml) was added to the reaction flask and the mixture was warmed to 50-55° C. for 45 minutes and until all all contents had entered solution resulting in an orange biphasic mixture. The mixture was transferred to a separatory funnel and the layers were allowed to separate. The layers were separated and the aqueous layer was extracted with an additional 300 ml of THF. The resulting organic THF layers were combined. Darco® KB-B (5 g) (NORIT Americas Inc., Atlanta, Ga.) and Celite® (5 g) (Celite Corp., Lompoc, Calif.) were added to the THF layers and stirred at room temperature for one hour. The black mixture was vacuum filtered through a #2 Whatman paper filter (Whatman Inc., Clifton, N.J.) and the carbon cake was rinsed with THF. The filtrate was then collected, transferred to a clean flask. and atmospherically distilled at 70° C. to a volume of 450 ml. Ethanol (500 mL) was added to the flask and the mixture was atmospherically distilled at 85° C. to 450 ml. The addition of ethanol and subsequent distillation was repeated three more times. The resulting slurry was cooled to room temperature and allowed to granulate while stirring for three hours. The slurry was then filtered onto a #2 Whatman filter paper and rinsed with THF. The resulting white crystalline solid was allowed to dry for about 48 hours in a vacuum oven at 45 to 50° C. resulting in 52.2 g of N-(5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carbonyl)-guanidine.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([NH2:10])=[N:8][CH:9]=1)([CH3:3])[CH3:2].N#N.[Li][CH2:14]CCC.IC>C1COCC1.O>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][CH3:14])=[N:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: [Li]CCCC
Reactant: CC(C)c1ccc(N)nc1
Agent: N#N
Solvent: C1CCOC1
Solvent: CI
Solvent: O
Product: CNc1ccc(C(C)C)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 36.3 %

Procedure:
A solution of 5-isopropyl-pyridin-2-ylamine (0.5 g, 3.67 mmol) in dry THF was purged with N2 and cooled to −78° C. n-BuLi (1.62 mL, 4.04 mmol) was added dropwise. The reaction was stirred at 0° C. for 0.5 h, and then iodomethane (0.25 mL, 4.04 mmol) was added dropwise. The resulting mixture was stirred overnight while warming to r.t. Water (20 mL) was added, and the mixture was extracted with EtOAc. The organic layer was dried over Na2SO4, concentrated, and purified by silica gel chromatography (10% to 30% EtOAc in PE) to give 200 mg (36%) of the title compound as a brown oil. [M+H] Calc'd for C9H14N2, 151. Found, 151.
Reaction SMILES: Cl.[C:2](=[NH:10])([O:7][CH2:8][CH3:9])[CH2:3][CH2:4][CH2:5][CH3:6].C(N(CC)CC)C.[Cl-].[C:19]([O:30][CH3:31])(=[O:29])[C:20]1[CH:28]=[CH:27][C:23]([C:24]([O-])=[O:25])=[CH:22][CH:21]=1>C1(C)C=CC=CC=1>[CH3:31][O:30][C:19](=[O:29])[C:20]1[CH:28]=[CH:27][C:23]([C:24]([N:10]=[C:2]([O:7][CH2:8][CH3:9])[CH2:3][CH2:4][CH2:5][CH3:6])=[O:25])=[CH:22][CH:21]=1
Reactant: CCCCC(=N)OCC
Reactant: COC(=O)c1ccc(C(=O)[O-])cc1
Agent: Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCC(=NC(=O)c1ccc(C(=O)OC)cc1)OCC
Temperature: 25 °C
Reaction time: 19 h
Yield: 12.1 %

Procedure:
To a solution of ethyl pentanimidate hydrochloride (9 g, 54 mmol) and triethyl amine (17 mL, 120 mmol) in toluene (110 mL) at 0° C. was added, over 20 minutes, a solution of terephthalic acid, monomethyl ester chloride (10.8 g, 54 mmol) in toluene (21 mL). After stirring at ambient temperature for 19 hours, the reaction was filtered and the solids were rinsed with toluene (200 mL). The combined filtrates were concentrated in vacuo. Flash chromatography (silica gel, CH2Cl2) of a portion of this material afforded the title compound (1.9 g, 47%).
Reaction SMILES: [ClH:1].[NH:2]1[CH:6]=[C:5]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])[N:4]=[CH:3]1.Cl.[CH3:13]O>>[ClH:1].[NH:2]1[CH:6]=[C:5]([CH:7]=[CH:8][C:9]([O:11][CH3:13])=[O:10])[N:4]=[CH:3]1
Reactant: CO
Reactant: O=C(O)C=Cc1c[nH]cn1
Agent: Cl
Product: COC(=O)C=Cc1c[nH]cn1

Procedure:
A solution of 4-imidazoleacrylic acid hydrochloride (20.0 g, 145 mmol) in MeOH (300 mL) was saturated with HCl (g). The resulting solution was refluxed for 90 min., then concentrated to dryness in vacuo to afford the titled ester as a white solid.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)=[O:4].C(Cl)Cl.[Cl:23][S:24](O)(=[O:26])=[O:25]>O>[F:19][C:2]([F:1])([F:18])[C:3]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([S:24]([Cl:23])(=[O:26])=[O:25])=[CH:16][CH:17]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: O=S(=O)(O)Cl
Reactant: O=C(N1CCC(Cc2ccccc2)CC1)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: O=C(N1CCC(Cc2ccc(S(=O)(=O)Cl)cc2)CC1)C(F)(F)F
Temperature: 0 °C
Yield: 41.3 %

Procedure:
To the mixture of 1-(trifluoroacetyl)-4-benzylpiperidine (29.2 g, 108 mmol) and methylene chloride (10 ml) was dropwise added chlorosulfonic acid (36 ml, 539 mmol) at −10° C. for an hour. The mixture was stirred at 0° C. for an hour and then stirred at room temperature for an hour. The reaction mixture was poured into ice-cooled water (500 ml) and extracted with methylene chloride (200 ml×2). The extract was washed with an aqueous solution of 5% sodium bicarbonate (500 ml) and saturated brine (500 ml) successively. The organic phase was dried over magnesium sulfate (anhydrous), then concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel 100 g, ethyl acetate/hexane=1/20→1/5) to give the title compound as a colorless powdery crystal (16.5 g, 41%).
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][OH:4].N1C=CN=C1.[Si:11](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C)C=O.C(OCC)(=O)C>[Si:11]([O:4][CH2:3][CH2:2][CH2:1][OH:5])([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OCCCO
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCCCO)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 1,3-propanediol (1.25 g, 16.4 mmol) in N,N-dimethylformamide (50 mL) was added imidazole (2.23 g, 32.8 mmol) and tert-butyldiphenylsilyl chloride (4.97 g, 18.1 mmol). The reaction was stirred for 3 days at room temperature, then was diluted with ethyl acetate and was washed with water and brine. Concentration in vacuo afforded the crude product as a thick colorless oil which was used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[C:17]3[C:16](=[O:18])[N:15]([CH2:19][CH2:20][CH2:21]OC4CCCCO4)[C:14](=[O:29])[N:13]([CH3:30])[C:12]=3[S:11][C:10]=2[O:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38][C:39]([F:42])([F:41])[F:40])[CH:33]=2)=[CH:4][CH:3]=1.C([SiH](CC)CC)C.[C:51]([OH:57])([C:53]([F:56])([F:55])[F:54])=[O:52]>C(Cl)Cl.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[C:17]3[C:16](=[O:18])[N:15]([CH2:19][CH2:20][CH2:21][O:52][C:51](=[O:57])[C:53]([F:56])([F:55])[F:54])[C:14](=[O:29])[N:13]([CH3:30])[C:12]=3[S:11][C:10]=2[O:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38][C:39]([F:40])([F:41])[F:42])[CH:33]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(C(O)c3ccc(Cl)cc3)c(Oc3cccc(OC(F)(F)F)c3)sc21
Agent: CC[SiH](CC)CC
Solvent: O
Solvent: ClCCl
Product: Cn1c(=O)n(CCCOC(=O)C(F)(F)F)c(=O)c2c(Cc3ccc(Cl)cc3)c(Oc3cccc(OC(F)(F)F)c3)sc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.9 %

Procedure:
To a solution of 5-((4-chlorophenyl)(hydroxy)methyl)-1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)-6-(3-(trifluoromethoxy)phenoxy)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (See Compound 21, Step 2, 30 mg, 0.047 mmol) in TFA (2 mL) was added triethylsilane (1 mL). The reaction was stirred at RT for 3 h then diluted with DCM (5 mL) and water (5 mL). The organic layer was dried over Na2SO4 and concentrated to give 3-(5-(4-chlorobenzyl)-1-methyl-2,4-dioxo-6-(3-(trifluoromethoxy)phenoxy)-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)propyl2,2,2-trifluoroacetate (25 mg, 83.9% yield) as an oil. LCMS: MH+ 637 and TR=2.274 min.
Reaction SMILES: [C:1]1([C:7]2[N:8]([N:18]=[C:19]([CH3:23])[C:20](=O)[CH3:21])[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C=O)C.[N:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[N:36]([NH2:46])[C:37]([C:40]3[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=3)=[CH:38][CH:39]=2)[CH:30]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.O>[C:1]1([C:7]2[N:8]([N:18]=[C:19]([C:20](=[N:46][N:36]3[C:37]([C:40]4[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=4)=[CH:38][CH:39]=[C:35]3[C:31]3[CH:30]=[N:29][CH:34]=[CH:33][CH:32]=3)[CH3:21])[CH3:23])[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nn1c(-c2cccnc2)ccc1-c1cccnc1
Reactant: CC(=O)C(C)=Nn1c(-c2ccccc2)ccc1-c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=Nn1c(-c2ccccc2)ccc1-c1ccccc1)C(C)=Nn1c(-c2cccnc2)ccc1-c1cccnc1
Temperature: 25 °C

Procedure:
A suspension of 3-(2,5-Diphenyl-pyrrol-1-ylimino)-butan-2-one (1.0 g, 3.4 mmol) in toluene (12 ml) is treated with DMF (6 ml), 2,5-di-pyridin-3-yl-pyrrol-1-ylamine (850 mg, 3.6 mmol) and p-toluene sulfonic acid (30 mg). The resulting suspension is fitted with a Dean Stark trap and heated to reflux with azeotropic removal of water in an oil bath until no starting materials remain by TLC. The solution is cooled to rt and concentrated in vacuo. The residue is purified by flash chromatography to afford 2-(2,5-diphenyl-pyrrol-1-ylimino)-3-(2,5-dipyridine-3-yl-pyrrol-1-ylimino)-butane.
Reaction SMILES: C[C:2]1([CH3:10])[O:7][C:6](=O)[CH:5]=[C:4](C)[O:3]1.[CH:11]([NH:13][C:14](=[O:19])[CH2:15][C:16]([CH3:18])=O)=O.CN(C)C1C=CC=CC=1>>[NH:13]1[CH:11]=[CH:18][CH:16]=[CH:15][C:14]1=[O:19].[O:7]1[CH:6]=[CH:5][C:4](=[O:3])[CH:10]=[CH:2]1
Reactant: CC1=CC(=O)OC(C)(C)O1
Reactant: CC(=O)CC(=O)NC=O
Solvent: CN(C)c1ccccc1
Product: O=c1cccc[nH]1
Product: O=c1ccocc1

Procedure:
In addition, the reaction for obtaining an 4-pyrone compound from 2,2,6-trimethyl-1,3-dioxin-4-one has been known. That is, T. Kato et al [Chem, Pharm. Bull., 30, 1315(1982)] studied on the reaction between amides or acetoacetyl derivatives thereof and 2,2,6-trimethyl-1,3-dioxin-4-one and reported that the reaction of N-formylacetoacetamide with 2,2,6-trimethyl-1,3-dioxin-4-one in the presence of N,N-dimethylaniline gave a pyridone compound as the main product and 4-pyrone compound as the by-product.
Reaction SMILES: N1CCCCC1.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH:12]=O.C([CH2:22][C:23]([NH:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28]([OH:30])=[O:29])=[O:24])(O)=O>C1(C)C=CC=CC=1>[CH3:7][O:8][C:9]1[CH:10]=[C:11](/[CH:12]=[CH:22]/[C:23]([NH:25][C:26]2[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=2[C:28]([OH:30])=[O:29])=[O:24])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]
Reactant: O=C(O)CC(=O)Nc1ccccc1C(=O)O
Reactant: COc1ccc(C=O)cc1OC
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: COc1ccc(/C=C/C(=O)Nc2ccccc2C(=O)O)cc1OC
Temperature: 25 °C
Yield: 74.6 %

Procedure:
Piperidine (0.96 mL, 9.7 mmol) was added to a suspension of 3,4-dimethoxybenzaldehyde (1.6 g, 9.7 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (1.9 g, 8.6 mmol) in toluene (5.0 mL). The reaction flask was fitted with a Dean-Stark apparatus and heated to reflux for 4 h, then cooled to rt and the resulting suspension was filtered and washed with toluene. The piperidinium salt was dissolved in MeOH (5.0 mL) and water (2.0 mL) at 40° C. and the solution was acidified with concentrated HCl. The precipitate was filtered, providing (E)-2-[[3-(3,4-dimethoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid (tranilast) (2.1 g, 74%) as a yellow crystalline solid; mp 208-209° C., lit.2 206° C.; δH (500 MHz, DMSO-d6) 3.79 (s, 3H, OCH3), 3.82 (s, 3H; OCH3), 6.79 (d, J=15.5 Hz, 1H, CH═CHCO), 6.99 (d, J5′,4′=8.5 Hz, 1H, H5′), 7.16 (t, J3,4=J4,5=7.9 Hz, 1H, H4), 7.25 (d, J5′,6′=8.5 Hz, 1H, H6′), 7.38 (s, 1H, H2′), 7.56 (d, J=15.5 Hz, 1H, CH═CHCO), 7.61 (t, J4,5=J5,6=7.9 Hz, 1H, H5), 8.00 (d, J3,4=7.9 Hz, 1H, H3), 8.62 (d, J5,6=7.9 Hz, 1H, H6), 11.30 (s, 1H, NH), 13.61 (br s, 1H, CO2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.C=O.[C:15](OCC)(=[O:17])C>CS(C)=O.C[O-].[Na+]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH2:15][OH:17])[C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1
Reactant: CCOC(C)=O
Reactant: COC(=O)Cc1ccc(F)cc1
Agent: C=O
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)C(CO)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.91 %

Procedure:
Methyl 2-(4-fluorophenyl)acetate (5.0 g, 29.73 mmol), NaOMe (0.08031 g, 1.487 mmol) and paraformaldehyde (0.9374 g, 31.22 mmol) were dissolved/suspended in 200 mL of DMSO and allowed to stir overnight at ambient temperature. The reaction was quenched with the addition of 1000 mL of ice-cold water. The reaction was neutralized with the addition of HCl solution, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water twice, once with brine, separated, dried over MgSO4, filtered, and concentrated in vacuo to afford the crude product as a yellow oil. Column chromatography on silica gel eluting with 25:75 hexanes:ethyl acetate afforded methyl 2-(4-fluorophenyl)-3-hydroxypropanoate (3.0 g, 50.91% yield) as a colorless oil.
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][CH2:5][NH2:6])[CH3:2].[CH:9]1[CH:10]=[CH:11][C:12]2[C:23](=[O:24])[C:22]3[C:17](=[C:18](O)[CH:19]=[CH:20][C:21]=3O)[C:15](=[O:16])[C:13]=2[CH:14]=1>>[CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][CH2:5][NH:6][C:18]1[C:17]2[C:15](=[O:16])[C:13]3[C:12](=[CH:11][CH:10]=[CH:9][CH:14]=3)[C:23](=[O:24])[C:22]=2[C:21]([NH:6][CH2:5][CH2:4][N:3]([CH2:7][CH3:8])[CH2:1][CH3:2])=[CH:20][CH:19]=1)[CH3:2]
Reactant: O=C1c2ccccc2C(=O)c2c(O)ccc(O)c21
Reactant: CCN(CC)CCN
Product: CCN(CC)CCNc1ccc(NCCN(CC)CC)c2c1C(=O)c1ccccc1C2=O

Procedure:
A mixture of 42 ml. of N,N,N',N'-tetramethylenediamine, 17.43 g. of N,N-diethylethylenediamine and 12.01 g. of quinizarin is stirred and heated under reflux for 15 hours. The resulting solution is evaporated to dryness and a chloroform solution of the residue is filtered through 300 g. of alumina. The blue filtrate is chromatographed on silica gel in a Nylon® film column, developing with a chloroform:methanol (6:1) mixture. The major blue band is cut out and then eluted with a chloroform:methanol:triethylamine (6:2:1) mixture. The eluate is evaporated. The residue is crystallized from hexane and washed with petroleum ether, giving 1.43 g. of the desired product as blue-black plates, mp. 109° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([O:11]S(C=C)(=O)=O)=[C:4]([CH3:17])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O.C(O)C>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([OH:11])=[C:4]([CH3:17])[CH:3]=1
Reactant: C=CS(=O)(=O)Oc1cc([N+](=O)[O-])c(Cl)cc1C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Cc1cc(Cl)c([N+](=O)[O-])cc1O
Yield: 101.3 %

Procedure:
A solution of compound 106 (27.8 g, 100 mmol) and potassium carbonate (27.6 g, 200 mmol) in ethanol water 1/1 (600 ml) was refluxed for one hour. Citric acid (5%) was added and the mixture was extracted three times with DCM. The organic phase was dried with sodium sulphate and evaporated under reduced pressure which gave the title compound (19 g, 100%).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C:12]#[N:13])=[CH:11][C:5]=2[C:4](=[O:14])[O:3]1.C(O)(=O)C.N#N>CO.[Pd]>[C:2]([OH:7])(=[O:3])[CH3:1].[NH2:13][CH2:12][C:10]1[CH:9]=[CH:8][C:6]2[O:7][C:2]([CH3:15])([CH3:1])[O:3][C:4](=[O:14])[C:5]=2[CH:11]=1
Reactant: CC1(C)OC(=O)c2cc(C#N)ccc2O1
Agent: [Pd]
Agent: N#N
Solvent: CC(=O)O
Solvent: CO
Product: CC1(C)OC(=O)c2cc(CN)ccc2O1
Reaction time: 22 h
Yield: 74.8 %

Procedure:
To a solution of 2,2-dimethyl-4-oxo-4H-1,3-benzodioxine-6-carbonitrile (12 g, 0.06 mol) in methanol (500 mL) was added glacial acetic acid (3.5 g, 0.059 mol) and passed N2 for 30 min. To this was added Pd/C (2.4 g, 20%) and hydrogenated under 2 Bars of pressure for 22 h. The reaction mixture was filtered through celite and filtrate concentrated under vacuum. To the solid was added EtOAc (200 mL), stirred for 20 h and filtered. The solid was dried under vacuum to give the title compound (6 g, 38%). TLC: CHCl3/MeOH, 9:1, Rf: 0.15
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[N:8]=[CH:9][N:10]([C:12]2[CH:13]=[C:14]3[C:19](=[C:20]([CH3:22])[CH:21]=2)[NH:18][C:17](=[O:23])[CH:16]=[CH:15]3)[CH:11]=1.[I:24]I.[Cl-].[NH4+]>CCCCCC.O1CCCC1.O>[I:24][C:9]1[N:10]([C:12]2[CH:13]=[C:14]3[C:19](=[C:20]([CH3:22])[CH:21]=2)[NH:18][C:17](=[O:23])[CH:16]=[CH:15]3)[CH:11]=[C:7]([CH3:6])[N:8]=1
Reactant: Cc1cn(-c2cc(C)c3[nH]c(=O)ccc3c2)cn1
Reactant: II
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1cn(-c2cc(C)c3[nH]c(=O)ccc3c2)c(I)n1
Temperature: 25 °C

Procedure:
n-Butyllithium (2.94 cm3 of a 1.43M solution in n-hexane) was added dropwise to a stirred suspension of 6-(4-methylimidazol-1-yl)-8-methyl-2-(1H)-quinolone (0.45 g) (see Example 6) in tetrahydrofuran (THF) (25 cm3) at -70° C. under nitrogen. After one hour iodine (0.51 g) was added and the mixture warmed to room temperature over 1.5 hours. Ammonium chloride solution was added (5 cm3), and the mixture was poured into water (20 cm3). The aqueous mixture was extracted with dichloromethane (3×50 cm3) and the combined and dried (MgSO4) organic extracts were evaporated in vacuo to give a residue which was chromatographed on silica (Merck "MK 60.9385" [Trade Mark]). Elution with chloroform followed by combination and evaporation of appropriate fractions gave a solid which was recrystallised from ethyl acetate to afford 6-(2-iodo-4-methylimidazol-1-yl)-8-methyl-2-(1H)-quinolone, m.p. (d) 260° (0.22 g).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][CH:12]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[OH:13])[C:6]3[CH2:20][CH2:21][NH:22][CH2:23][C:5]=3[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][CH:32]([OH:34])[CH3:33]>C(#N)C.O>[OH:13][CH:12]([C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)[CH2:11][N:7]1[C:8]2[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][C:4]=2[C:5]2[CH2:23][N:22]([CH2:31][CH:32]([OH:34])[CH3:33])[CH2:21][CH2:20][C:6]1=2
Reactant: Cc1ccc2c(c1)c1c(n2CC(O)c2ccncc2)CCNC1
Reactant: CC(O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1ccc2c(c1)c1c(n2CC(O)c2ccncc2)CCN(CC(C)O)C1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(8-methyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethanol (200 mg, 0.651 mmol) in acetonitrile (4 mL), potassium carbonate (270 mg, 1.95 mmol) and 1-bromopropan-2-ol (135 mg, 0.977 mmol) were added and stirred the reaction mixture at 100° C. for 2 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3×20 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase HPLC to yield 1-[5-(2-hydroxy-2-pyridin-4-yl-ethyl)-8-methyl-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl]-propan-2-ol. 1H NMR, (CDCl3, freebase) δ (ppm): 8.58 (s, 2H), 7.36 (m, 2H), 7.2 (m, 2H), 7.02 (d, 1H), 5.1 (s, 1H), 4.3 (m, 1H), 4.1 (m, 2H), 4.0 (m, 2H), 3.56 (m, 1H), 3.37 (m, 1H), 3.1-3.3 (m, 2H), 2.8 (m, 2H), 2.42 (s, 3H), 1.2 (d, 3H). Separation by chiral HPLC provides diastereomers II-83a-d.