Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([NH2:10])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[C:11](Cl)([CH3:13])=[O:12]>C(Cl)Cl>[CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11](=[O:12])[CH3:13])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: Nc1ccc2c(c1)CCC2
Reactant: CC(=O)Cl
Solvent: ClCCl
Product: CC(=O)Nc1ccc2c(c1)CCC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of indan-5-amine (43 g, 0.31 mol) and TEA (51.3 mL, 0.370 mol) in 400 mL of anhydrous DCM was added a solution of AcCl (23.6 mL, 0.340 mol) in 100 mL of anhydrous DCM dropwise at 0° C. then and stirred for 0.5 h at r.t. After the reaction was completed, the reaction mixture was added 500 mL of DCM, washed with water, 10% HCl solution, 10% NaHCO3 and brine. The organic phase was dried over anhydrous Na2SO4 and concentrated to give N-(2,3-dihydro-1H-inden-5-yl)acetamide. 1H-NMR (300 MHz, CDCl3) δ ppm 7.43 (s, 1H), 7.13˜7.14 (m, 2H), 2.86 (q, J=7.9 Hz, 4H), 2.15 (s, 3H), 2.0˜2.10 (m, 2H);
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:18])=[CH:5][C:6]=1[CH:7]1[CH2:12][C:11](=O)[C:10](=[C:14](O)[CH3:15])[C:9](=[O:17])[CH2:8]1.O.[NH2:20][NH2:21]>C(O)C>[Cl:1][C:2]1[S:3][C:4]([Cl:18])=[CH:5][C:6]=1[CH:7]1[CH2:12][C:11]2[NH:21][N:20]=[C:14]([CH3:15])[C:10]=2[C:9](=[O:17])[CH2:8]1
Reactant: NN
Reactant: CC(O)=C1C(=O)CC(c2cc(Cl)sc2Cl)CC1=O
Solvent: O
Solvent: CCO
Product: Cc1n[nH]c2c1C(=O)CC(c1cc(Cl)sc1Cl)C2
Yield: 87.8 %

Procedure:
A solution of 5-(2,5-dichlorothiophen-3-yl)-2-(1-hydroxyethylidene)cyclohexane-1,3-dione (2.48 g) and hydrazine hydrate (0.508 g) in ethanol (10 ml) was refluxed for 2 hours. Under reduced pressure, the solvent was evaporated, and to the residue was added water. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and concentrated under reduced pressure. The residue was washed with diisopropylether to give 6-(2,5-dichlorothiophen-3-yl)-3-methyl-4,5,6,7-tetrahydroindazol-4-one (2.15 g) as pale yellow crystals.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[O:5]1[CH2:9][CH2:8][C:7]2[CH:10]=[CH:11][CH:12]=[C:13]([C:14]([OH:16])=[O:15])[C:6]1=2>FC(F)(F)C(O)=O>[N+:1]([C:11]1[CH:12]=[C:13]([C:14]([OH:16])=[O:15])[C:6]2[O:5][CH2:9][CH2:8][C:7]=2[CH:10]=1)([O-:4])=[O:2]
Reactant: O=C(O)c1cccc2c1OCC2
Reactant: O=[N+]([O-])O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1cc([N+](=O)[O-])cc2c1OCC2

Procedure:
Nitric acid (9 ml) was added to a cooled (ice bath) solution of 2,3-dihydrobenzo[b]furan-7-carboxylic acid (5.1 g, 31 mmol) in trifluoroacetic acid (45 ml). After 4 hours the mixture was quenched into ice-water (150 ml) and the mixture filtered to give 5-nitro-2,3-dihydrobenzo[b]furan-7-carboxylic acid, which was washed with water and used crude (wet) in the next stage.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[O:13]CCCO2)[CH:5]=[CH:6][CH:7]=1.[CH:14]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)([CH3:16])[CH3:15].C(O[Na])(C)(C)C>C1(C)C=CC=CC=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH:14]([N:17]1[CH2:22][CH2:21][N:20]([C:2]2[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=2)[CH:8]=[O:13])[CH2:19][CH2:18]1)([CH3:16])[CH3:15]
Reactant: Brc1cccc(C2OCCCO2)c1
Reactant: CC(C)N1CCNCC1
Agent: CC(C)(C)O[Na]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CC(C)N1CCN(c2cccc(C=O)c2)CC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 87.4 %

Procedure:
A mixture of 2-(3-bromophenyl)-1,3-dioxane (2, 1.58 g, 6.5 mmol), 1-isopropylpiperazine (1.0 g, 7.8 mmol), rac-BINAP (60 mg, 0.096 mmol), and tert-BuONa (1.06 g, 11.1 mmol) in toluene (15 mL) was degassed under vacuum and flushed with nitrogen. Pd2(dba)3 (30 mg, 0.033. mmol) was added. The reaction mixture was degassed again and flushed with nitrogen and was heated at 100° C. under nitrogen for 16 h. The reaction mixture was poured into cold 1N HCl (30 mL) and stirred for 2 h. It was adjusted to pH 8 with 6N NaOH and extracted with EtOAc (3×50 mL). The combined organic layers were dried (MgSO4), filtered, concentrated, and purified by silica gel chromatography eluting with 0-100% EtOAc (containing 5% v/v Et3N) in hexanes to afford the title compound as a viscous yellow oil (1.32 g, 87%): 1H NMR (500 MHz, CDCl3) δ 9.96 (s, 1H), 7.44-7.37 (m, 2H), 7.34-7.30 (m, 1H), 7.21-7.16 (m, 1H), 3.28 (t, J=5.0 Hz, 4H), 2.73 (sept, J=6.5 Hz, 1H), 2.69 (t, J=5.0 Hz, 4H), 1.10 (d, J=6.5 Hz, 6H); ESI MS m/z 233 [M+H]+.
Reaction SMILES: [ClH:1].CCOCC.C(OC(=O)[NH:13][CH2:14][CH2:15][CH2:16][C:17](=[O:38])[NH:18][CH2:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[CH2:22][N:23]([CH:30]1[CH2:35][CH2:34][C:33](=[O:36])[NH:32][C:31]1=[O:37])[C:24]2=[O:29])(C)(C)C>CN(C=O)C.C(Cl)Cl>[ClH:1].[NH2:13][CH2:14][CH2:15][CH2:16][C:17]([NH:18][CH2:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[CH2:22][N:23]([CH:30]1[CH2:35][CH2:34][C:33](=[O:36])[NH:32][C:31]1=[O:37])[C:24]2=[O:29])=[O:38]
Reactant: CC(C)(C)OC(=O)NCCCC(=O)NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: CN(C)C=O
Product: NCCCC(=O)NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Temperature: 25 °C
Reaction time: 168 h
Yield: 87 %

Procedure:
2N HCl/ether (4 mL) was added to a stirred solution of (3-{[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-carbamoyl}-propyl)-carbamic acid t-butyl ester (1 g, 2.2 mmol) in DMF (20 mL). The mixture was stirred at room temperature for 7 days. The mixture was diluted with CH2Cl2 (20 mL) and filtered to give 4-amino-N-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-butyramide hydrochloride (0.8 g, 87%) as a white solid: mp 268-270° C.; 1H NMR (DMSO-d6) δ 1.74-1.86 (m, 2H, CH2), 2.00-2.04 (m, 1H), 2.24-2.79 (m, 6H), 2.86-2.98 (m, 1H), 4.32-4.39 (m, 3H), 4.49 (d, J=17.5 Hz, 1H), 5.10-5.18 (dd, J=5.0 and 12.5 Hz, 1H, CH), 7.49-7.64 (m, 3H, Ar), 8.01 (b, 3H, NH3), 8.61 (t, J=5.0 Hz, 1H, NH), 11.01 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.59, 23.10, 31.18, 31.87, 38.40, 38.98, 46.20, 51.57, 121.64, 128.28, 130.64, 131.63, 134.61, 140.09, 168.03, 170.99, 171.37, 172.85; Anal. calcd. for C18H23N4O4Cl: C, 54.75; H, 5.87; N, 14.19; Cl, 8.98. Found: C, 54.50; H, 5.81; N, 13.90; Cl, 8.92.
Reaction SMILES: [CH3:1][N:2]1[CH2:14][CH2:13][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[H-].[Na+].[O:17]1[CH2:19][CH:18]1[C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1.[CH3:26]N(C=O)C>>[CH3:1][N:2]1[CH2:14][CH2:13][C:5]2[N:6]([CH2:19][C:18]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)([OH:17])[CH3:26])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: c1cc(C2CO2)ccn1
Reactant: CN(C)C=O
Reactant: CN1CCc2[nH]c3ccccc3c2C1
Agent: [H-]
Agent: [Na+]
Product: CN1CCc2c(c3ccccc3n2CC(C)(O)c2ccncc2)C1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
2-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (740 mg, 3.9 mmol) was dissolved in DMF and the mixture stirred for 5 min. NaH (60% in oil, 468 mg, 11.7 mmol) was added and the mixture stirred for 10 min, followed by 4-(oxiran-2-yl)pyridine (1.0 g, 7.9 mmol) and the mixture stirred at RT for 3 h. The progress of reaction was monitored by TLC. The reaction mixture was poured into ice water and filtered. The filtrate was washed with water and concentrated. The residue was recrystallized from ether to get pure product. 1HNMR (CD3OD, HCl salt) d (ppm): 8.70 (d, 2H), 8.20 (d, 2H), 7.40 (m, 1H), 7.10 (m, 1H), 7.0 (m, 2H), 4.70 (d, 1H), 4.45 (m, 2H), 4.38 (m, 1H), 3.90 (m, 1H), 3.45 (m, 2H), 3.40 (m, 1H), 3.10 (s, 3H), 1.70 (d, 3H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH3:9].C(=O)([O-])[O-].[K+].[K+].[CH3:16][N:17]1[C:22](=[O:23])[C:21]2=[C:24]([C:38]3[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=3)[N:25]([CH2:27][C:28]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:31]=[CH:30][CH:29]=3)[N:26]=[C:20]2[NH:19][C:18]1=[O:44]>>[CH3:16][N:17]1[C:22](=[O:23])[C:21]2=[C:24]([C:38]3[CH:39]=[CH:40][N:41]=[CH:42][CH:43]=3)[N:25]([CH2:27][C:28]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:31]=[CH:30][CH:29]=3)[N:26]=[C:20]2[N:19]([CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[CH3:9])[C:18]1=[O:44]
Reactant: Cc1ccccc1CCl
Reactant: Cn1c(=O)[nH]c2nn(Cc3cccc4ccccc34)c(-c3ccncc3)c2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccccc1Cn1c(=O)n(C)c(=O)c2c(-c3ccncc3)n(Cc3cccc4ccccc34)nc21
Temperature: 80 °C

Procedure:
1-(chloromethyl)-2-methylbenzene (0.045 ml) and potassium carbonate (0.6 g) were added to a solution of 5-methyl-2-(1-naphthylmethyl)-3-pyridin-4-yl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (2 ml). The mixture was heated at 80° C. for 18 hours then cooled to room temperature. Solids removed by filtration and the crude product was purified on preparative HPLC to give the title compound (0.057 g). Mass: 487.87 (M+H).
Reaction SMILES: Br[C:2]1[C:23]([O:24][CH3:25])=[CH:22][C:5]2[C:6]([CH3:21])([CH3:20])[C:7]3[NH:8][C:9]4[C:14]([C:15]=3[C:16](=[O:17])[C:4]=2[CH:3]=1)=[CH:13][CH:12]=[C:11]([C:18]#[N:19])[CH:10]=4.[CH:26]([B-](F)(F)F)=[CH2:27].[K+].O>C(O)CC>[CH3:25][O:24][C:23]1[C:2]([CH:26]=[CH2:27])=[CH:3][C:4]2[C:16](=[O:17])[C:15]3[C:14]4[C:9](=[CH:10][C:11]([C:18]#[N:19])=[CH:12][CH:13]=4)[NH:8][C:7]=3[C:6]([CH3:20])([CH3:21])[C:5]=2[CH:22]=1
Reactant: COc1cc2c(cc1Br)C(=O)c1c([nH]c3cc(C#N)ccc13)C2(C)C
Reactant: C=C[B-](F)(F)F
Agent: [K+]
Solvent: CCCO
Solvent: O
Product: C=Cc1cc2c(cc1OC)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O
Temperature: 60 °C
Reaction time: 120 h
Yield: 56.2 %

Procedure:
9-Bromo-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound E3-1-1, 50 mg, 0.13 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloride dichloromethane complex (1:1) (10.3 mg, 0.1 eq.), TEA (53 μl, 3 eq.) and potassium vinyltrifluoroborate (51 mg, 3 eq.) were dissolved in n-propanol and the mixture was stirred at 60° C. for 5 days. The reaction solution was added to water and then extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (brown powder, 25 mg, 19%).
Reaction SMILES: [C:1]1(=[O:19])[C:10]2[C:5]3[C:6](=[CH:15][CH:16]=[CH:17][C:4]=3[C:3](=[O:18])[NH:2]1)[CH:7]=[C:8]1[CH:14]=[CH:13][CH:12]=[CH:11][C:9]1=2.[OH-:20].[K+].Br[CH2:23][CH2:24][NH:25][CH2:26][CH2:27][CH2:28][NH:29][CH2:30][CH2:31]Br>C(O)C>[O:19]=[C:1]1[C:10]2[C:5]3[C:6](=[CH:15][CH:16]=[CH:17][C:4]=3[C:3](=[O:18])[N:2]1[CH2:23][CH2:24][NH:25][CH2:26][CH2:27][CH2:28][NH:29][CH2:30][CH2:31][N:2]1[C:3](=[O:20])[C:4]3[CH:17]=[CH:16][CH:15]=[C:6]4[C:5]=3[C:10](=[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]3=[CH:7]4)[C:1]1=[O:19])[CH:7]=[C:8]1[CH:14]=[CH:13][CH:12]=[CH:11][C:9]1=2
Reactant: BrCCNCCCNCCBr
Reactant: [OH-]
Reactant: O=C1NC(=O)c2c3ccccc3cc3cccc1c23
Agent: [K+]
Solvent: CCO
Product: O=C1c2cccc3cc4ccccc4c(c23)C(=O)N1CCNCCCNCCN1C(=O)c2cccc3cc4ccccc4c(c23)C1=O
Yield: 20 %

Procedure:
A mixture of 1.23 g (5 mmol) of 1,2-dihydro-3H-dibenz[de,h]isoquinoline-1,3-dione in 100 ml of ethanol is treated with 280 mg (5 mmol) of potassium hydroxide in 50 ml of ethanol. After refluxing for 3 hours, 0.65 g (2.5 mmol) of N,N'-bis(2-bromoethyl)-1,3-propanediamine in 50 ml of ethanol are added and the whole is refluxed for 24 hours. The reaction mixture is concentrated in vacuo. The residue is treated with water (100 ml) and extracted with dichloromethane. The organic layers are combined, dried with magnesium sulfate, filtered, and concentrated in vacuo. The residue is chromatographed, eluting with dichloromethane, methanol, acetic acid (80:15:5). The appropriate fractions are combined, concentrated in vacuo and crystallized from toluene to give 0.31 g (20%) of N,N'-bis[2-(1,2-dihydro-1,3-dioxo-3H-dibenz[de,h]isoquinolin-2-yl)ethyl]-1,3-propanediamine. M.p. 191° C.
Reaction SMILES: C(N(C(C)C)C(C)C)C.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([C@@H:17]([C@@H:21]2[CH2:25][CH2:24][C:23]([CH3:27])([CH3:26])[N:22]2[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:18](O)=[O:19])=[CH:13][C:12]=1[F:35].Cl.Cl.[CH3:38][C@H:39]1[C:47]2[C:46]([N:48]3[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]3)=[N:45][CH:44]=[N:43][C:42]=2[C@@H:41]([OH:54])[CH2:40]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([C@@H:17]([C@H:21]2[N:22]([C:28]([O:30][C:31]([CH3:34])([CH3:32])[CH3:33])=[O:29])[C:23]([CH3:26])([CH3:27])[CH2:24][CH2:25]2)[C:18]([N:51]2[CH2:52][CH2:53][N:48]([C:46]3[C:47]4[C@H:39]([CH3:38])[CH2:40][C@@H:41]([OH:54])[C:42]=4[N:43]=[CH:44][N:45]=3)[CH2:49][CH2:50]2)=[O:19])=[CH:13][C:12]=1[F:35]
Reactant: CC(C)(C)OC(=O)N1[C@H]([C@@H](C(=O)O)c2ccc(Br)c(F)c2)CCC1(C)C
Reactant: C[C@@H]1C[C@H](O)c2ncnc(N3CCNCC3)c21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)[C@@H](c4ccc(Br)c(F)c4)[C@@H]4CCC(C)(C)N4C(=O)OC(C)(C)C)CC3)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 23 %

Procedure:
N-Ethyl-N-isopropylpropan-2-amine (0.045 mL, 0.26 mmol) was added to a solution of (S)-2-(4-bromo-3-fluorophenyl)-2-((S)-1-(tert-butoxycarbonyl)-5,5-dimethylpyrrolidin-2-yl)acetic acid (0.035 g, 0.081 mmol; prepared analogously to that described in Example B), (5R,7R)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochloride (0.025 g, 0.081 mmol; see Example 3, Step 12), and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.031 g, 0.081 mmol) in DCM (5 mL). The reaction was stirred overnight at room temperature. The reaction was then quenched with H2O, washed with H2O (3×30 mL), dried with MgSO4, filtered and concentrated. The resulting residue was purified by flash chromatography to give (S)-tert-butyl 5-((S)-1-(4-bromo-3-fluorophenyl)-2-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-oxoethyl)-2,2-dimethylpyrrolidine-1-carboxylate (23% yield). LCMS (APCI+) 648.2 m/z [M+H]+; Retention time=4.28 minutes.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]([C:13]2[CH:14]=[C:15]([N:19]3[CH2:28][C:27]4[CH:26]=[N:25][CH:24]=[C:23]([C:29](O)=[O:30])[C:22]=4[CH2:21][CH2:20]3)[CH:16]=[CH:17][CH:18]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.CCCP(=O)=O.[O:45]1[CH2:50][CH2:49][N:48]([CH2:51][CH2:52][CH2:53][NH2:54])[CH2:47][CH2:46]1>CN(C1C=CN=CC=1)C.ClCCCl>[CH:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]([C:13]2[CH:14]=[C:15]([N:19]3[CH2:28][C:27]4[CH:26]=[N:25][CH:24]=[C:23]([C:29]([NH:54][CH2:53][CH2:52][CH2:51][N:48]5[CH2:49][CH2:50][O:45][CH2:46][CH2:47]5)=[O:30])[C:22]=4[CH2:21][CH2:20]3)[CH:16]=[CH:17][CH:18]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: NCCCN1CCOCC1
Reactant: CC(C)c1cccc(NC(=O)c2cccc(N3CCc4c(cncc4C(=O)O)C3)c2)c1
Agent: CCCP(=O)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC(C)c1cccc(NC(=O)c2cccc(N3CCc4c(cncc4C(=O)NCCCN4CCOCC4)C3)c2)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 52.3 %

Procedure:
To a mixture of 7-(3-{[(3-isopropylphenyl)amino]carbonyl}phenyl)-5,6,7,8-tetrahydro-2,7-naphthyridine-4-carboxylic acid (25 mg, 0.06 mmol), triethylamine (0.017 mL, 0.12 mmol), and catalytic DMAP in 1.1 mL 1,2-dichloroethane at rt was added propylphosphonic anhydride solution (50 wt % in EtOAc, 0.043 mL, 0.072 mmol). After 5 min at rt, 3-morpholinopropylamine (0.011 mL, 0.072 mmol) was added and the reaction stirred at rt for 1.5 hours. The reaction was partitioned between EtOAc and brine/aqueous NaHCO3 solution, the EtOAc layer washed with brine/aqueous NaHCO3 solution, dried with anhydrous Na2SO4 and rotary evaporated. This material was chromatographed eluting with CHCl3/MeOH to give the title compound as an off-white solid (17 mg, 54%). 1H NMR (CDCl3) δ: 8.50 (s, 1H), 8.48 (s, 1H), 7.83-7.92 (m, 2H), 7.54 (d, J=4.7 Hz, 2H), 7.46 (d, J=8.2 Hz, 1H), 7.34-7.41 (m, 1H), 7.20-7.33 (m, 2H), 7.13 (d, J=7.9 Hz, 1H), 7.03 (d, J=7.3 Hz, 1H), 4.50 (s, 2H), 3.52-3.63 (m, 8H), 3.23 (t, J=5.7 Hz, 2H), 2.87-2.98 (m, 1H), 2.56 (t, J=6.0 Hz, 2H), 2.47 (br. s., 4H), 1.75-1.85 (m, 2H), 1.27 (d, J=7.0 Hz, 6H)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[C:6]([O:13][CH3:14])=[CH:5][C:4]=1[CH3:15].[CH3:16][O:17]C(Cl)Cl.O>C(Cl)Cl.CCOC(C)=O.Cl[Ti](Cl)(Cl)Cl>[CH3:15][C:4]1[C:5]([CH:16]=[O:17])=[C:6]([O:13][CH3:14])[C:7]([O:11][CH3:12])=[C:8]([O:9][CH3:10])[C:3]=1[O:2][CH3:1]
Reactant: COc1cc(C)c(OC)c(OC)c1OC
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: COc1c(C)c(C=O)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 89.2 %

Procedure:
According to the procedure by Ohkawa et al.,15 6 (0.690 g, 3.25 mmol) was dissolved in CH2Cl2 (2.0 mL) in a flame-dried 25 mL round bottom flask and cooled to 0° C. α,α-dichloromethyl methyl ether (0.85 ml, 9.6 mmol) was then added at 0° C., followed by TiCl4 (1 M in CH2Cl2, 9.0 ml, 9.0 mmol) at 0° C. The reaction was warmed slowly to room temperature and stirred for 6 hours under argon. The reaction was then poured into chilled water and stirred for 10 minutes. The reaction was diluted with EtOAc, washed with brine, dried over MgSO4, filtered, and condensed. The crude oil was then purified by flash chromatography (1:49 EtOAc:hexanes if made via p-cresol; 3:17 EtOAc:hexanes if made via Wolffe-Kishner reduction) to provide 7 (0.696 g, 2.90 mmol, 89%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([F:22])[C:19]([N:23]2[C:28](=[O:29])[CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[N:25]([CH3:34])[C:24]2=[O:35])=[CH:18][C:3]=1[O:4][C:5]1[CH:17]=[CH:16][CH:15]=[CH:14][C:6]=1[O:7][CH:8]([CH3:13])[C:9]([O:11]C)=[O:10].C(OCC)(=O)C.[Cl-].[Na+]>O1CCOCC1.Cl.O>[Cl:1][C:2]1[CH:21]=[C:20]([F:22])[C:19]([N:23]2[C:28](=[O:29])[CH:27]=[C:26]([C:30]([F:31])([F:32])[F:33])[N:25]([CH3:34])[C:24]2=[O:35])=[CH:18][C:3]=1[O:4][C:5]1[CH:17]=[CH:16][CH:15]=[CH:14][C:6]=1[O:7][CH:8]([CH3:13])[C:9]([OH:11])=[O:10]
Reactant: COC(=O)C(C)Oc1ccccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(Oc1ccccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl)C(=O)O
Temperature: 0 °C
Yield: 51.5 %

Procedure:
First, 0.365 g of methyl 2-[2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenoxy]propionate was dissolved in 4 ml of 1,4-dioxane, to which a mixed solution of 1 ml of concentrated hydrochloric acid and 1 ml of water was added under stirring, and the mixture was heated and stirred under reflux for 5 hours and 45 minutes. The reaction mixture was then left for cooling, into which ice water was poured, and after addition of ethyl acetate and saturated aqueous sodium chloride solution, the mixture was subjected to phase separation. To the organic layer was added aqueous sodium hydrogencarbonate solution, and the mixture was subjected to phase separation. To the aqueous layer was added aqueous hydrochloric acid solution for acidification, to which ethyl acetate was added, and the mixture was subjected to phase separation. The organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and then concentrated to give 0.183 g of 2-[2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenoxy]propionic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[CH2:18]([N:20]([CH2:34][CH3:35])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[NH:27][C:28]([CH:32]=O)=[C:29]([CH3:31])[CH:30]=1)=[O:25])[CH3:19]>C(O)C.N1CCCCC1>[CH2:34]([N:20]([CH2:18][CH3:19])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[NH:27][C:28]([CH:32]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=3)[NH:12][C:11]2=[O:17])=[C:29]([CH3:31])[CH:30]=1)=[O:25])[CH3:35]
Reactant: O=C1Cc2c(cccc2-c2cccc(Br)c2)N1
Reactant: CCN(CC)CCNC(=O)c1cc(C)c(C=O)[nH]1
Solvent: C1CCNCC1
Solvent: CCO
Product: CCN(CC)CCNC(=O)c1cc(C)c(C=C2C(=O)Nc3cccc(-c4cccc(Br)c4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 34.5 %

Procedure:
To a solution of 4-(3-bromo-phenyl)-1,3-dihydro-indol-2-one (72 mg, 0.25 mmol) and 5-formyl-4-methyl-1H-pyrrole-2-carboxylic acid (2-diethylamino-ethyl)-amide (65.3 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. The reaction solution was evaporated, and purified on a silica gel column eluting with MeOH—CH2Cl2 5:95 to provide pure product 5-[4-(3-bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-2-carboxylic acid (2-diethylamino-ethyl)-amide as a yellow solid (45 mg, 35%).
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])O.[CH3:13][NH2:14]>>[CH3:13][NH:14][CH:11]1[O:12][C@H:3]([CH2:2][OH:1])[C@@H:5]([OH:6])[C@H:7]([OH:8])[C@H:9]1[OH:10]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CN
Product: CNC1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 50 °C
Reaction time: 5 h

Procedure:
Anhydrous glucose (36.00 g; Aldrich Chemical Company) is weighed into a glass liner. The glass liner is placed into a dry-ice bath and methyl amine gas (68.00 g; Matheson) is condensed into the glass liner. The liner is then loaded into a rocking autoclave (500 ml capacity). The autoclave is heated to 50° C. and rocked for 5 hours at 50° C. under 600 psig nitrogen to form the adduct (N-methylglucosylamine). The reaction is then cooled in a dry-ice bath. The autoclave is then vented cold. Raney nickel (7.2 g of a 50% suspension in water, W/2 type, Aldrich Chemical Company) is added. The reaction is heated to 50° C. under 500-600 psig hydrogen and is rocked for 16 hours. The reaction is cooled in dry-ice bath and vented and purged with nitrogen. The reaction solution is pressure filtered through a Zeofluor filter (PTFE, 47 mm, 0.5 micron filter) with a 4 inch bed of Celite 545 (Fisher Scientific Company). The filtrate is concentrated under a stream of nitrogen to give 8.9 g of white solid. The Celite plug is washed with about 300 mls of water and the water is stripped on a rotary evaporator to give 18.77 g of white solid. The two solids are combined as they are analyzed to be of similar composition (90+ purity by GC analysis). The product is N-methyl glucamine.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][C:5]([F:8])([F:7])[CH2:4][C@@H:3]1[NH:9][S:10]([C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:12])=[O:11].[N:17]1[N:18]([C:22]2[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=2[C:24](O)=[O:25])[N:19]=[CH:20][CH:21]=1.C(Cl)CCl.N1C2C(=NC=CC=2)N(O)N=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:8][C:5]1([F:7])[CH2:6][C@H:2]([NH:1][C:24](=[O:25])[C:23]2[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=2[N:18]2[N:19]=[CH:20][CH:21]=[N:17]2)[C@@H:3]([NH:9][S:10]([C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:12])=[O:11])[CH2:4]1
Reactant: CC(C)(C)S(=O)(=O)N[C@H]1CC(F)(F)C[C@@H]1N
Reactant: O=C(O)c1ccccc1-n1nccn1
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)S(=O)(=O)N[C@H]1CC(F)(F)C[C@@H]1NC(=O)c1ccccc1-n1nccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-[(1S,2S)-2-amino-4,4-difluorocyclopentyl]-2-methylpropane-2-sulfonamide (1.03 g, 4.02 mmol) in dry DCM (13.4 ml) was added 2-(2H-1,2,3-triazol-2-yl)benzoic acid (CAS number 1001401-62-2; 0.91 g, 4.82 mmol), EDC (2.31 g, 12.06 mmol), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (1.64 g, 12.06 mmol) and DIPEA (2.11 ml, 12.06 mmol). The reaction was stirred at room temperature overnight then partitioned between ethyl acetate and water. The organics were washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by column chromatography (silica, 30-80% ethyl acetate/petrol) to afford the title compound.