Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH3:40])[C:10]([O:12][C:13]1[CH:18]=[CH:17][C:16]([C@@H:19]2[CH2:24][CH2:23][N:22]([C@@H:25]3[CH2:29][CH2:28][N:27]([CH2:30][C:31]4[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=4)[C:26]3=[O:38])[CH2:21][C@H:20]2[F:39])=[CH:15][CH:14]=1)=[O:11])=O)(C)(C)C.[ClH:41].C(OCC)C>C(Cl)Cl>[ClH:41].[NH2:8][C@@H:9]([CH3:40])[C:10]([O:12][C:13]1[CH:18]=[CH:17][C:16]([C@@H:19]2[CH2:24][CH2:23][N:22]([C@@H:25]3[CH2:29][CH2:28][N:27]([CH2:30][C:31]4[CH:32]=[CH:33][C:34]([CH3:37])=[CH:35][CH:36]=4)[C:26]3=[O:38])[CH2:21][C@H:20]2[F:39])=[CH:15][CH:14]=1)=[O:11]
Reactant: Cc1ccc(CN2CC[C@@H](N3CC[C@@H](c4ccc(OC(=O)[C@H](C)NC(=O)OC(C)(C)C)cc4)[C@H](F)C3)C2=O)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1ccc(CN2CC[C@@H](N3CC[C@@H](c4ccc(OC(=O)[C@H](C)N)cc4)[C@H](F)C3)C2=O)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 16 %

Procedure:
To a solution of (S)-4-((3S,4S)-3-fluoro-1-((R)-1-(4-methylbenzyl)-2-oxopyrrolidin-3-yl)piperidin-4-yl)phenyl 2-((tert-butoxycarbonyl)amino)propanoate (0.032 g, 0.058 mmol) in DCM (2 mL) at −20° C. was added HCl in diethyl ether (2.0 ml, 2.0 mmol, 1.0 M). The reaction mixture was slowly warmed to rt over 10 min and then allowed to stir at rt for 19 h. The solvent was then removed in vacuo to provide a pale yellow semisolid. The crude product was then purified by RP-HPLC on a Kinetex C18 (250×20 mm) 5 μm column using a gradient of 10% solvent B to 40% solvent B over 7 minutes at 15 mL/min where solvent A=0.05% HCl in water and solvent B=acetonitrile. Active fractions were concentrated by lyophilization to provide 4.7 mg (16%) of (S)-4-((3S,4S)-3-fluoro-1-((R)-1-(4-methylbenzyl)-2-oxopyrrolidin-3-yl)piperidin-4-yl)phenyl 2-aminopropanoate hydrochloride, the titled compound of example 4 as an off-white solid. LC-MS (Method A) RT=1.762 min, (M+H)+=454. 1H NMR (400 MHz, DMSO-d6) δ 7.41 (d, J=9.0 Hz, 2H), 7.24-7.10 (m, 6H), 5.10-4.85 (m, 1H), 4.45-4.22 (m, 4H), 4.04-3.94 (m, 1H), 3.34-3.18 (m, 4H), 3.06 (d, J=12.0 Hz, 2H), 2.43-2.31 (m, 1H), 2.27 (s, 3H), 2.24-2.14 (m, 1H), 2.13-2.01 (m, 1H), 2.01-1.85 (m, 1H), 1.58 (d, J=7.0 Hz, 3H). 19F NMR (376 MHz, DMSO-d6) δ −183.778.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[O:5][C:6]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]([O:16]C)=[O:15])=[CH:9][C:7]=2[CH:8]=1.[CH3:18][C:19]([CH3:35])([CH3:34])[CH2:20][C:21]1[C:25]2[CH:26]=[CH:27][C:28](O)=[C:29]([CH2:30][CH2:31][CH3:32])[C:24]=2[O:23][N:22]=1>>[CH3:18][C:19]([CH3:34])([CH3:35])[CH2:20][C:21]1[C:25]2[CH:26]=[CH:27][C:28]([O:1][CH2:2][CH2:3][C:4]3[O:5][C:6]4[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=[O:15])=[CH:9][C:7]=4[CH:8]=3)=[C:29]([CH2:30][CH2:31][CH3:32])[C:24]=2[O:23][N:22]=1
Reactant: COC(=O)Cc1ccc2oc(CCO)cc2c1
Reactant: CCCc1c(O)ccc2c(CC(C)(C)C)noc12
Product: CCCc1c(OCCc2cc3cc(CC(=O)O)ccc3o2)ccc2c(CC(C)(C)C)noc12

Procedure:
Using the procedure from Example 1, steps F and G, the title compound was prepared from methyl 2-(2-hydroxyethyl)benzofuran-5-acetate and 3-(2,2-dimethylpropyl)-7-propyl-6-hydroxybenz[4,5]isoxazole as a colorless oil.
Reaction SMILES: [OH:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:17]1[CH2:20][CH:19]([NH:21][C:22]([CH2:24][NH:25][C:26](=[O:37])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)=[O:23])[CH2:18]1>>[OH:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])[CH2:7][CH2:6][CH:5]([N:17]2[CH2:20][CH:19]([NH:21][C:22]([CH2:24][NH:25][C:26](=[O:37])[C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:34])[F:35])[CH:28]=3)=[O:23])[CH2:18]2)[CH2:4][CH2:3]1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: COc1ccccc1C1(O)CCC(=O)CC1
Product: COc1ccccc1C1(O)CCC(N2CC(NC(=O)CNC(=O)c3cccc(C(F)(F)F)c3)C2)CC1

Procedure:
The title compound was prepared as a white solid by reductive amination of 4-hydroxy-4-(2-methoxy-phenyl)-cyclohexanone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in step B of Example 4) using the procedure described in Step C of Example 4.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:7][CH:6]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])[CH:5]=[C:4]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][C:20]=2[N+:25]([O-])=O)[CH2:3]1.[H][H]>C(O)(=O)C.[Pd]>[NH2:25][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][C:19]=1[C:4]1[CH2:3][C:2]([CH3:28])([CH3:1])[CH2:7][CH:6]([N:8]2[C:9](=[O:18])[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:16]2=[O:17])[CH:5]=1
Reactant: [H][H]
Reactant: CC1(C)CC(c2ccncc2[N+](=O)[O-])=CC(N2C(=O)c3ccccc3C2=O)C1
Agent: [Pd]
Solvent: CC(=O)O
Product: CC1(C)CC(c2ccncc2N)=CC(N2C(=O)c3ccccc3C2=O)C1
Yield: 89 %

Procedure:
A solution of 2-(5,5-dimethyl-3-(3-nitropyridin-4-yl)cyclohex-2-enyl)isoindoline-1,3-dione (1 eq) in Acetic Acid (0.1 M) was purged with nitrogen for 10 min. Then 10% Pd/C (0.10 eq) was added. The reaction mixture was stirred at room temperature overnight an atmosphere of hydrogen. Solids were removed by filtration over celite, then rinsed with EtOAc and MeOH. The filtrate was concentrated, diluted with EtOAc and washed 2× with sat. aq. 2M Na2CO3. Organic layer was dried with MgSO4, filtered, and concentrated. The residue was purified by column (5% methanol in 1:1 ethyl acetate and hexanes) to give 2-(3-(3-aminopyridin-4-yl)-5,5-dimethylcyclohex-2-enyl)isoindoline-1,3-dione (89%). LC/MS (m/z): MH+=348.3, Rt=0.79 min.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:13](=[O:15])[CH3:14].[CH3:16][N:17]([CH3:28])[CH2:18][CH2:19][O:20][C:21]1[N:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1>>[Cl:12][C:9]1[N:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:13](=[O:15])[CH3:14])=[C:2]2[NH:27][C:24]1[CH:25]=[N:26][C:21]([O:20][CH2:19][CH2:18][N:17]([CH3:28])[CH3:16])=[CH:22][CH:23]=1
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1Cl
Reactant: CN(C)CCOc1ccc(N)cn1
Product: CC(=O)c1cnc2ccc(Cl)nc2c1Nc1ccc(OCCN(C)C)nc1
Yield: 43.8 %

Procedure:
Following general procedure I, 1-(4,6-dichloro-1,5-naphthyridin-3-yl)ethanone (170 mg, 0.71 mmol) was reacted with 6-[2-(dimethylamino)ethoxy]pyridin-3-amine (160 mg, 0.90 mmol) to afford the desired product (120 mg, 44%) as a light brown solid: 1H NMR (500 MHz, CDCl3) δ 11.63 (br s, 1H), 9.08 (s, 1H), 8.11 (d, J=8.8 Hz, 1H), 7.99 (d, J=2.7 Hz, 1H), 7.47 (d, J=8.7 Hz, 1H), 7.41 (dd, J=8.8, 2.8 Hz, 1H), 6.80 (d, J=8.7 Hz, 1H), 4.46 (t, J=5.6 Hz, 2H), 2.76 (t, J=5.6 Hz, 2H), 2.74 (s, 3H), 2.36 (s, 6H); ESI MS m/z 386 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:12]N1C(=O)CCC1=O>CN(C)C=O>[NH2:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([Br:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Nc1cc(F)ccc1C(=O)O
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: Nc1cc(F)c(Br)cc1C(=O)O
Temperature: -10 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
To a solution of 2-amino-4-fluorobenzoic acid (10 g, 64.5 mmol) in N,N-dimethylformamide (100 mL) at −10° C., was added dropwise a solution of N-bromosuccinimide (11.2 g, 62.9 mmol) in N,N-dimethylformamide (50 mL) over 1 hour. After the addition was complete, the mixture was stirred at −10° C. for 1 hour. The reaction was quenched with aqueous sodium bisulfate and partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with water and then with brine, and then dried over sodium sulfate. The sample was concentrated to give the crude product 27 (14.5 g, yield: 96.5%), which was used for the next step without further purification.
Reaction SMILES: Cl.[CH2:2]([C:4]1[CH:17]=[C:16]2[C:7]([C:8](=[O:18])[O:9][C:10]32[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)=[CH:6][CH:5]=1)[CH3:3].[C:19]1([C:25]2[N:26]=[CH:27][C:28]([NH:31][C:32](=O)[O:33]C3C=CC=CC=3)=[N:29][CH:30]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[OH-].[Na+]>CS(C)=O>[CH2:2]([C:4]1[CH:17]=[C:16]2[C:7]([C:8](=[O:18])[O:9][C:10]32[CH2:11][CH2:12][N:13]([C:32]([NH:31][C:28]2[CH:27]=[N:26][C:25]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)=[CH:30][N:29]=2)=[O:33])[CH2:14][CH2:15]3)=[CH:6][CH:5]=1)[CH3:3]
Reactant: O=C(Nc1cnc(-c2ccccc2)cn1)Oc1ccccc1
Reactant: CCc1ccc2c(c1)C1(CCNCC1)OC2=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCc1ccc2c(c1)C1(CCN(C(=O)Nc3cnc(-c4ccccc4)cn3)CC1)OC2=O
Reaction time: 0.08 h
Yield: 54.2 %

Procedure:
To a suspension of 6-ethylspiro[isobenzofuran-1(3H),4′-piperidine]-3-one hydrochloride (53 mg) and phenyl N-(5-phenyl-2-pyrazinyl)carbamate (58 mg) in dimethyl sulfoxide (1 mL) was added 10 M sodium hydroxide aqueous solution (0.02 mL). The mixture was vigorously stirred for 5 minutes followed by partition between water and ethyl acetate. The organic layer was separated and then washed with saturated saline solution and then dried over anhydrous Na2SO4 The concentration of the organic solvent left a residue, which was subjected to the crystallization from ethyl acetate to give the subject compound (46 mg) as crystals (melting point 176-178° C.).
Reaction SMILES: [CH2:1]([CH:5]1[S:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[NH:7][C:6]1=[O:15])[CH2:2][CH2:3][CH3:4].[H-].[Na+].Br[CH2:19][C:20]([O:22]CC)=[O:21]>CN(C=O)C.O>[CH2:1]([CH:5]1[S:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]([CH2:19][C:20]([OH:22])=[O:21])[C:6]1=[O:15])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1Sc2ccccc2NC1=O
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCC1Sc2ccccc2N(CC(=O)O)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-butyl-2H-benzo[b][1,4]thiazin-3(4H)-one (6.3 mmol, 1400 mg) in DMF (5 ml) was added NaH (6.9 mmol, 167 mg) and the reaction mixture was stirred at room temperature for 1 h before the dropwise addition of ethyl bromoacetate (6.3 mmol, 1052 mg). The reaction mixture was stirred at room temperature overnight, diluted with water and extracted with ethyl acetate. The organic layer was washed with 1N HCl, Sat. NaHCO3, dried over Na2SO4 and evaporated to dryness. The crude compound was dissolved in MeOH (10 ml) and 1 N NaOH (10 ml) and stirred at room temperature for 2 h. The MeOH was removed under reduced pressure and the resulting aqueous solution extracted with EtOAc. The aqueous layer was acidified to pH 2 with 1N HCl and extracted with EtOAc. The organic phase was dried over Na2SO4 and the solvent was evaporated to give the title compound. LC/MS (10% to 99%): M/Z (M+H)+ (obs)=280.2; tR=3.01.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:27]#[C:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22][CH2:21]1)[C:11]([CH:13]1[CH2:18][CH2:17][C:16]([CH3:19])=[CH:15][CH2:14]1)=[O:12])=[O:4].[CH3:33][N:34]([CH2:36][C:37]1[CH:42]=[CH:41][N:40]=[C:39](F)[CH:38]=1)[CH3:35].[H-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C.O>[CH3:33][N:34]([CH2:36][C:37]1[CH:42]=[CH:41][N:40]=[C:39]([O:26][C@H:23]2[CH2:24][CH2:25][C@H:20]([N:10]([C:11]([CH:13]3[CH2:18][CH2:17][C:16]([CH3:19])=[CH:15][CH2:14]3)=[O:12])[C:9]3[CH:8]=[C:7]([C:27]#[C:28][C:29]([CH3:30])([CH3:31])[CH3:32])[S:6][C:5]=3[C:3]([OH:2])=[O:4])[CH2:21][CH2:22]2)[CH:38]=1)[CH3:35]
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)C1CC=C(C)CC1)[C@H]1CC[C@H](O)CC1
Reactant: CN(C)Cc1ccnc(F)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1=CCC(C(=O)N(c2cc(C#CC(C)(C)C)sc2C(=O)O)[C@H]2CC[C@H](Oc3cc(CN(C)C)ccn3)CC2)CC1
Temperature: 90 °C

Procedure:
5-(3,3-Dimethyl-but-1-ynyl)-3-[(4-hydroxy-trans-cyclohexyl)-(4-methyl-cyclohex-3-enecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (40 mg, 0.088 mmol) and (N,N-dimethyl)-(2-fluoro-pyridin-4-ylmethyl)amine (84 mg, 0.55 mmol) in DMF (1 mL) were treated with sodium hydride (22 mg, 60% oil dispersion, 0.55 mmol). After the bubbling slowed, the reaction mixture was sealed and heated by microwave (90° C.) for 70 min. The reaction mixture was treated with 10% citric acid (2-3 mL) followed by water (2-3 mL). The organics were extracted twice with ethyl acetate, dried over sodium sulfate, filtered and concentrated. The residue was purified by reverse phase HPLC to give the Compound 337, 18 mg (35% yield): MS (m/z): 578.0 [M+H]+; HPLC retention time 3.53 min (2-98% acetonitrile:water with 0.05% trifluoroacetic acid).
Reaction SMILES: BrCC[C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[NH:10][C:8](=[O:9])[C:7]2=[CH:13][CH:14]=1.[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>C(OCC)C>[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH:17]1[CH2:5][CH2:4][CH2:14][CH2:13][C:5]1[CH:4]=[CH:14][CH:13]=[C:7]2[C:8]([NH:10][C:11](=[O:12])[C:6]=12)=[O:9]
Reactant: CN1CCNCC1
Reactant: O=C1NC(=O)c2cc(CCBr)ccc21
Solvent: CCOCC
Product: CN1CCNCC1CCCCc1cccc2c1C(=O)NC2=O

Procedure:
4-Bromoethylphthalimide (564 mg; 2.0 mmoles) and N-methylpiperazine (0.44 ml; 4.0 mmoles) were dissolved in anhydrous ethyl ether (5 ml). Reaction times and process as per Example 1.
Reaction SMILES: [CH2:1]1[CH2:10][O:9][CH:8]2[CH:3]([CH2:4][C:5]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)([C:11]#N)[CH2:6][CH2:7]2)[O:2]1.CC(C[AlH]CC(C)C)C.Cl.C(=O)(O)[O-:30].[Na+]>C1(C)C=CC=CC=1>[CH2:1]1[CH2:10][O:9][C:3]2([CH2:8][CH2:7][CH2:6][C:5]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)([CH:11]=[O:30])[CH2:4]2)[O:2]1
Reactant: N#CC1(c2ccccc2)CCC2OCCOC2C1
Reactant: O=C([O-])O
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=CC1(c2ccccc2)CCCC2(C1)OCCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
At −78° C., 3-ethylenedioxy-1-phenylcyclohexanecarbonitrile (1.66 g, 6.83 mmol) in toluene (20 mL) was added DIBAL-H (1.0 M solution in toluene, 8.88 mL) slowly and was stirred for 1 hr. The reaction mixture was warmed up to room temperature and was added 1N HCl solution (2.60 mL) and was stirred for 1 hr. Saturated sodium bicarbonate was added to quench the reaction and the organic layer was separated. The aqueous layer was extracted with dichloromethane 3 times and the combined organic layers were dried over magnesium sulfate, filtered and concentrated under vacuum. The crude material was purified by filtering through a short silica gel pad with dichloromethane to give the title compound as a white sticky oil (1.43 g, 85% yield). 1H NMR (400 MHz, CDCl3) δ 1.32-1.40 (1H, m), 1.46-1.54 (1H, m), 1.72-1.86 (3H, m), 2.08 (1H, d, J=16 Hz), 2.59-2.67 (2H, m), 3.94-4.07 (4H, m), 7.15-7.36 (5H, m), 9.36 (1H, d, J=4 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=[O:5].[Br:12]Br>CO>[NH2:1][C:2]1[C:3]([C:4]([OH:6])=[O:5])=[C:7]([F:11])[C:8]([Br:12])=[CH:9][CH:10]=1
Reactant: BrBr
Reactant: Nc1cccc(F)c1C(=O)O
Solvent: CO
Product: Nc1ccc(Br)c(F)c1C(=O)O
Temperature: -78 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
To a solution of 2-amino-6-fluorobenzoic acid (12.0 g, 77.35 mmol) in methanol (150 mL) was added bromine (15.7 mL) at −78° C., and the mixture was stirred 2 hours at −78° C. The reaction mixture was quenched with ice-water (100 mL) and aqueous solution of sodium sulfothioate, and extracted with ethyl acetate (150 mL×3). The organic layers were separated, combined, washed with water (100 mL) and brine (100 mL), dried over sodium sulfate, filtered and concentrated to afford the title crude product (9.0 g, 50%). MS (ES+) C7H5BrFNO2 requires: 232, found: 233, 235 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[I:9]I>C(O)C.S([O-])([O-])(=O)=O.[Ag+2]>[Cl:8][C:5]1[CH:6]=[C:7]([I:9])[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: II
Reactant: Nc1ccc(Cl)cn1
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: Nc1ncc(Cl)cc1I
Reaction time: 72 h

Procedure:
Silver sulfate (3.40 g, 10.9 mmol) and 2-amino-5-chloropyridine (1 g, 7.8 mmol) was added to a solution of iodine (2.76 g, 10.9 mmol) in ethanol (50 ml) and the reaction mixture stiffed at rt for 72 h. The mixture was filtered, washed with methanol and the filtrate concentrated in vacuo. The residue was partitioned between saturated Na2S2O3 solution (50 ml) and DCM (2×50 ml). The combined organics were dried (MgSO4), concentrated in vacuo and purified by chromatography on silica gel eluting with DCM to give the title compound as a beige solid. δH (CDCl3): 4.95 (2H, br s), 7.84 (1H, d), 7.98 (1H, d).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11].Cl[CH2:13][C:14]([OH:16])=[O:15].[OH-].[K+].Cl>O>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][CH2:13][C:14]([OH:16])=[O:15])=[C:3]([O:10][CH3:11])[CH:4]=1)=[O:7]
Reactant: COc1cc(C=O)ccc1O
Reactant: O=C(O)CCl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1cc(C=O)ccc1OCC(=O)O
Yield: 57 %

Procedure:
A solution of 30.4 g of 4-hydroxy-3-methoxybenzaldehyde, 31.2 g of chloroacetic acid and 34 g of potassium hydroxide in 300 ml of water was refluxed for 7 hours. After cooling, hydrochloric acid was added and the precipitate was filtered off and dried. Yield 57%.
Reaction SMILES: F[C:2]1[N:26]=[CH:25][CH:24]=[CH:23][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH3:22])([CH:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)[CH3:14])=[CH:9][CH:8]=1)=[O:5].[F:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH2:33])=[CH:30][CH:29]=1.C([O-])(O)=O.[Na+]>N1C=CC=CC=1>[F:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH:33][C:2]2[N:26]=[CH:25][CH:24]=[CH:23][C:3]=2[C:4]([NH:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]([CH3:22])([CH:15]3[CH2:16][CH2:17][N:18]([CH3:21])[CH2:19][CH2:20]3)[CH3:14])=[CH:9][CH:8]=2)=[O:5])=[CH:30][CH:29]=1
Reactant: CN1CCC(C(C)(C)c2ccc(NC(=O)c3cccnc3F)cc2)CC1
Reactant: NCc1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CN1CCC(C(C)(C)c2ccc(NC(=O)c3cccnc3NCc3ccc(F)cc3)cc2)CC1
Temperature: 105 °C

Procedure:
A solution of 2-fluoro-N-{4-[1-methyl-1-(1-methyl-piperidin-4-yl)-ethyl]-phenyl}-nicotinamide (355 mg) and 4-fluorobenzylamine (250 mg) in pyridine (10 mL) was suspended with NaHCO3 (1 g). The mixture was heated to 105° C. overnight. Solids were removed by filtration and the filtrate was concentrated in vacuo. The residue was purified on prep. TLC plates (silica, EtOAc:TEA=10:1) to provide the desired product. MS (ES+): 461 (M+1)+, Calc'd for C28H33FN4O-460.59.
Reaction SMILES: [OH-].[Na+].[CH3:3][S:4]([NH:7][C:8]1[CH:9]=[C:10]([OH:21])[CH:11]=[CH:12][C:13]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:6])=[O:5].Cl[CH2:23][CH2:24][C:25]([OH:27])=[O:26].Cl>O.C(OCC)(=O)C>[CH3:3][S:4]([NH:7][C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][C:13]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[O:21][CH2:23][CH2:24][C:25]([OH:27])=[O:26])(=[O:6])=[O:5]
Reactant: CS(=O)(=O)Nc1cc(O)ccc1Oc1ccccc1
Reactant: O=C(O)CCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Nc1cc(OCCC(=O)O)ccc1Oc1ccccc1
Yield: 23.1 %

Procedure:
4 g of sodium hydroxide was dissolved in 250 ml of water. Therein was dissolved 27.9 g of 3-methylsulfonylamino-4-phenoxyphenol. Thereto was added an aqueous solution obtained by dissolving 10.9 g of 3-chloropropionic acid and 4 g of sodium hydroxide in 30 ml of water. The mixture was refluxed for 30 minutes. The reaction mixture was water-cooled and adjusted to pH 8 with 4N hydrochloric acid. 70 ml of ethyl acetate was added thereto. The aqueous layer was separated, adjusted to pH 4 with 4N hydrochloric acid and extracted with 100 ml of ethyl acetate. The resulting extracts were washed with water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was mixed with diethyl ether. The resulting solid was collected by filtration to obtain 8.1 g (yield: 23.1%) of 3-(3-methylsulfonylamino-4-phenoxyphenoxy)propionic acid having a melting point of 145°-149° C.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5])[CH3:3].C(N(CC)CC)C.[CH2:21]([O:23][C:24](=[O:35])[C:25](=O)[CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH3:22].Cl>C(O)C.[Ni]>[CH2:21]([O:23][C:24]([C@@H:25]([NH:1][C@H:2]([C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5])[CH3:3])[CH2:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:35])[CH3:22]
Reactant: CCOC(=O)C(=O)CCc1ccccc1
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)O
Agent: [Ni]
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 2 h

Procedure:
50 mmoles (9.3 g) Ala-Pro were suspended in 100 ml ethanol, mixed with 10 moles (1 g) triethylamine, 75 mmoles (15.5 g) 2-oxo-4-phenyl-butyric acid ethyl ester and 18 g molecular sieve 3 A and agitated for 2 hours under anhydrous conditions. One teaspoon of dehydrated Raney nickel and 15 g molecular sieve 3 A were now added, briefly reacted and subsequently hydrogenated for 22 hours under an atmosphere of 4 bars of H2. The reaction mixture was filtered and evaporated to concentrate it to a small volume. Conversion (according to HPLC) relative to Ala-Pro used: 95.6%, product yield (according to HPLC): 95%. The residue was taken up in 250 ml ethanol and adjusted to pH 4.25 with conc. HCl (an aliquot was removed for this purpose, diluted with water and the pH adjusted, then the entire amount of HCl required was calculated). The solution was evaporated to low bulk under reduced pressure at 40° C. to 50 g, filtered with Celite and diluted to 100 ml total volume with ethyl acetate. 5.2 g maleic acid dissolved in ethyl acetate+ethanol were added and the mixture was seeded with enalapril maleate. The crystallizate formed was separated off and dried.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH2:11][CH3:12])(=[O:10])=[O:9])=[N:6][CH:7]=1.[N:13]1([CH2:18][C@@H:19]2[CH2:23][CH2:22][CH2:21][N:20]2[C:24]([C:26]2[CH:31]=[CH:30][C:29](B3OC(C)(C)C(C)(C)O3)=[CH:28][CH:27]=2)=[O:25])[CH2:17][CH2:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:11]([S:8]([C:5]1[N:6]=[CH:7][C:2]([C:29]2[CH:30]=[CH:31][C:26]([C:24]([N:20]3[CH2:21][CH2:22][CH2:23][C@H:19]3[CH2:18][N:13]3[CH2:14][CH2:15][CH2:16][CH2:17]3)=[O:25])=[CH:27][CH:28]=2)=[CH:3][CH:4]=1)(=[O:10])=[O:9])[CH3:12]
Reactant: CC1(C)OB(c2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)cc2)OC1(C)C
Reactant: CCS(=O)(=O)c1ccc(Cl)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCS(=O)(=O)c1ccc(-c2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)cc2)cn1

Procedure:
Procedure KK: Place 5-Chloro-2-ethanesulfonyl-pyridine (1.0 mmol), (2-(S)-Pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanone (1.1 mmol), ethanol (0.10M), potassium carbonate (3.0 mmol) and dihydrogen di-μ-chlorotetrakis(di-tert-butylphosphino-kP)dipalladate (2-) (0.01 mmol, also known as POPd1) in a microwave reactor vessel with a stir bar. Run the reaction in a CEM microwave reactor for 1 hour at 90° C. and 65 W power with cooling. After this time, concentrate the reaction in vacuo. Purify the title compound via radial chromatography eluting with 2M ammonia and dichloromethane. MS (m/e): 428.2 (M+1)
Reaction SMILES: [C:1]([N:11](C(OCC1C=CC=CC=1)=O)[CH2:12][CH2:13][NH2:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[ClH:25]>C(O)(=O)C>[ClH:25].[C:1]([NH:11][CH2:12][CH2:13][NH2:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: NCCN(C(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: Cl
Solvent: CC(=O)O
Product: NCCNC(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
N,N-Bis-Carbobenzyloxyethylenediamine 11 (23.91 g, 72.8 mmol) in glacial acetic acid (100 mL) was treated with 12M HCl (12.1 mL, 2 equiv). The stirred mixture was heated at reflux for 1 h and then left to stand at rt overnight. A small amount of solid was removed by filtration and the filtrate was diluted with ether (700 mL) and left to stand at rt for 2 h. The resulting white solid product was collected by filtration, washed repeatedly with ether, and dried in a vacuum dessicator overnight (9.2440 g, 55%). 1H-NMR (DMSO-d6) δ 2.87 (t, 2H), 3.30 (q, 2H), 5.04 (s, 2H), 7.33 (m, 5H), 7.49 (brt, 1H), 8.22 (br, 3H).