Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].C(O[C@@H:13]1[O:30][C@H:29]([CH2:31][O:32][C:33](=[O:35])[CH3:34])[C@@H:24]([O:25][C:26](=[O:28])[CH3:27])[C@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:14]1[O:15][C:16](=[O:18])[CH3:17])(=O)C.[Sn](Cl)(Cl)(Cl)Cl>C1C=CC=CC=1.ClCCCl>[C:16]([O:15][C@@H:14]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:24]([O:25][C:26](=[O:28])[CH3:27])[C@@H:29]([CH2:31][O:32][C:33](=[O:35])[CH3:34])[O:30][C@H:13]1[N:1]1[CH:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]1=[O:3])(=[O:18])[CH3:17]
Reactant: O=c1cc[nH]c(=O)[nH]1
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCCl
Solvent: c1ccccc1
Product: CC(=O)OC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
Uracil is bis-trimethylsilylated according to the procedure of Niedballa and Vorbruggeno Uracil is dissolved in benzene, and added to 1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose 33.1b (Xi=β-OAc) (Niedbala and Vorbruggen) in 1,2 dichloroethane followed by tin tetrachloride in 1,2-dichloroethane according to the method of Vorbruggen and Niedballa to provide the 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)uracil 33.1b (Xi=β-uracil-1-yl). Following methanolysis with sodium methoxide in methanol the 1-(B-D-glucopyranosyl)uracil 33.1a (Xi=β-uracil-1-yl) is obtained. This is converted into the morpholino subunit 32.2b (Xi=β-uracil-1-yl) by the general procedure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:33]=[CH:32][C:18]([C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)=[O:20])=[C:17]([O:34][CH3:35])[CH:16]=2)[N:10]=1.[C:36]([Cu])#[N:37]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:36]#[N:37])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:33]=[CH:32][C:18]([C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)=[O:20])=[C:17]([O:34][CH3:35])[CH:16]=2)[N:10]=1
Reactant: COc1cc(-n2nc(-c3c(Cl)cccc3I)[nH]c2=O)ccc1C(=O)Nc1cccc(C(F)(F)F)c1
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Product: COc1cc(-n2nc(-c3c(Cl)cccc3C#N)[nH]c2=O)ccc1C(=O)Nc1cccc(C(F)(F)F)c1
Temperature: 80 °C
Yield: 13.8 %

Procedure:
To a solution of 4-(3-(2-chloro-6-iodophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxy-N-(3-(trifluoromethyl)phenyl)benzamide (Intermediate-34, 0.130 g, 0.211 mmol) in DMF (5 mL) was added CuCN (0.020 g, 0.232 mmol) and reaction mixture was heated at 80° C. for 4-5 h. The reaction mass was quenched with aq. KMnO4 solution and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and concentrated to afford 0.015 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 3.95 (s, 3H), 7.44 (d, J=7.8 Hz, 1H), 7.59 (t, J=8.4 Hz, 1H), 7.68 (d, J=8.1 Hz, 1H), 7.80-7.86 (m, 3H), 7.95 (d, J=8.7 Hz, 1H), 8.06-8.12 (m, 2H), 8.25 (s, 1H), 10.38 (s, 1H), 13.00 (br s, 1H); MS (m/z): 512.14 (M−H)−.
Reaction SMILES: C[C:2]1[NH:6][C:5]([C:7](OCC)=O)=[C:4]2[CH2:12][CH2:13][CH2:14][C:3]=12.[OH-].[K+]>C(O)C>[CH3:7][C:5]1[NH:6][CH:2]=[C:3]2[CH2:14][CH2:13][CH2:12][C:4]=12
Reactant: CCOC(=O)c1[nH]c(C)c2c1CCC2
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1[nH]cc2c1CCC2
Temperature: 180 °C

Procedure:
A solution of ethyl 3-methyl-2,4,5,6-tetrahydrocyclopenta[c]pyrrolecarboxylate 4j (9.1 g, 0.04mol) and potassium hydroxide (26 g, 0.47 mol) in ethanol (200 ml) was heated at 80° C. for 4 hours and concentrated. The residue was combined with ice water (400 ml), and made slightly acidic by the additionof acetic acid to bring about the precipitation of crude 3-methyl-2,4,5,6-tetrahydrocyclopenta[c]pyrrolecarboxylic acid. The crude acid was combined with ethanolamine (5 g), heated at 180° C. for 1 hour, and diluted with ice water (100 ml). Extraction by methylene chloride (3×100 ml) followed by solvent removal and distillation of a residual oil, bp 110°-111° C. (20 mm) gave 3-methyl-2,4,5,6-tetrahydrocyclopenta[c]pyrrole 5j, 3.6 g (64%) as a colorless oil; 1H NMR (CDCl3): δ 7.57 (s, 1H), 6.33 (s, 1H), 2.67 (t, 2H), 2.59 (t7 2H), 2.35 (m, 2H), 2.22 (s, 3H). Anal. calcd for C8H11N: C, 79.34; H, 9.09; N, 11.59. Found: C, 79.12; H, 9.29; N, 11.60.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([OH:10])[C:5]([OH:11])=[CH:4][CH:3]=1.Br[CH2:13]Br.[F-].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:13][O:10][C:6]=2[C:7]=1[CH:8]=[O:9]
Reactant: O=Cc1c(Br)ccc(O)c1O
Reactant: BrCBr
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1c(Br)ccc2c1OCO2
Temperature: 100 °C
Yield: 31.2 %

Procedure:
6-Bromo-2,3-dihydroxybenzaldehyde (1.82 g, 8.39 mmol) was dissolved in DMF (20 mL) and dibromomethane (1.57 g, 9.00 mmol) and potassium fluoride (2.44 g, 42.00 mmol) were added. The reaction mixture was heated to 100° C. for 2 h at which time TLC analysis indicated the reaction complete. The reaction mixture was cooled to ambient temperature and partitioned between water and methylene chloride. The organic layers were washed 4× with water, dried with magnesium sulfate, and concentrated by rotary evaporation to afford 0.60 g of product (2.62 mmol, 31% yield) as an oil. 1H NMR (CDCl3) δ 10.24 (s, 1H), 7.09 (d, J=8.3 Hz, 1H), 6.79 (d, J=8.3 Hz, 1H), 6.10 (s, 2H).
Reaction SMILES: [ClH:1].[Br:2][C:3]1[CH:4]=[C:5]([C:29]([CH3:32])([CH3:31])[CH3:30])[C:6]([OH:28])=[C:7]([C@@H:9]([NH:16][C:17](=[O:27])[CH2:18][NH:19]C(OC(C)(C)C)=O)[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:8]=1.C(#N)C>O1CCOCC1>[ClH:1].[NH2:19][CH2:18][C:17]([NH:16][C@H:9]([C:7]1[CH:8]=[C:3]([Br:2])[CH:4]=[C:5]([C:29]([CH3:32])([CH3:31])[CH3:30])[C:6]=1[OH:28])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:27]
Reactant: CCOC(=O)C[C@H](NC(=O)CNC(=O)OC(C)(C)C)c1cc(Br)cc(C(C)(C)C)c1O
Agent: Cl
Solvent: CC#N
Solvent: C1COCCO1
Product: CCOC(=O)C[C@H](NC(=O)CN)c1cc(Br)cc(C(C)(C)C)c1O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
4M HCl in 1,4-dioxane (3.0 mL) was added to a solution of a crude sample of (S)-ethyl 3-(5-bromo-3-(tert-butyl)-2-hydroxyphenyl)-3-(2-((tert-butoxycarbonyl)amino)acetamido)propanoate (0.922 g, 1.84 mmol) in 1,4-dioxane (3.0 mL) at 0° C. (ice-bath) and the reaction mixture was stirred at 0° C. for 30 min and then at room temperature for 30 min. The reaction mixture was then heated at 50° C. for 2.5 h under nitrogen atmosphere to give a yellow-orange suspension. The solvent was evaporated in-vacuo to afford a dirty yellow-orange foamy solid. Acetonitrile (25 mL) was added to the solid, stirred for 5 min to give a cream-yellow suspension and evaporated in vacuo to afford a dirty cream solid (0.935 g). LC/MS analysis of the product shows the desired product's mass: m/z 402 (79BrM+H) and m/z 404 (81BrM+H), Calcd for C17H25BrN2O4: 401.29.
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>C(O)(=O)C>[C:12]([O:1][CH2:2][C:3]1[NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[N:4]=1)(=[O:14])[CH3:13]
Reactant: OCc1nc2ccccc2[nH]1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)OCc1nc2ccccc2[nH]1

Procedure:
A mixture of 1.0 g of 2-hydroxymethylbenzimidazole and 0.64 ml of acetic anhydride in 10 ml of acetic acid was heated to reflux for 1 hour. The solvent was removed in vacuo and the residue dissolved in chloroform and washed with a sodium bicarbonate solution. The organic layer was separated, dried and concentrated to give 1.2 g of the desired intermediate.
Reaction SMILES: [CH2:1](C1C2N=C(OC)C=CC=2CC2(OCCO2)C1)C.[CH3:19][O:20][C:21]([C:23]12[C:38](=[O:39])[CH:27]([CH:28]([CH3:37])[C:29]3[C:34]1=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[N:30]=3)[CH2:26][C:25](=[CH2:40])[CH2:24]2)=[O:22]>>[CH3:19][O:20][C:21]([C:23]12[C:38](=[O:39])[CH:27]([CH:28]([CH2:37][CH3:1])[C:29]3[C:34]1=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[N:30]=3)[CH2:26][C:25](=[CH2:40])[CH2:24]2)=[O:22]
Reactant: C=C1CC2C(=O)C(C(=O)OC)(C1)c1ccc(OC)nc1C2C
Reactant: CCC1CC2(Cc3ccc(OC)nc31)OCCO2
Product: C=C1CC2C(=O)C(C(=O)OC)(C1)c1ccc(OC)nc1C2CC

Procedure:
10-Ethyl-7,8,9,10-tetrahydro-2-methoxy-7-methylene-11-oxo-5,9-methanocycloocta[b]pyridine-5(6H)-carboxylic Acid Methyl Ester (6c) was prepared from 4c in the same manner as described for the preparation of compound 6b: IR (neat) 2953, 1743, 1724, 1601, 1577, 1479, 823 cm-1 ; 1H NMR (major isomer) δ6.94 (d, 1H, J=8.7 Hz), 6.56 (d, 1H, J=8.7 Hz), 4.73 (s, 1H), 4.41 (s, 1H), 3.87 (s, 3H), 3.77 (s, 3H), 3.01 (m, 1H), 2.90 (m, 2H), 2.75 (m, 1H), 2.55 (m, 2H), 1.85 (m, 1H), 1.60 (m, 1H), 1.22 (t, 3H, J=7.4 Hz); 13C NMR δ209.0, 208.6, 171.5, 171.4, 162.9, 162.4, 155.2, 154.2, 139.3, 139.1, 137.3, 124.6, 124.2, 115.9, 115.7, 109.7, 62.9, 62.3, 53.4, 53.3, 53.0, 52.6, 50.0, 48.1, 47.6, 47.3, 43.5, 36.0, 29.9, 21.6, 11.6, 11.4; MS m/z 315 (M+), 287, 256, 228.
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[S:11][C:10](Cl)=[C:9]([Cl:13])[C:8]=1[Cl:14].CN(C)[CH:17]=[O:18].Cl>O1CCCC1.CCCCCC.C(OCC)(=O)C>[Cl:13][C:9]1[C:8]([Cl:14])=[C:7]([Cl:6])[S:11][C:10]=1[CH:17]=[O:18]
Reactant: Clc1sc(Cl)c(Cl)c1Cl
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=Cc1sc(Cl)c(Cl)c1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
Butyllithium (2.5 molar in tetrahydrofuran, 3.96 mL, 9.9 mmol) is added to a solution of tetrachlorothiophene (2.00 g, 9.01 mmol) in tetrahydrofuran at 0° C. The reaction mixture is stirred at 0° C. for 30 minutes, warmed to room temperature over 45 minutes, treated with N,N-dimethylformamide (0.79 g, 10.8 mmol), stirred for three hours, poured into one molar hydrochloric acid at 4° C. and extracted with ether. The combined organic extracts are washed sequentially with water and brine, dried over MgSO4 and concentrated in vacuo to obtain a brown solid. Flash chromatography of the solid using silica gel and a 5% ethyl acetate in hexane solution gives a beige solid which is recrystallized from ethyl acetate and hexane to obtain the title product as beige needles (1.63 g, 84%, mp 81°-82° C.).
Reaction SMILES: Cl.Br[C:3]1[C:4]2[N:5]([CH:11]=[CH:12][N:13]=2)[N:6]=[C:7]([Cl:10])[C:8]=1[CH3:9].[CH3:14][CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([NH2:23])=[CH:21][CH:22]=1.COC1C=CC(N)=CC=1.C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1.O>[Cl:10][C:7]1[C:8]([CH3:9])=[C:3]([NH:23][C:20]2[CH:19]=[CH:18][C:17]([O:16][CH2:15][CH3:14])=[CH:22][CH:21]=2)[C:4]2[N:5]([CH:11]=[CH:12][N:13]=2)[N:6]=1
Reactant: CCOc1ccc(N)cc1
Reactant: Cc1c(Cl)nn2ccnc2c1Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COc1ccc(N)cc1
Solvent: O
Solvent: CN1CCCC1=O
Product: CCOc1ccc(Nc2c(C)c(Cl)nn3ccnc23)cc1
Temperature: 225 °C
Yield: 90 %

Procedure:
(1d variation 1) A mixture of 8-bromo-6-chloro-7-methylimidazo[1,2-b]pyridazine HCl salt (30 mg, 0.1 mmol) from 1c, p-methoxyaniline (20 μL, 0.15 mmol) and K2CO3 (75 mg) were suspended in NMP (600 μL) and heated in a microwave at 225° C. for 15 min. The mixture was cooled to room temperature and then treated with H2O (5 mL). The solid that precipitated out was filtered, washed with water and dried to provide 6-chloro-N-(4-ethoxyphenyl)-7-methylimidazo[1,2-b]pyridazin-8-amine (21 mg, >90% pure by HPLC).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[CH:19][C:20]([O:32][CH3:33])=[C:21]([NH:23][C:24](=[O:31])[CH2:25][C:26]4[S:27][CH:28]=[CH:29][CH:30]=4)[CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[CH3:34][N:35]([CH3:46])[CH:36]1[CH2:44][C:43]2[C:38](=[CH:39][CH:40]=[C:41]([NH2:45])[CH:42]=2)[CH2:37]1.Cl>CC(O)C>[CH3:34][N:35]([CH3:46])[CH:36]1[CH2:44][C:43]2[C:38](=[CH:39][CH:40]=[C:41]([NH:45][C:2]3[N:7]=[C:6]([C:8]4[C:9]([C:17]5[CH:18]=[CH:19][C:20]([O:32][CH3:33])=[C:21]([NH:23][C:24](=[O:31])[CH2:25][C:26]6[S:27][CH:28]=[CH:29][CH:30]=6)[CH:22]=5)=[N:10][N:11]5[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=45)[CH:5]=[CH:4][N:3]=3)[CH:42]=2)[CH2:37]1
Reactant: COc1ccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)cc1NC(=O)Cc1cccs1
Reactant: CN(C)C1Cc2ccc(N)cc2C1
Agent: Cl
Solvent: CC(C)O
Product: COc1ccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)CC(N(C)C)C4)n2)cc1NC(=O)Cc1cccs1
Temperature: 180 °C
Yield: 23.1 %

Procedure:
To a solution of N-{5-[3-(2-chloropyrimidin-4-yl)pyrazolo[1,5-a]pyridin-2-yl]-2-methoxyphenyl}-2-(2-thienyl)acetamide (90 mg, 0.19 mmol) in anhydrous i-PrOH (3 mL) was added N2,N2-dimethylindane-2,5-diamine (37 mg, 0.21 mmol) followed by catalytic 12M HCl. After heating for 10 min. in the microwave at 180° C., the reaction was quenched with saturated NaHCO3 (25 mL) and the solvent was removed by rotary evaporation. The aqueous layer was extracted with DCM (25 mL), the organic layer-concentrated, and purified by column chromatography (1-10% MeOH in DCM) to provide the product (27 mg, 24%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 2.18 (s, 6H), 2.65-2.71 (m, 2H), 2.88-2.97 (m, 2H), 3.89 (s, 3H), 3.98 (s, 2H), 6.51 (d, 1H, J=5.3 Hz), 6.94-6.96 (m, 2H), 7.02-7.14 (m, 3H), 7.26-7.28 (m, 1H), 7.35-7.43 (m, 3H), 7.63 (s, 1H), 8.20 (d, 1H, J=5.3 Hz), 8.31 (s, 1H), 8.43 (d, 1H, J=8.9 Hz), 8.79 (d, 1H, J=7.0 Hz) 9.38 (s, 1H), 9.45 (s, 1H) ppm. ES-LC/MS m/z=616 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:10]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:9]2[C:5]([CH:6]=[C:7]([C:21](=[S:23])[NH2:22])[NH:8]2)=[CH:4][CH:3]=1.Br[CH:25]([CH:28]=O)[CH:26]=[O:27].CN(C)C(=O)C>O>[Cl:1][C:2]1[C:10]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:9]2[C:5]([CH:6]=[C:7]([C:21]3[S:23][C:25]([CH2:26][OH:27])=[CH:28][N:22]=3)[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=CC(Br)C=O
Reactant: CN(c1c(Cl)ccc2cc(C(N)=S)[nH]c12)S(=O)(=O)c1cccs1
Solvent: O
Solvent: CC(=O)N(C)C
Product: CN(c1c(Cl)ccc2cc(-c3ncc(CO)s3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 90 °C
Reaction time: 3 h
Yield: 55.6 %

Procedure:
A mixture of 6-chloro-7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carbothioamide (0.60 g), bromomalonaldehyde (0.38 g) and N,N-dimethylacetamide (10 ml) was stirred at 90° C. for 3 hr. Water was added to the reaction mixture, and the resulting crystals were collected by filtration, washed with water, and dried. To a mixture of the obtained crystals, tetrahydrofuran (10 ml) and methanol (5 ml) was added sodium borohydride (70 mg) at 0° C., and the mixture was stirred at the same temperature for 30 min. 10% Aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to give the title compound (0.38 g, yield 54%) as pale-yellow crystals from a fraction eluted with tetrahydrofuran-hexane (2:1, volume ratio). melting point 214-215° C.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:26]=[CH:25][C:11]([NH:12][CH:13]=[C:14]([C:20]([O:22]CC)=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:10][CH:9]=1)(=[O:3])[CH3:2]>C1(OC2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1>[C:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:11](=[CH:25][CH:26]=1)[N:12]=[CH:13][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:20]2[OH:22])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(=CNc1ccc(OCCOC(C)=O)cc1)C(=O)OCC
Solvent: Cc1ccccc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2ccc(OCCOC(C)=O)cc2c1O
Temperature: 250 °C
Yield: 8.7 %

Procedure:
Sodium hydroxide (6.22 g) is added to a solution of p-nitrophenol (21.45 g) in DMF (300 mL) and stirred until the reagents are fully dissolved. After a dropwise addition of 2-chloroethanol (10.66 ml), the reaction mixture is heated to 100° C. for 72 hours. After filtering and evaporating the solvent under reduced pressure, the resulting oil is recrystallized in a methanol/water mixture and filtered to afford 21.62 g (92%) of 2-(4-nitrophenoxy)-1-ethanol. A mixture of 2-(4-nitrophenoxy)-1-ethanol (6.17 g) and palladium on carbon (0.08 g) in EtOH (120 mL) is hydrogenated in a 500 mL Parr jar at 33 psi for 18 hrs. Vacuum filtration through celite and evaporation under reduced pressure affords 5.00 g (96%) of 2-(4-aminophenoxy)-1-ethanol. This material is combined with diethyl ethoxymethylenemalonate (7 mL) and heated to 130° C. for 1 hr in a round bottom flask under a gentle stream of nitrogen. The mixture is cooled, diluted with 1:1 cyclohexane/toluene (20 mL), and filtered to afford 9.1 g (86%) of diethyl 2-{[4-(2-hydroxyethoxy)anilinorlmethylene}-malonate. A solution the resulting malonate (8.59 g) in acetic acid (15 mL) and acetic anhydride (4 mL) is heated to 60° C. for 36 hrs. The reaction mixture is diluted with water, extracted with ethyl acetate and washed with saturated sodium bicarbonate. Evaporation under reduced pressure leaves a brown oil which is recrystallized from 1:1 methanol/water and filtered to afford 7.09 g (73%) diethyl 2-({4-[2-(acetyloxy)ethoxy]anilino}methylene)malonate. Diethyl 2-({4-[2-(acetyloxy)ethoxy]anilino}methylene)malonate (6.55 g) is dissolved in diphenyl ether (75 mL) and refluxed at 250° C. for 1 hr. After the mixture is cooled and diluted with 250 mL toluene, the resulting precipitate is collected by filtration, washed with toluene and recrystallized from aqueous acetic acid. This procedure yielded 0.50 g (9%) of ethyl 6-[2-(acetyloxy)ethoxy]-4-hydroxy-3-quinolinecarboxylate. The resulting carboxylate ester (0.49 g) and 4-chlorobenzylamine (0.90 mL) are heated to 175° C. for 2 hrs. After the reaction mixture is cooled and diluted with xylenes, the dark solid is filtered. Recrystallization from acetic acid and water affords 0.150 g (26%) of the title compound as a beige solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[CH3:9][C:10]([CH3:17])([C:14](O)=O)[C:11](O)=O>O>[CH3:9][C:10]([C:14]1[S:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=1)([C:17]1[S:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=1)[CH3:11]
Reactant: Nc1ccccc1S
Reactant: CC(C)(C(=O)O)C(=O)O
Solvent: O
Product: CC(C)(c1nc2ccccc2s1)c1nc2ccccc2s1
Reaction time: 3 h

Procedure:
To a flask were added 50 g polyphosphoric acid. After heating to 70 C under nitrogen, a mixture of 3.13 g 2-aminothiophenol and 1.65 g dimethylmalonic acid was added. The reaction mixture was heated to 150 C for 2 hours, then 165 C for 3 hours. After cooling to 80 C, the mixture was poured into 100 ml water. The slurry was cooled to 5 C, filtered and the solid was washed with water. The solid was added to a mixture of 20 ml ethanol and 210 ml water at 50 C and basified with aqueous ammonium hydroxide. After cooling to 10 C, the solid was filtered and washed with water. The solid was dissolved in 50 ml hot ethanol, hot filtered and 5 ml water was added and the solution was cooled to 5 C. Following filtration, the white solid was washed with 75% ethanol and dried.
Reaction SMILES: [C:1]([CH2:4][N:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)[CH3:6])([OH:3])=O.Cl.[CH3:18][NH:19][CH3:20]>>[CH3:18][N:19]([CH3:20])[C:1]([CH2:4][N:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)[CH3:6])=[O:3]
Reactant: CN(CC(=O)O)Cc1ccc([N+](=O)[O-])cc1
Reactant: CNC
Agent: Cl
Product: CN(CC(=O)N(C)C)Cc1ccc([N+](=O)[O-])cc1

Procedure:
Prepared from 4-[(N-carboxymethyl-N-methyl-amino)-methyl]-nitrobenzene and dimethylamine hydrochloride
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[C:9]([C:12]1[O:13][CH:14]=[CH:15][CH:16]=1)(=[O:11])[CH3:10]>CN(C)C=O.C([O-])(=O)C.[Co+2].C([O-])(=O)C>[O:13]1[CH:14]=[CH:15][CH:16]=[C:12]1[C:9](=[O:11])[CH:10]=[CH:7][C:4]1[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=1
Reactant: O=Cc1ccncc1
Reactant: CC(=O)c1ccco1
Agent: [Co+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: O=C(C=Cc1ccncc1)c1ccco1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 0.3 %

Procedure:
Dissolve anhydrous cobalt(II) acetate (700 mg, 4 mmol ) in dimethylformamide (150 mL). Add 2,2'-dipyridyl (600 mg, 4 mmol) and stir for 30 minutes. Add 4-pyridinecarboxaldehyde (5 g, 50 mmol) and 2-acetylfuran (5.5 g, 50 mmol). Heat at 80° C. for 18 hours. Evaporate the solvent and purify the residue by silica gel chromatography (1:1 toluene/ethyl acetate) to yield 30 mg of the title compound; mp 122°-124° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:23]2[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][CH:24]=2)[C:8]2[C:18](=[O:19])[N:17]3[CH2:20][CH2:21][CH2:22][N:16]3[C:9]=2[NH:10][C:11]=1[C:12]([F:15])([F:14])[F:13])=[O:5])[CH3:2].[F:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH2:36][NH2:37]>>[F:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH2:36][NH:37][C:27]([C:26]1[CH:30]=[CH:31][C:23]([C:7]2[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:11]([C:12]([F:14])([F:15])[F:13])[N:10]=[C:9]3[N:16]4[CH2:22][CH2:21][CH2:20][N:17]4[C:18](=[O:19])[C:8]=23)=[CH:24][CH:25]=1)=[O:29]
Reactant: CCOC(=O)C1=C(C(F)(F)F)Nc2c(c(=O)n3n2CCC3)C1c1ccc(C(=O)O)cc1
Reactant: NCc1cccc(F)c1
Product: CCOC(=O)c1c(C(F)(F)F)nc2c(c1-c1ccc(C(=O)NCc3cccc(F)c3)cc1)c(=O)n1n2CCC1

Procedure:
The product from Step A was treated as described in Step E of Example 8 followed by coupling to 3-fluorobenzylamine as described in Step F of Example 8 to provide the title compound as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ 9.19 (t, 1H, J=6), 7.93 (d, 2H, J=8), 7.45 (d, 2H, J=8), 7.35 (dd, 1H, J=14, 8), 7.14 (m, 2H), 7.05 (t, 1H, J=9), 4.49 (d, 2H, J=6), 3.98 (m, 4H), 3.84 (t, 2H, J=7), 2.60 (quint., 2H, J=7), 0.91 (t, 3H, J=7) ppm; ; ESI-MS m/z 543 (M+H)+; Anal. calcd. for C27H22F4N4O4.⅓H2O: C, 59.12; H, 4.17; N, 10.21; found: C, 59.12; H, 4.14; N, 10.26.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][Si](OC)(OC)OC.[CH2:12]([C:15]1C=CC=C[C:16]=1[OH:21])[CH:13]=[CH2:14]>C1(C)C=CC=CC=1>[O:21]1[C:16]2[CH:15]=[CH:12][CH:13]=[CH:14][C:4]=2[CH:3]=[CH:2][NH:1]1
Reactant: CO[Si](CCCN)(OC)OC
Reactant: C=CCc1ccccc1O
Solvent: Cc1ccccc1
Product: C1=Cc2ccccc2ON1
Yield: 94 %

Procedure:
This compound was prepared according to the method described in the previous examples using 3-aminopropyltrimethoxysilane (17.9 g, 100 mmole), paraformaldehade (6.3 g, 210 mmole), 2-allyl-phenol (13.4 g, 0.1 mmole), and toluene (200 ml). The final product was obtained as a slightly yellow, mobile liquid. The yield was 94% of theory.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]3[C:20]([C:21]([OH:23])=[O:22])=[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([Br:30])[CH:17]=4)[C:12]3=[O:31])=[CH:9][C:4]=2[O:3][CH2:2]1.[CH2:32](O)[CH2:33][CH3:34]>>[CH2:32]([O:22][C:21]([C:20]1[N:11]([CH2:10][C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH2:2][O:3][C:4]=3[CH:9]=2)[C:12](=[O:31])[C:13]2[C:18]([C:19]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:17][C:16]([Br:30])=[CH:15][CH:14]=2)=[O:23])[CH2:33][CH3:34]
Reactant: O=C(O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc2c(c1)OCO2
Reactant: CCCO
Product: CCCOC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc2c(c1)OCO2

Procedure:
The present compound was synthesized by a method similar to that in Example 200 and using 2-(benzo[1,3]dioxol-5-ylmethyl)-6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (300 mg) and propanol. Colorless crystals (190 mg).