Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[S:9][C:8]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[N:7][CH:6]=1.[Se](=O)=[O:20].C(Cl)Cl.CO>O1CCOCC1>[CH3:1][O:2][C:3](=[O:18])[C:4]([C:5]1[S:9][C:8]([NH:10][C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])=[N:7][CH:6]=1)=[O:20]
Reactant: O=[Se]=O
Reactant: COC(=O)Cc1cnc(NC(=O)OC(C)(C)C)s1
Solvent: CO
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)C(=O)c1cnc(NC(=O)OC(C)(C)C)s1
Yield: 23.3 %

Procedure:
Methyl(2-tert-butoxycarbonylamino 1,3-thiazole-5-yl)acetate (4.08 g, 15 mmol) in dioxane (60 ml) was reacted with selenium dioxide (4 g, 36 mmol) at reflux for 45 minutes. The mixture was cooled, CH2Cl2/MeOH 8/2 (150 ml) was added, the insoluble material was filtered, the organic phase was washed with a saturated solution of sodium bicarbonate, and extracted with CH2Cl2, dried, purified by chromatography over alumina, eluant CH2Cl2/MeOH 9/1 to give title compound (1 g, 23%).
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CN[C@@H]1CCCC[C@H]1NC.Cl.[OH2:23]>CN[C@@H]1CCCC[C@H]1NC>[OH:23][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O
Reactant: Cc1ccc(C(=O)O)c(Cl)c1
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: Cl
Product: Cc1ccc(C(=O)O)c(O)c1
Temperature: 85 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
Under nitrogen, 1.86 g (10.0 mmol) of 2-chloro-4-methylbenzoic acid was combined with 10 g of H2O. 1.11 g (15 mmol) of Ca(OH)2was then added. The mixture was heated at 85° C. under stirring for 60 min, remaining under a nitrogen atmosphere. Separately, 43 mg of CuBr and 94 mg of rac-trans-N,N′-dimethylcyclohexane-1,2-diamine (Ligand F) were combined with 1 mL deionized water under nitrogen. The resulting mixture was stirred under an air atmosphere until the CuBr was dissolved to give a blue solution. This solution was added to the stirred reaction mixture via syringe at 80° C. under nitrogen and stirred for 24 h at 80° C. After cooling to 25° C., the reaction mixture was acidified with 15% HCl, producing a white precipitate. The white precipitate was filtered and washed with water. After drying, a total of 1.45 g (9.5 mmol, 95% yield) of 2-hydroxy-4-methylbenzoic acid was collected. The purity was determined by 1H NMR to be >99%.
Reaction SMILES: [Br:1][C:2]1[C:11]([C@H:12]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:13][OH:14])=[C:10]([CH3:20])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:21])=[N:7]2.CC(C)=[O:24]>O>[Br:1][C:2]1[C:11]([C@H:12]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])[C:13]([OH:24])=[O:14])=[C:10]([CH3:20])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:21])=[N:7]2
Reactant: CC(C)=O
Reactant: Cc1ccc2c(Br)c([C@@H](CO)OC(C)(C)C)c(C)cc2n1
Solvent: O
Product: Cc1ccc2c(Br)c([C@H](OC(C)(C)C)C(=O)O)c(C)cc2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of (S)-2-(5-bromo-2,7-dimethylquinolin-6-yl)-2-tert-butoxyethanol (38 g, 108 mmol) in acetone (500 mL) was added RuCl3.3H2O (2.83 g, 10.83 mmol) followed by NaIO4 (116 g, 540 mmol) in H2O (400 mL) at 0° C. The mixture was stirred at room temperature for 2 hours. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide the desired product. LCMS-ESI+: calc'd for C17H20BrNO3: 366.1 (M+H+); Found: 366.0 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[H][H]>O1CCCC1.C(O)(=O)C.[Pd]>[OH:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([S:19]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)(=[O:21])=[O:20])=[CH:17][CH:18]=2)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: [H][H]
Reactant: O=C(O)c1cc(C=Cc2ccc(S(=O)(=O)Nc3ccccn3)cc2)ccc1O
Agent: [Pd]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C(O)c1cc(CCc2ccc(S(=O)(=O)Nc3ccccn3)cc2)ccc1O

Procedure:
A solution of 2-hydroxy-5-[2-[4-[(2-pyridinylamino)sulfonyl]phenyl]ethenyl]benzoic acid (3 g, 7.5 mmol) in tetrahydrofuran (100 ml) and acetic acid (100 ml) was hydrogenated over palladium on charcoal (10%, 0.3g) and hydrogen at atmospheric pressure and room temperature for 27 h. The catalyst was filtered off and the solvent was evaporated. The residue was dissolved in a solution of sodium hydroxide (0.3 g) in acetone (30 ml) and water (30 ml). The solution was acidified with hydrochloric acid at ca 50° C. After cooling, the product crystallized yielding 1.6g (52%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[O:10][CH3:11])[NH2:6].C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:30][O:31][C:32]1[C:33](=[O:56])[C:34]([CH3:55])=[C:35]([CH2:41][C:42]2[CH:43]=[CH:44][C:45]([O:51][C:52](=[O:54])[CH3:53])=[C:46]([CH:50]=2)[C:47](O)=[O:48])[C:36](=[O:40])[C:37]=1[O:38][CH3:39]>C(Cl)Cl>[CH3:30][O:31][C:32]1[C:33](=[O:56])[C:34]([CH3:55])=[C:35]([CH2:41][C:42]2[CH:43]=[CH:44][C:45]([O:51][C:52](=[O:54])[CH3:53])=[C:46]([CH:50]=2)[C:47]([NH:6][C:5]2[CH:7]=[C:8]([O:12][CH3:13])[C:9]([O:10][CH3:11])=[C:3]([O:2][CH3:1])[CH:4]=2)=[O:48])[C:36](=[O:40])[C:37]=1[O:38][CH3:39]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Reactant: COc1cc(N)cc(OC)c1OC
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3cc(OC)c(OC)c(OC)c3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 37.8 %

Procedure:
3,4,5-Trimethoxyaniline (0.216 g, 1.18 mmol), triethylamine (0.119 g, 1.18 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.199 g, 1.18 mmol) were added to a methylene chloride solution (20 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.200 g, 0.535 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) to obtain the titled compound (0.109 g, 0.202 mmol, 38%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([CH:7]=[CH:8][CH:9]=O)=[CH:5][CH:4]=1.[C:13](#[N:17])[CH2:14][C:15]#[N:16]>C(O)C.N1CCCCC1>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([CH:7]=[CH:8][CH:9]=[C:14]([C:13]#[N:17])[C:15]#[N:16])=[CH:5][CH:4]=1
Reactant: COc1ccc(C=CC=O)cc1
Reactant: N#CCC#N
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1ccc(C=CC=C(C#N)C#N)cc1
Yield: 90.7 %

Procedure:
To 0.52 g (3.2 mmol) of the aldehyde from step (a) and 0.26 g (4 mmol) malononitrile in 30 ml ethanol was added 2 drops piperidine and the reaction mixture was refluxed for 40 minutes, cooled, filtered and washed with ethanol to yield 0.61 g (90% yield) of an orange solid, m.p. 160° C.
Reaction SMILES: [F:1][CH:2]([F:13])[C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[C:5](OC)=[O:6].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1.C(OCC)(=O)C.[OH-].[Na+]>[F:1][CH:2]([F:13])[C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[CH2:5][OH:6]
Reactant: COC(=O)c1ccccc1C(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OCc1ccccc1C(F)F
Temperature: 0 °C
Yield: 80.7 %

Procedure:
To a solution of methyl 2-(difluoromethyl)benzoate (700 mg, 3.76 mmol) in THF was added 1M lithium aluminum hydride in THF (5.64 mL, 11.3 mmol) dropwise at room temperature for 1 h. The reaction was then poured into ice water (100 mL) and diluted with ethyl acetate (200 mL) and 2N sodium hydroxide aqueous solution (100 mL). The organic phase was then separated and washed with brine (50 mL), dried over sodium sulfate and concentrated, to give (2-(difluoromethyl)phenyl)methanol as an oil (480 mg). 1H NMR (400 MHz, CDCl3) δ 7.56 (d, 1H), 7.41 (m, 3H), 6.93 (t, 1H), 4.82 (s, 2H).
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4](C=O)=[CH:3][CH:2]=1.[NH:10]1[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[NH:29][C:28]4[CH:30]=[CH:31][C:32]([C:34]([NH2:36])=[O:35])=[CH:33][C:27]=4[N:26]=3)=[CH:21][CH:20]=2)[CH2:12][CH2:11]1.N1CCCCC1CCOC1C=CC(C2NC3C=CC(C(N)=O)=CC=3N=2)=CC=1>>[CH2:9]([N:10]1[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][O:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[NH:29][C:28]4[CH:30]=[CH:31][C:32]([C:34]([NH2:36])=[O:35])=[CH:33][C:27]=4[N:26]=3)=[CH:23][CH:24]=2)[CH2:12][CH2:11]1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC(=O)c1ccc2[nH]c(-c3ccc(OCCC4CCNCC4)cc3)nc2c1
Reactant: Cc1ccc(C=O)cc1
Agent: NC(=O)c1ccc2[nH]c(-c3ccc(OCCC4CCCCN4)cc3)nc2c1
Product: NC(=O)c1ccc2[nH]c(-c3ccc(OCCC4CCN(Cc5ccccc5)CC4)cc3)nc2c1

Procedure:
This compound was prepared using the methods outlined in Example 27, substituting benzaldehyde for p-tolualdehyde and 2-[4-(2-piperidin-4-yl-ethoxy)-phenyl]-1H-benzoimidazole-5-carboxylic acid amide for 2-[4-(2-piperidin-2-yl-ethoxy)-phenyl]-1H-benzoimidazole-5-carboxylic acid amide. HPLC (Method C): Rt=4.41. MS (ESI+): mass calcd. for C28H30N4O2, 454.24; m/z found, 455.4 [M+H]+. 1H NMR (500 MHz, CD3OD): 8.15 (s, 1H), 8.00 (d, J=8.9 Hz, 2H), 7.91 (d, J=8.5 Hz, 1H), 7.67 (d, J=8.7 Hz, 1H), 7.40 (br m, 5H), 7.12 (d, J=8.8 Hz, 2H), 4.21 (s, 2H), 4.11 (t, J=6.1 Hz, 2H), 3.43-3.40 (m, 2H), 2.95-2.89 (m, 2H), 2.00-1.97 (m, 2H), 1.87-1.78 (m, 1H), 1.78-1.72 (m, 2H), 1.48-1.37 (m, 2H).
Reaction SMILES: C([N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([O:18][CH3:19])[C:13]([S:15]([CH3:17])=[O:16])=[CH:14][C:7]=2[CH2:6][CH2:5]1)(=O)C.[ClH:20]>>[ClH:20].[CH3:19][O:18][C:12]1[C:13]([S:15]([CH3:17])=[O:16])=[CH:14][C:7]2[CH2:6][CH2:5][NH:4][CH2:10][CH2:9][C:8]=2[CH:11]=1
Reactant: COc1cc2c(cc1S(C)=O)CCN(C(C)=O)CC2
Agent: Cl
Product: COc1cc2c(cc1S(C)=O)CCNCC2

Procedure:
Following the general procedure of Example 4, 3-acetyl-8-methoxy-7-methylthio-2,3,4,5-tetrahydro-1H3-benzazepine is reacted with one equivalent of 3-chloroperbenzoic acid to give 3-acetyl-8-methoxy-7-methylsulfinyl-2,3,4,5-tetrahydro-1H-3-benzazepine. Following the procedure of Example 4, 3-acetyl-8-methoxy-7-methylsulfinyl-2,3,4,5-tetrahydro-1H-3-benzazepine is reacted with 3N hydrochloric acid to give 8-methoxy-7-methylsulfinyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride. This methoxy compound is treated with pyridine hydrochloride to give 8-hydroxy-7-methylsulfinyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]1[C:13](=[O:14])[C:12]2[C:15]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:16][C:17]([CH2:19][OH:20])=[N:18][C:11]=2[O:10][CH2:9][CH2:8]1.[OH-].[Na+].[Mn]([O-])(=O)(=O)=[O:39].Cl>S([O-])([O-])(=O)=S.[Na+].[Na+]>[F:35][C:2]([F:1])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]1[C:13](=[O:14])[C:12]2[C:15]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:16][C:17]([C:19]([OH:39])=[O:20])=[N:18][C:11]=2[O:10][CH2:9][CH2:8]1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: O=C1c2c(-c3ccccc3)cc(CO)nc2OCCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Product: O=C(O)c1cc(-c2ccccc2)c2c(n1)OCCN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C2=O
Temperature: 25 °C
Reaction time: 45 h
Yield: 76.4 %

Procedure:
A mixture of 4-[3,5-bis(trifluoromethyl)benzyl]-8-hydroxymethyl-2,3,4,5-tetrahydro-5-oxo-6-phenylpyrido[3,2-f][1,4]oxazepine (Example 55) (3.49 g), 2N-NaOH (100 ml) and pottasium permanganate (2.22 g) was stirred for 45 hours at room temperature. To the reaction mixture was added saturated aqueous sodium thiosulfate (10 ml). After the pH of the mixture was adjusted to ca.3 using hydrochloric acid. The mixture was extracted with ethyl acetate-THF (1:2). The extract was washed with aqueous sodium chloride solution, dried and evaporated to give the entitled compound as colorless crystals (2.74 g).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:18]=[CH:19][C:20]([N:23]4[CH:27]([CH3:28])[CH2:26][NH:25][C:24]4=[O:29])=[N:21][CH:22]=3)=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH3:30]I>>[CH3:1][C:2]1[C:3]([N:9]2[CH2:10][CH2:11][N:12]([C:15]([C:17]3[CH:18]=[CH:19][C:20]([N:23]4[CH:27]([CH3:28])[CH2:26][N:25]([CH3:30])[C:24]4=[O:29])=[N:21][CH:22]=3)=[O:16])[CH2:13][CH2:14]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)NCC4C)nc3)CC2)c(C)c1
Reactant: CI
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)N(C)CC4C)nc3)CC2)c(C)c1

Procedure:
Using 1-{5-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]pyridin-2-yl}-5-methylimidazolidin-2-one (166 mg) described in Example 426 and methyl iodide (31 μL) and by the reaction and treatment in the same manner as in Example 36, the title compound (123 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH3:18])[C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:10]=1[CH:16]=O.C[O-].[Na+].Cl>C(=O)(OC)OC.CO>[CH3:1][O:2][C:3]([C:4]1[CH2:5][CH2:6][CH2:7][N:8]([CH3:18])[C:9]2[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:10]=2[CH:16]=1)=[O:19]
Reactant: COC(=O)CCCCN(C)c1ccc(Br)cc1C=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: COC(=O)OC
Solvent: CO
Product: COC(=O)C1=Cc2cc(Br)ccc2N(C)CCC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 31.7 %

Procedure:
To a solution of 5-(4-bromo-2-formyl-N-methylanilino)pentanoic acid methylester (3.0 g) in dimethyl carbonate (40 ml), a solution of 28% sodium methoxide in methanol (2.3 g) was added at room temperature, and the resulting mixture was stirred at 50° C. for 2 hours. The mixture was allowed to cool to room temperature, and neutralized with 1N hydrochloric acid. After ethyl acetate extraction, the organic layer was washed with saturated salt water, dried over anhydrous sodium sulfate, and concentrated. The concentrate was purified by silica gel column chromatography (h-hexane/ethyl acetate=10/1) and the appropriate eluate was concentrated. The precipitated crystal was washed with IPE and collected by filtration. Drying under reduced pressure (40° C., 1 hour) gave yellow crystal of 8-bromo-1-methyl-1,2,3,4-tetrahydro-1-benzazocin-5-carboxylic acid methylester (0.9 g, yield 31%). mp. 88–89° C. 1H-NMR(CDCl3, δ, 300 MHz): 1.44(2H, m), 2.54(2H, t, J=6.2 Hz), 2.87(3H, s), 3.42(2H, t, J=5.6 Hz), 3.78(3H, s), 6.56(1H, d, J=6.0 Hz), 7.19–7.23(2H, m), 7.68(1H, s). Anal. Calcd for C14 H16 NO2 Br: C,54.21; H,5.20; N,4.52; Br,25.76. Found: C,54.19; H,5.29; N,4.37; Br,25.74. IR(KBr, cm−1): 1689, 1189.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[N:12]1([CH2:17][CH2:18][CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3([CH2:33][OH:34])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[CH:23][CH:22]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1.S([O-])([O-])(=O)=O.[Mg+2]>ClCCl>[N:12]1([CH2:17][CH2:18][CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3([CH:33]=[O:34])[CH2:28][CH2:29][O:30][CH2:31][CH2:32]3)=[CH:23][CH:22]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: OCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Agent: O=[Cr](=O)([O-])Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: O=CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Yield: 50.2 %

Procedure:
Pyridinium chlorochromate (20.3 g, 0.09415 mol), 1.69 wt) was charged to a stirred suspension of celite (24 g, 2 wt) and {4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-yl}methanol (12.03 g, 0.03766 mol) in dichloromethane (120 ml, 10 vol) with stirring. The mixture was stirred at 18-25° C. for 3.5 hours after which time LC analysis showed the reaction to be 70% complete. Magnesium sulphate (12 g, 1 wt) was added and the resulting slurry filtered through a pad of aluminium oxide (activated, basic, Brockmann I, standard grade, ˜150 mesh) (481 g, 40 wt) eluting with 1% methanol/dichloromethane. Clean fractions were combined and evaporated to dryness at 40° C. The resulting brown solid was stirred in tertbutylmethylether (120 ml, 10 vol). Undissolved residue was removed by filtration and rinsed with tertbutylmethylether (3×120 ml, 3×10 vol). The combined filtrates were evaporated at 40° C. to yield 4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carbaldehyde (6.0 g, 50.2%) as a beige waxy solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[C:6](=[O:16])[CH2:5]2.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>N1C=CC=CC=1>[CH3:17][S:18]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[C:6](=[O:16])[CH2:5]2)(=[O:20])=[O:19]
Reactant: COC(=O)CN1C(=O)Cc2cc(N)ccc21
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: COC(=O)CN1C(=O)Cc2cc(NS(C)(=O)=O)ccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 81.8 %

Procedure:
To a solution of methyl 2-(5-amino-2-oxoindolin-1-yl)acetate (0.120 g, 0.545 mmol) in pyridine (8 ml) cooled to 0° C., methanesulfonyl chloride (0.047 ml, 0.599 mmol) was added, and the mixture was allowed to warm to room temperature and stirred for 1.5 hours. The solvent was removed and the crude was portioned between DCM and 1N HCl. The organic phase was dried over sodium sulfate, and the solvent was removed. The crude was purified by filtration on silica gel cartridge (DCM:MeOH from 99:1 to 97:3) affording methyl 2-(5-(methylsulfonamido)-2-oxoindolin-1-yl)acetate (0.133 g, 0.446 mmol, 82% yield). MS/ESI+ 298.9 [MH]+.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[IH:12].C(O)(=O)C>O>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([I:12])[N:3]=1
Reactant: I
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Solvent: CC(=O)O
Solvent: O
Product: Nc1nc(I)c2[nH]cnc2n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a 2 liter single-neck round bottom flask with a mechanical stirrer was charged 2-amino-6-chloropurine (41.0 g, 242 mmol). The flask was cooled in an ice-water bath. The the reaction flask was charged HI (47% solution, pre-cooled in a refrigerator, 250 mL) in one portion. The resulting suspension was stirred for 16 hours at ice-water bath temperature. Water (500 mL) was charged to the reaction flask. The suspension was stirred at 0° C. for 1 hour. The precipitate was filtered and washed with water (3×250 mL). The filter cake was transferred to a 250 mL filtration flask. 6 M NaOH solution (85 mL) was added to the solid through the filter to rinse out residual solid and wash into the filter flask. The solution obtained was added slowly to a boiling solution of acetic acid (25 mL) and water (250 mL). The resulting suspension was cooled to room temperature and stirred at room temperature for 2 hours. The solid was collected by centrifugation, washed with water (2×250 mL), followed by heptane (250 mL). The solid was first spin-dried on the centrifuge for 30 minutes and then dried in a vacuum oven overnight to provide the desired product (61.3 g).
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11]([O-])=O>C(OCC)(=O)C.[Pd]>[F:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[NH:4][C:5]1[C:6]([NH2:11])=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=[N+]([O-])c1ccccc1Nc1ccccc1F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccccc1Nc1ccccc1F
Reaction time: 2 h
Yield: 98.9 %

Procedure:
2-fluoro-N-(2-nitrophenyl)aniline (1.4 g, 6.0 mmol) was dissolved in ethyl acetate (20 mL) and 10% palladium on activated carbon (150 mg) was added. The mixture was shaken under a hydrogen atmosphere (40 psi) for 2 hours. The mixture was filtered through a pad of Celite and concentrated to give N-(2-fluorophenyl)benzene-1,2-diamine (1.2 g) that was carried on directly to the next step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:21]=[CH:20][C:12]([C:13]([O:15]C(C)(C)C)=[O:14])=[CH:11][N:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>C(Cl)Cl>[F:8][C:6]1[CH:5]=[C:4]([C:9]2[CH:21]=[CH:20][C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2cc(F)cc(F)c2)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=C(O)c1ccc(-c2cc(F)cc(F)c2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
To tert-butyl 6-(3,5-difluorophenyl)nicotinate in DCM (80 mL) was added trifluroacetic acid (20 mL). After stirring at rt overnight, toluene was added (100 mL) and the solvent removed to give the crude product as a white powder. The solid was re-crystallized from MeOH to afford the title compound 1.269 g (74%) as a white solid. 1H NMR (400 MHz, DMSO-d6) □ ppm 9.16 (1H, d, J=1.7 Hz), 8.37 (1 H, dd, J=8.2, 2.0 Hz), 8.23 (1 H, d, J=8.2 Hz), 7.86-7.95 (2H, m), 7.36-7.47 (1H, m).
Reaction SMILES: [ClH:1].[CH2:2]([N:4]1[C:9]([CH3:10])=[CH:8][C:7](=[O:11])[C:6]([O:12]CC2C=CC=CC=2)=[C:5]1[CH2:20][O:21]C)[CH3:3]>Cl>[ClH:1].[CH2:2]([N:4]1[C:9]([CH3:10])=[CH:8][C:7](=[O:11])[C:6]([OH:12])=[C:5]1[CH2:20][OH:21])[CH3:3]
Reactant: CCn1c(C)cc(=O)c(OCc2ccccc2)c1COC
Agent: Cl
Product: CCn1c(C)cc(=O)c(O)c1CO
Yield: 79.7 %

Procedure:
1.3 g (4 mmol) 1-ethyl-2-methoxymethyl-3-benzyloxy-6-methyl-pyridin-4(1H)-one hydrochloride was added to 40 ml of 4N hydrochloric acid and refluxed for 6 hours. Concentration to dryness in vacuo afforded the crude product. Recrystallisation from methanol/diethyl ether gave the pure title compound (0.7 g, 80%) as a yellow crystalline solid. m.p. 160-162° C.
Reaction SMILES: [OH-].[Na+].[C:3]([NH:6][C@H:7]([CH2:14][F:15])[CH2:8][CH2:9][C:10]([O:12]C)=[O:11])(=[O:5])[CH3:4]>CO>[C:3]([NH:6][C@H:7]([CH2:14][F:15])[CH2:8][CH2:9][C:10]([OH:12])=[O:11])(=[O:5])[CH3:4]
Reactant: COC(=O)CC[C@@H](CF)NC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)N[C@H](CF)CCC(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.2 ml of 1N aqueous sodium hydroxide solution was added drop-by-drop to 0.22 g of 6 in 2 ml of methanol and the resulting mixture was stirred for one hour at room temperature. The methanol was evaporated, water and ethyl acetate were added to the residue, and the resulting mixture was acidified with a few drops of 12N hydrochloric acid. The mixture was stirred at room temperature for 30 minutes, the organic layer was separated, dried (Na2SO4), and stripped of solvent under reduced pressure. The residue, an oil, was triturated with ether/pentane to give 7, as a light brown powder, m.p.: 80°-83° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][C:6](=[O:15])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:2].S(Cl)([Cl:20])(=O)=O.O>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:16])[CH:5]([Cl:20])[C:6](=[O:15])[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH3:2]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)CC(=O)CCc1ccccc1
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C(Cl)C(=O)CCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 3-oxo-5-phenyl-pentanoic acid ethyl ester (1.6 g, 7.76 mmol) in methylene chloride (18 mL) is added sulfuryl chloride (1.15 g, 8.53 mmol) dropwise. After stirred at room temperature for 6 hours, the reaction mixture is poured into water, extracted with methylene chloride, washed wwashed water and brine, dried over sodium sulfate. Concentration gave the crude title compounds, which is used for the next step without further purification.