Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:17]([C:18]#[C:19][CH2:20]O)=[CH:16][N:15]([CH2:22][C:23]3[C:28]([CH3:29])=[C:27]([O:30][CH3:31])[C:26]([CH3:32])=[CH:25][N:24]=3)[C:4]=2[N:5]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[N:7]=1.CS(Cl)(=O)=O.S([O-])(=O)(=O)C.[CH:43]([NH:46][CH:47]([CH3:49])[CH3:48])([CH3:45])[CH3:44]>C(Cl)Cl.CCN(CC)CC>[Cl:1][C:2]1[C:3]2[C:17]([C:18]#[C:19][CH2:20][N:46]([CH:47]([CH3:49])[CH3:48])[CH:43]([CH3:45])[CH3:44])=[CH:16][N:15]([CH2:22][C:23]3[C:28]([CH3:29])=[C:27]([O:30][CH3:31])[C:26]([CH3:32])=[CH:25][N:24]=3)[C:4]=2[N:5]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[N:7]=1
Reactant: COc1c(C)cnc(Cn2cc(C#CCO)c3c(Cl)nc(NC(=O)C(C)(C)C)nc32)c1C
Reactant: CC(C)NC(C)C
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(C)cnc(Cn2cc(C#CCN(C(C)C)C(C)C)c3c(Cl)nc(NC(=O)C(C)(C)C)nc32)c1C
Reaction time: 72 h

Procedure:
A solution of N-[4-chloro-5-(3-hydroxy-prop-1-ynyl)-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]-2,2-dimethyl-propionamide (9.0 g, 19.7 mmol) and Et3N (2 mL) in DCM (50 mL) was treated with MsCl (15.3 mL, 19.7 mmol) at 0° C. for 20 min and evaporated to give a yellow solid, containing mostly the desired mesylate (10.7 g). An aliquot of this solid (106.8 mg, 0.2 mmol) was treated with diisopropylamine (20.3 mg, 28.1 μL) in DCM (2 mL) at 0° C. for 10 h, and then at 25° C. for 3 days. Evaporation and preparative plate chromatography gave the title compound.
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.[Cl-].[Al+3].[Cl-].[Cl-].[OH-].[Na+].[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:2]([C:3]2[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=2)=[O:9])=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: Fc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(c1ccc(F)cc1)c1cccnc1
Temperature: 0 °C

Procedure:
To a suspension of 140 g of nicotinic acid chloride hydrochloride in 500 ml of fluorobenzene cooled to 0° C. are added 280 g of aluminum chloride portionwise. The mixture is held under reflux for 6 hours, cooled and then poured onto ice. After the addition of sodium hydroxide up to pH=8, the mixture is extracted with dichloromethane. The organic phase is dried over magnesium sulfate and then evaporated under vacuum. The residue crystallizes in a pentane/diisopropyl ether mixture giving 108.5 g of 3-(4-fluorobenzoyl)pyridine in the form of crystals melting at 91° C.
Reaction SMILES: O.NN.[Cl:4][C:5]1[CH:6]=[C:7]([C:13](=O)[C:14]([OH:16])=[O:15])[CH:8]=[CH:9][C:10]=1[S:11][CH3:12].[OH-].[K+].Cl>O>[Cl:4][C:5]1[CH:6]=[C:7]([CH2:13][C:14]([OH:16])=[O:15])[CH:8]=[CH:9][C:10]=1[S:11][CH3:12]
Reactant: CSc1ccc(C(=O)C(=O)O)cc1Cl
Agent: Cl
Agent: NN
Agent: [K+]
Solvent: O
Product: CSc1ccc(CC(=O)O)cc1Cl
Temperature: 80 °C
Yield: 88.6 %

Procedure:
A reaction flask equipped with mechanical stirrer was charged with hydrazine hydrate (8.5 mL, 273 mmol). The hydrazine hydrate was cooled to −50° C. and then treated with (3-chloro-4-methylsulfanyl-phenyl)-oxo-acetic acid (12.6 g, 54.6 mmol) in one portion. An exotherm ensued that raised the temperature. The resulting white milky mixture was then heated to 80° C. After reaching 80° C., the heating element was removed, and the reaction mixture was then treated with potassium hydroxide (2.09 g, 31.7 mmol) in one portion. An exotherm was observed. The reaction was then stirred at 25° C. until the reaction temperature cooled back to 80° C. At this time, another portion of potassium hydroxide (2.09 g, 31.7 mmol) was added. Again, an exotherm was observed, and the resulting reaction mixture was allowed to cool back to 80° C. Once at 80° C., a third portion of potassium hydroxide (2.09 g, 31.7 mmol) was added to the reaction mixture. Another exotherm was observed, and after cooling back to 80° C., the fourth and final portion of potassium hydroxide (2.09 g, 31.7 mmol) was added. At this point, the heating element was added, and the reaction mixture was heated at 100° C. for 16 h. The resulting homogenous reaction mixture was cooled to 25° C. and then diluted with water (12 mL). The reaction mixture was then transferred to a separatory funnel, rinsing with additional water (12 mL) and diethyl ether (40 mL). The layers were separated, and the aqueous layer was transferred to a flask. The organic layer was extracted with water (2×15 mL) The aqueous layers were combined and treated with heptane (20 mL), and the resulting reaction mixture was vigourously stirred. This stirred solution was then treated dropwise with concentrated hydrochloric acid (26 mL) over 30 min while the temperature was kept under 50° C. with an ice bath. A cloudy suspension formed, and this suspension was stirred at 25° C. for 3 h. The solid that formed was collected by filtration and then washed sequentially with a 1N aqueous hydrochloric acid solution (2×6 mL), heptane (1×12 mL), and a solution of heptane/diethyl ether (15 mL, 4:1). The resulting solid was dried under high vacuum to afford (3-chloro-4-methylsulfanyl-phenyl)-acetic acid (10.48 g, 89%) as an off-white solid: mp 105.6-108.4° C.; EI-HRMS m/e calcd for C9H9ClSO2 (M+) 216.0012, found 216.0022.
Reaction SMILES: CO[C:3]1[C:4]([N+:16]([O-:18])=[O:17])=[C:5]([CH:9]=[C:10](OC)[C:11]=1[O:12][CH3:13])[C:6](O)=O.C1C[O:22][CH2:21]C1>>[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:21][OH:22])=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1
Reactant: C1CCOC1
Reactant: COc1cc(C(=O)O)c([N+](=O)[O-])c(OC)c1OC
Product: COc1ccc(CCO)c([N+](=O)[O-])c1

Procedure:
To a stirred solution of the 3,4,5-Trimethoxy-2-nitrobenzoic acid (2 g, 7.77 mmol) and BH3 (1.0 M in THF, 13.2 ml) in THF (10 ml) was stirred and refluxed for 3 hours. After cooling, the reaction mixture was extracted with water and CH2Cl2. The combined organic layers were dried over MgSO4, and then evaporated to afford 4-methoxy-2-nitrobenzyl methanol. The crude 4-methoxy-2-nitrobenzyl methanol was dissolved in anhydrous CH2Cl2 (20 mL) and was subjected to pyridinium dichromate, PDC oxidation (5.84 g, 15.55 mmol)/molecular sieves (powder, 6 g) at room temperature for 16 h. The reaction mixture was filtrated by Celite and extracted with water and CH2Cl2. The organic layers were combined and evaporated. The residue was purified by flash chromatography (EtOAc:n-hexane=1:1) to afford compound A1 as a yellow solid, yield 69%. mp 73.8-75.1° C., 1H NMR (500 MHz, CDCl3) δ 3.97 (s, 3H), 3.99 (s, 6H), 7.21 (s, 1H), 9.86 (s, 1H).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([S:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[C:7]2[C:12]=1[C@H:11]([CH2:13][NH2:14])[CH2:10][CH2:9][CH2:8]2.C(#N)C.C(N(CC)CC)C.[C:32](OC(=O)C)(=[O:34])[CH3:33]>CN(C1C=CN=CC=1)C.O>[F:2][C:3]1[CH:4]=[C:5]([S:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[C:7]2[C:12]=1[C@H:11]([CH2:13][NH:14][C:32](=[O:34])[CH3:33])[CH2:10][CH2:9][CH2:8]2
Reactant: NC[C@@H]1CCCc2cc(Sc3ccccc3)cc(F)c21
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)NC[C@@H]1CCCc2cc(Sc3ccccc3)cc(F)c21
Temperature: 25 °C
Yield: 97.4 %

Procedure:
A mixture of C—((R)-8-fluoro-6-phenylsulfanyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-methylamine hydrochloride (1.36 kg), DMAP (10 g), acetonitrile (8.6 L), triethylamine (1.27 L), and acetic anhydride (0.41 L) was stirred at 25° C. After thirty minutes water (17.5 L) was added. The resulting slurry was stirred for 30 minutes at 25° C. The product was isolated by filtration and washed with 7.5 L of water. Drying overnight at 50° C. provided 1.34 kg of N—((R)-8-fluoro-6-phenylsulfanyl-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl)-acetamide (97.4% yield, 99.66% pure by HPLC, 98.08% ee): MP=94.6-95.9° C.; MS (M+1)=330; H1 NMR (300 MHz): δ (DMSO): 1.44-1.91 (4H, m), 1.83 (3H, s), 2.54-2.79 (2H, m), 3.06 (1H, m), 3.16 (2H, m), 6.83 (1H, dd, =1.51, 10.17 Hz), 6.90 (1H, bs), 7.30-7.45 (5H, m, phenyl), 8.01 (1H, bt, J=5.65 Hz, NH); [α]D=7.4° (MeOH). Chiral Assay (Area Norm): Column: Chiralpak AD-H (150×4.6 mm), mobile phase 88/12 hexane/ethanol(isocratic) Flow rate 0.7 ml/min, 25° C., uv @230 nm.: (R)-isomer 99.04/(S)-isomer 0.96
Reaction SMILES: [CH3:1][S:2]([C:5](C(OC)=O)([CH2:16][CH2:17][CH2:18][CH:19]([O:29]CC1C=CC=CC=1)[CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14]C)=[O:13])(=[O:4])=[O:3].[Cl-].[Na+].CN(C)C=O>O>[CH3:1][S:2]([CH:5]([CH2:16][CH2:17][CH2:18][CH:19]([OH:29])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])(=[O:4])=[O:3]
Reactant: COC(=O)CCCCCCC(CCCC(COc1ccc(F)cc1)OCc1ccccc1)(C(=O)OC)S(C)(=O)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)C(CCCCCCC(=O)O)CCCC(O)COc1ccc(F)cc1
Temperature: 160 °C

Procedure:
A mixture of methyl 8-methylsulfonyl-8-methoxycarbonyl-12-benzyloxy-13-(4-fluorophenoxy)tridecanoate (2.60 g., 4.5 mmoles), sodium chloride (0.5 g., 8.5 mmoles), dimethylformamide (8 ml.) and water (0.2 ml.) is heated with an oil bath at 160° C. overnight (ca. 15 hours). The reaction mixture is allowed to cool to room temperature, quenched with cold water, and then extracted with chloroform three times. The combined extracts are washed with brine and dried over anhydrous magnesium sulfate. The solvent is removed by evaporation in vacuo leaving the desired product as a viscous oil residue (2.30 g., 4.4 mmoles, 98%). ir (neat) 3.40, 5.72, 6.20, 6.62, 6.87, 7.71, 8.00, 8.28, 8.90, 12.04, 13.17, 14.37μ; pmr CCl4) δ 1.0-2.9 (22H, m, containing a methyl singlet at 2.60 δ), 3.54 (3H, s); 3.5-4.1 (3H, m), 4.47 (1H, d, J=12Hz), 4.70 (1H, d, J= 12Hz), 6.6-7.1 (4H, m), 7.20 (5H, s).
Reaction SMILES: CON(C)[C:4]([C:6]1[O:10][CH:9]=[N:8][C:7]=1[CH3:11])=[O:5].[CH2:13]([Mg]Br)[CH3:14].C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:11][C:7]1[N:8]=[CH:9][O:10][C:6]=1[C:4](=[O:5])[CH2:13][CH3:14]
Reactant: CC[Mg]Br
Reactant: CON(C)C(=O)c1ocnc1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(=O)c1ocnc1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
N-Methoxy-N-methyl-4-methyl-5-oxazolecarboxamide (5 g) in dry tetrahydrofuran at -40° C. was stirred under a nitrogen atmosphere and ethylmagnesium bromide (1M solution in tetrahydrofuran, 35 ml) was added dropwise. After 30 minutes the mixture was allowed to warm to room temperature and then stirred for a further 1 hour. Aqueous sodium hydrogen carbonate was added, the organic layer was separated and the aqueous layer was extracted with diethylether. The material thus obtained was purified by flash chromatography to yield a pale yellow liquid which solidified on cooling.
Reaction SMILES: Br[CH:2]([CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:12])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[NH:19]1[CH:23]=[N:22][CH:21]=[N:20]1.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[N:19]1([CH:2]([CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:12])[C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:4])[CH:23]=[N:22][CH:21]=[N:20]1
Reactant: CC(c1ccccc1)C(Br)C(=O)c1ccccc1
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(c1ccccc1)C(C(=O)c1ccccc1)n1cncn1
Temperature: 25 °C

Procedure:
2-Bromo-3-phenyl-butyrophenone (0.02 mol), 1,2,4-triazole (0.02 mol) and potassium carbonate (0.04 mol) were refluxed in methyl ethyl ketone (100 ml) for 36 hours. After cooling to room temperature, the solution was filtered and the solvent removed in vacuo. Recrystallisation of the residue from ethanol/petroleum ether (60°-80°) gave the title compound as a colourless solid, m.p. 166°-8°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[NH:10][S:9]1(=[O:18])=[O:17].C(=O)([O-])[O-].[Cs+].[Cs+].[Br:25][CH2:26]/[CH:27]=[CH:28]/[CH2:29]Br>>[Br:25][CH2:26]/[CH:27]=[CH:28]/[CH2:29][N:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[S:9]1(=[O:18])=[O:17]
Reactant: BrC/C=C/CBr
Reactant: O=S1(=O)Nc2ccccc2N1c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=S1(=O)N(C/C=C/CBr)c2ccccc2N1c1ccccc1F

Procedure:
In an analogous manner to general procedure IV, 1-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (prepared in an analogous manner as described in general procedure I, 0.264 g, 1.0 mmol) was treated with cesium carbonate (0.49 g, 1.5 mmol) and (E)-1,4-dibromobut-2-ene (1.07 g, 5.0 mmol) to give 0.26 g of 1-[(2E)-4-bromobut-2-en-1-yl]-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]2[CH:9]=[C:10]([CH3:13])[N:11]([CH3:12])[C:7]=2[C:6]([C:14]([OH:16])=O)=[CH:5][N:4]=1.C(N(CC)C(C)C)(C)C.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>CN(C)C=O.C(OCC)(=O)C>[Cl:2][C:3]1[C:8]2[CH:9]=[C:10]([CH3:13])[N:11]([CH3:12])[C:7]=2[C:6]([C:14]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[O:16])=[CH:5][N:4]=1
Reactant: Cc1cc2c(Cl)ncc(C(=O)O)c2n1C
Reactant: C1COCCN1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc2c(Cl)ncc(C(=O)N3CCOCC3)c2n1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 4-chloro-1,2-dimethyl-1H-pyrrolo[3,2-c]pyridine-7-carboxylic acid hydrochloride (60 mg), N,N-diisopropylethylamine (0.2 ml) and morpholine (0.04 ml) in dry dimethylformamide (2 ml) was added O-benzotriazol-1-yl-N,N,N,N′-tetramethyluronium hexafluorophosphate (131 mg). The reaction mixture was stirred at room temperature for one hour. The reaction mixture was diluted with ethyl acetate, washed twice with saturated sodium bicarbonate and water, dried (MgSO4), filtered and evaporated to afford the title compound as a white foam 68 mg.
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].[NH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.Cl.C(N=C=NCCCN(C)C)C.C(=O)([O-])O.[Na+]>ClCCl>[C:1]([CH2:3][C:4]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:6])#[N:2]
Reactant: N#CCC(=O)O
Reactant: NCc1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Product: N#CCC(=O)NCc1ccccn1
Yield: 88.6 %

Procedure:
Cyanoacetic acid (8.51 g) was dissolved in dichloromethane (400 ml). To the solution was added 2-aminomethylpyridine (10.81 g). The mixture was stirred for a while, to which was then added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (19.17 g). The mixture was stirred for 15 minutes at 25° C. To the reaction mixture was added a saturated aqueous solution of sodium hydrogencarbonate (200 ml). The mixture was shaken and left standing. The.aqueous layer was subjected to extraction with ethyl acetate (200 ml) three times. The organic layers were combined and dried over anhydrous magnesium sulfate, followed by concentration to afford the title compound (15.51 g).
Reaction SMILES: [O:1]1[C@H:3]([C@H:4]([O:8][CH2:9][CH:10]([O:12][CH3:13])[CH3:11])[CH2:5][CH2:6][CH3:7])[CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C(OCC)C>[CH3:13][O:12][CH:10]([CH3:11])[CH2:9][O:8][C@H:4]([CH2:5][CH2:6][CH3:7])[C@@H:3]([OH:1])[CH3:2]
Reactant: CCC[C@@H](OCC(C)OC)[C@@H]1CO1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CCC[C@@H](OCC(C)OC)[C@H](C)O
Temperature: 20 °C
Reaction time: 36 h
Yield: 83 %

Procedure:
3.62 g (19.2 mmol) of (2S,3R)-1,2-epoxy-3-(2-methoxy-2-methylethoxy)hexane in 30 ml of diethyl ether were added dropwise at 0° C. under argon over the course of 15 minutes to a stirred suspension of 0.85 g (22.2 mmol) of lithium aluminum hydride in 100 ml of diethyl ether. The mixture was subsequently then stirred at 20° C. for 36 hours. The excess of lithium aluminum hydride was decomposed by cautious addition of 1.2 ml of water. After 5 minutes, 4 ml of a 10% strength by weight sodium hydroxide solution were added and the mixture was vigorously stirred for 10 minutes. The precipitate was then filtered off, and the filter residue was extracted three times with 50 ml of tetrahydrofuran. The combined organic phases were dried over anhydrous sodium sulfate and concentrated. The residue was distilled over potassium carbonate and yielded (25,3R)-3-(2-methoxy-2-methylethoxy)hexan-2-ol in a yield of 83% (b.p.: 71-73° C./3 hPa; [α]D19=−10.3° (c=2.3 in dichloromethane)).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][C:14]1([OH:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[CH:9][CH:8]=[C:7]([Cl:21])[CH:6]=2.CC(C)([O-])C.[K+]>CN(C)C=O>[Cl:21][C:7]1[CH:8]=[CH:9][C:10]2[C:11]3[N:12]=[CH:13][C:14]4([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]4)[O:20][C:2]=3[CH:3]=[N:4][C:5]=2[CH:6]=1
Reactant: OC1(CNc2c(Br)cnc3cc(Cl)ccc23)CCCCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1ccc2c3c(cnc2c1)OC1(C=N3)CCCCC1
Temperature: 25 °C
Yield: 31.4 %

Procedure:
A solution of 16.4 g of 3-bromo-7-chloro-N-[1-hydroxycyclohexylmethyl]-4-quinolinamine in 176 ml of dimethylformamide was stirred at room temperature and to it was added 7.54 g of potassium tert-butoxide. The mixture was heated at 130°-140° C. for twenty hours. The reaction mixture was then cooled to room temperature, quenched with water, and extracted with an ether/ethyl acetate solution. Evaporation of solvents resulted in a crude oil which was purified by HPLC using 2:1 hexane/ethyl acetate as the eluent. A solid resulted which was recrystallized from isopropanol to yield 4 g of crystalline solid with a melting point of 216°-218° C.
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:20]2[CH:25]=[CH:24][C:23]([O:26]S(C3C=CC(C)=CC=3)(=O)=O)=[CH:22][C:21]=2[O:37][CH2:38][O:39][CH3:40])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[O-].[Na+].Cl>CO>[CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][C:21]=2[O:37][CH2:38][O:39][CH3:40])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COCOc1cc(OS(=O)(=O)c2ccc(C)cc2)ccc1-c1[nH]c2cc(C(=O)OC)ccc2c1C1CCCCC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COCOc1cc(O)ccc1-c1[nH]c2cc(C(=O)OC)ccc2c1C1CCCCC1
Temperature: 80 °C
Yield: 49 %

Procedure:
Methyl 3-cyclohexyl-2-(2-(methoxymethoxy)-4-{[(4-methylphenyl)sulfonyl]oxy}-phenyl)-1H-indole-6-carboxylate was suspended in MeOH 0.18 M) and NaOMe (5 eq) was added. The mixture was warmed in a closed vessel to 80° C. After 4 h additional NaOMe (5 eq) was added. The mixture was warmed overnight. The mixture was cooled to RT and 1N aqueous HCl was added to the mixture. After dilution with H2O the mixture was extracted with EtOAc. The organic phase was separated and washed with sat. aq. NaHCO3 and brine. After drying over Na2SO4 all volatiles were evaporated in vacuo. The residual material was filtered with PE:EtOAc (8:2) through a pad of silica gel. The product was obtained as a yellowish amorphous solid (49%). (ES+) m/z 410 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[C:5](=[O:11])[NH:6][C:7](=[O:10])[NH:8][CH:9]=1)([O-:3])=[O:2].[C:12](=O)([O-])[O-].[K+].[K+].IC.[OH-].[Na+]>CN(C)C=O.O>[N+:1]([C:4]1[C:5](=[O:11])[NH:6][C:7](=[O:10])[N:8]([CH3:12])[CH:9]=1)([O-:3])=[O:2]
Reactant: O=C([O-])[O-]
Reactant: O=c1[nH]cc([N+](=O)[O-])c(=O)[nH]1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1cc([N+](=O)[O-])c(=O)[nH]c1=O
Reaction time: 16 h
Yield: 77 %

Procedure:
5-nitrouracil (10.00 g, 64 mmole) and potassium carbonate were stirred in dimethylformamide (50 mL) for 15 min. A solid formed. Iodomethane (5.3 mL, 85 mmol) was added and the flask was shaken until the solid dissolved. After the reaction mixture was stirred for 30 min., 2% NaOH (w/v) (200 mL) was added, followed by water (100 mL). The solution was washed with ethyl acetate (100 mL), and the aqueous layer was acidified to pH 3 with 1.0N HCl. A precipitate formed as the pH was lowered. After allowing the heterogeneous solution to stand for 16 hours, the product was filtered, washing with water, and air dried. The title compound was isolated in 77% yield as a yellow powder. m.p. 249°-250° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:14]([C:15]([OH:17])=O)=[C:13]([CH3:18])[NH:12][C:11](=[O:19])[NH:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[F:20][C:21]1[CH:22]=[C:23]([NH:28][C:29]2[C:37]3[C:32](=[CH:33][CH:34]=[C:35]([NH2:38])[CH:36]=3)[NH:31][N:30]=2)[CH:24]=[C:25]([F:27])[CH:26]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:20][C:21]1[CH:22]=[C:23]([NH:28][C:29]2[C:37]3[C:32](=[CH:33][CH:34]=[C:35]([NH:38][C:15]([C:14]4[CH:9]([C:4]5[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=5)[NH:10][C:11](=[O:19])[NH:12][C:13]=4[CH3:18])=[O:17])[CH:36]=3)[NH:31][N:30]=2)[CH:24]=[C:25]([F:27])[CH:26]=1
Reactant: Nc1ccc2[nH]nc(Nc3cc(F)cc(F)c3)c2c1
Reactant: CC1=C(C(=O)O)C(c2cc(F)cc(F)c2)NC(=O)N1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1=C(C(=O)Nc2ccc3[nH]nc(Nc4cc(F)cc(F)c4)c3c2)C(c2cc(F)cc(F)c2)NC(=O)N1

Procedure:
The titled compound was prepared following the procedure of Example 175 using 4-(3,5-Difluoro-phenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid, N3-(3,5-difluoro-phenyl)-1H-indazole-3,5-diamine, PyBroP and diisopropylethylamine in methylene chloride. MS (ESI) m/z 511 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:34]=[CH:33][C:7]([C:8]([N:10]2[CH2:31][C@H:30]([OH:32])[CH2:29][C@H:11]2[C:12]([N:14]2[CH2:19][CH2:18][CH:17]([O:20][CH2:21][C:22]([O:24]C(C)(C)C)=[O:23])[CH2:16][CH2:15]2)=[O:13])=[O:9])=[CH:6][CH:5]=1)(=[NH:3])[NH2:2].[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38]>ClCCl>[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38].[C:1]([C:4]1[CH:34]=[CH:33][C:7]([C:8]([N:10]2[CH2:31][C@H:30]([OH:32])[CH2:29][C@H:11]2[C:12]([N:14]2[CH2:19][CH2:18][CH:17]([O:20][CH2:21][C:22]([OH:24])=[O:23])[CH2:16][CH2:15]2)=[O:13])=[O:9])=[CH:6][CH:5]=1)(=[NH:2])[NH2:3]
Reactant: CC(C)(C)OC(=O)COC1CCN(C(=O)[C@@H]2C[C@@H](O)CN2C(=O)c2ccc(C(=N)N)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N=C(N)c1ccc(C(=O)N2C[C@H](O)C[C@H]2C(=O)N2CCC(OCC(=O)O)CC2)cc1

Procedure:
A solution of 1.60 g of t-butyl [[1-[(4R)-1-(p-amidino-benzoyl)-4-hydroxy-L-prolyl]-4-piperidinyl]oxy]acetate in 20 ml of dichloromethane and 20 ml of trifluoroacetic acid is stirred at room temperature for 2 hours and evaporated. The residue is dissolved in ethanol and treated with ether. Suction filtration and drying of the precipitate gives 1.25 g of [[1-[(4R)-1-(p-amidinobenzoyl)-4-hydroxy-L-prolyl]-4-piperidinyl]oxy]acetic acid trifluoroacetate. M.p. 220° C.
Reaction SMILES: C([N:8]1[C:13](=[O:14])[CH2:12][CH2:11][C@H:10]([N:15]2[CH2:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][C:21]=3[O:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([CH2:32][N:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)=[CH:28][CH:27]=3)[C:16]2=[O:39])[C:9]1=[O:40])C1C=CC=CC=1>C(O)(=O)C.[Pd]>[O:36]1[CH2:37][CH2:38][N:33]([CH2:32][C:29]2[CH:30]=[CH:31][C:26]([CH2:25][O:24][C:21]3[CH:20]=[CH:19][CH:18]=[C:17]4[C:22]=3[CH2:23][N:15]([C@H:10]3[CH2:11][CH2:12][C:13](=[O:14])[NH:8][C:9]3=[O:40])[C:16]4=[O:39])=[CH:27][CH:28]=2)[CH2:34][CH2:35]1
Reactant: O=C1CC[C@H](N2Cc3c(OCc4ccc(CN5CCOCC5)cc4)cccc3C2=O)C(=O)N1Cc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Product: O=C1CC[C@H](N2Cc3c(OCc4ccc(CN5CCOCC5)cc4)cccc3C2=O)C(=O)N1

Procedure:
(S)-3-(4-((4-(Morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione is prepared from (S)-1-benzyl-3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione by hydrogenation in acetic acid in the presence of Pd/C for 2 days.