Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:12]2[CH2:28][CH2:27][C:15]3([O:20][CH2:19][C:18](=[O:21])[N:17]([C:22]4([CH2:25][OH:26])[CH2:24][CH2:23]4)[CH2:16]3)[CH2:14][CH2:13]2)[C:9]([NH2:11])=[O:10])=[C:4]([F:29])[CH:3]=1.CC1(C)C(C)(C)OB([C:38]2[CH:47]=[C:46]3[C:41]([CH:42]=[CH:43][CH:44]=[N:45]3)=[CH:40][CH:39]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[F:29][C:4]1[CH:3]=[C:2]([C:38]2[CH:47]=[C:46]3[C:41]([CH:42]=[CH:43][CH:44]=[N:45]3)=[CH:40][CH:39]=2)[CH:7]=[CH:6][C:5]=1[CH:8]([N:12]1[CH2:28][CH2:27][C:15]2([O:20][CH2:19][C:18](=[O:21])[N:17]([C:22]3([CH2:25][OH:26])[CH2:24][CH2:23]3)[CH2:16]2)[CH2:14][CH2:13]1)[C:9]([NH2:11])=[O:10]
Reactant: CC1(C)OB(c2ccc3cccnc3c2)OC1(C)C
Reactant: NC(=O)C(c1ccc(Br)cc1F)N1CCC2(CC1)CN(C1(CO)CC1)C(=O)CO2
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: NC(=O)C(c1ccc(-c2ccc3cccnc3c2)cc1F)N1CCC2(CC1)CN(C1(CO)CC1)C(=O)CO2
Yield: 16 %

Procedure:
A solution of crude (85% purity) 2-(4-bromo-2-fluorophenyl)-2-(4-(1-(hydroxymethyl)cyclopropyl)-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)acetamide (0.488 mmol) in 1,4-dioxane (2 mL) was treated with 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (0.537 mmol), PdCl2(dppf)-CH2Cl2 adduct (0.024 mmol), and 2M aq potassium carbonate (1.464 mmol). The reaction vessel was purged with nitrogen and sealed, and the mixture irradiated in a Biotage Initiator Microwave at 120° C. for 15 min. Additional portions of 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (0.117 mmol) and PdCl2(dppf)-CH2Cl2 adduct (0.012 mmol) were added. The reaction vessel was purged with nitrogen and sealed, and the mixture irradiated in a Biotage Initiator Microwave at 120° C. for 5 min. The resulting black mixture was diluted with water (50 mL) and brine (20 mL) and was extracted with ethyl acetate three times. The combined organic layers were treated with Silicycle Si-thiol (20 mg), dried over sodium sulfate, filtered and concentrated in vacuo. The resulting solid was purified by reverse phase HPLC (20-60% acetonitrile/water with 0.1% NH4OH). Fractions containing the desired product were selected, combined and concentrated to dryness in vacuo. Further purification by chiral HPLC (Chromegachiral CC4, methanol) followed by lyophilization from water (w/25% acetonitrile) afforded the title compound as a white solid in >98% ee (43 mg, 16% yield). MS(ES)+ m/e 519.3 [M+H]+. αD=+47 deg (c=0.05, methanol).
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6][C@@H:7]([CH2:9][CH2:10]O)[CH3:8])[CH3:3].N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:36]I>C1COCC1.CCCCCC>[I:36][CH2:10][CH2:9][C@@H:7]([CH3:8])[CH2:6][CH2:5][CH:4]=[C:2]([CH3:3])[CH3:1]
Reactant: CC(C)=CCC[C@H](C)CCO
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)=CCC[C@H](C)CCI
Reaction time: 1 h
Yield: 79.1 %

Procedure:
A solution of 3.12 g (20.0 mmol) of (S)-(-)-β-citronellol (purchased from Aldrich Chem. Co.) and 2.72 g (40.0 mmol) of imidazole in 50 mL of THF at 0° C. was treated with 5.0 g (19.5 mmol) of triphenylphosphine followed by 4.83 g (19.0 mmol) of I2 in 25 mL of THF dropwise over 20 minutes. The reaction mixture was stirred for 1.0 hour and was diluted with hexane. The organic mixture was washed with aqueous Na2SO3, brine, dried (Na2SO4) and evaporated to provide a crude white slurry. The slurry was purified by flash chromatography (300 g of silica gel) eluting with hexane to provide 4.00 g (79%) of title iodide as a colorless oil.
Reaction SMILES: [CH3:1][CH2:2][C@:3]12[CH2:19][C@:18]([OH:24])([C:20]([O:22][CH3:23])=[O:21])[N:17]3[C:9]4=[C:10]([CH2:25][CH2:26][N:7]([C@@H:8]14)[CH2:6][CH2:5][CH2:4]2)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=13.[CH3:27][O:28][S:29]([O:32]C)(=[O:31])=[O:30]>CC(C)=O>[CH3:1][CH2:2][C@:3]12[CH2:19][C@:18]([OH:24])([C:20]([O:22][CH3:23])=[O:21])[N:17]3[C:9]4=[C:10]([CH2:25][CH2:26][N:7]([C@@H:8]14)[CH2:6][CH2:5][CH2:4]2)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=13.[CH3:27][O:28][S:29]([O-:32])(=[O:31])=[O:30]
Reactant: COS(=O)(=O)OC
Agent: CC[C@]12CCCN3CCc4c(n(c5ccccc45)[C@@](O)(C(=O)OC)C1)[C@@H]32
Solvent: CC(C)=O
Product: COS(=O)(=O)[O-]
Reaction time: 6 h

Procedure:
7.08 g (2.10-2 moles) of vincamine are dissolved in 900 mls of boiling anhydrous acetone. Under stirring, 1.8 mls of dimethylsulfate are added and the resulting mixture is maintained under boiling for 6 hours. The mixture is concentrated to 400 mls and maintained on standing for a night. The mixture is filtered, washed onto the filter with ether and dried in a vacuum furnace at 50° C. There are obtained 7 g of a product having melting point of 191° C., soluble in water and alcohol.
Reaction SMILES: [C:1]1([C:11]2[CH:20]=[C:14]3[NH:15][CH:16]=[CH:17][C:18](=O)[N:13]3[N:12]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:18]1[N:13]2[N:12]=[C:11]([C:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:3][CH:2]=3)[CH:20]=[C:14]2[N:15]=[CH:16][CH:17]=1
Reactant: O=c1cc[nH]c2cc(-c3cccc4ccccc34)nn12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ccnc2cc(-c3cccc4ccccc34)nn12
Temperature: 25 °C
Reaction time: 5 h
Yield: 100 %

Procedure:
2-(naphthalen-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (4.0 g, 15 mmol) is heated in phosphoryl chloride (28 mL) in a sealed vial at 105° C. and stirred for 5 hours. The crude reaction mixture is cooled to room temperature and poured slowly over ice. The resulting solid is collected on a Buchner funnel to provide 7-chloro-2-(1-naphthyl)pyrazolo[1,5-a]pyrimidine (4.3 g, yield 100%). LCMS: (AA) M+1 280.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[S:9][CH:10]=[C:11]([C:13]([NH:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][C:21]=2[N:22]2[CH2:27][CH2:26][CH2:25][C@H:24]([NH:28]C(=O)OC(C)(C)C)[CH2:23]2)=[O:14])[N:12]=1.Cl>O1CCOCC1>[NH2:28][C@H:24]1[CH2:25][CH2:26][CH2:27][N:22]([C:21]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[NH:15][C:13]([C:11]2[N:12]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[S:9][CH:10]=2)=[O:14])[CH2:23]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccncc2NC(=O)c2csc(-c3ccccc3F)n2)C1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@H]1CCCN(c2ccncc2NC(=O)c2csc(-c3ccccc3F)n2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (S)-tert-butyl 1-(3-(2-(2-fluorophenyl)thiazole-4-carboxamido)pyridin-4-yl)piperidin-3-ylcarbamate (100 mg, 0.2 mmol) in 1,4-Dioxane (6 mL) was added 4.0 M of Hydrogen chloride in 1,4-Dioxane (3 mL). The resulting mixture was stirred at room temperature overnight. The mixture was concentrated and the residue was purified by reverse phase HPLC. (10.7 mg, 10.0%). 1H NMR (400 MHz, DMSO) δ 9.24 (s, 1H), 8.68 (s, 1H), 8.40 (t, J=7.1, 1H), 8.32-8.26 (m, 2H), 7.67-7.61 (m, 1H), 7.53-7.43 (m, 2H), 7.16 (d, J=5.3, 1H), 3.04 (s, 2H), 2.75 (t, J=9.5, 1H), 2.61-2.54 (m, 1H), 1.92-1.86 (m, 1H), 1.81 (d, J=4.2, 1H), 1.73 (d, J=9.9, 1H), 1.33-1.23 (m, 1H); ESIMS m/z=398.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:11]([NH:12][C@@H:13]2[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]2)=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:19]2[NH:27][C:26]3[CH2:25][CH2:24][NH:23][C:22](=[O:28])[C:21]=3[CH:20]=2)[N:3]=1.[CH3:29][C:30](OC(C)=O)=[O:31].C(Cl)Cl.C([O-])(O)=O.[Na+]>CO.C(Cl)Cl>[C:30]([N:15]1[CH2:16][CH2:17][CH2:18][C@@H:13]([NH:12][C:11]2[C:2]([CH3:1])=[N:3][C:4]3[C:9]([N:10]=2)=[C:8]([C:19]2[NH:27][C:26]4[CH2:25][CH2:24][NH:23][C:22](=[O:28])[C:21]=4[CH:20]=2)[CH:7]=[CH:6][CH:5]=3)[CH2:14]1)(=[O:31])[CH3:29]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1N[C@@H]1CCCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(=O)N1CCC[C@@H](Nc2nc3c(-c4cc5c([nH]4)CCNC5=O)cccc3nc2C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
Prepared according to Example 50, using TEA (39.9 μl, 0.287 mmol), 2-(2-methyl-3-((3R)-3-piperidinylamino)-5-quinoxalinyl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (Ex. 75, 90 mg, 0.239 mmol), Ac2O (45.1 μl, 0.478 mmol), and DCM (2.4 mL) and stirring at 25° C. for 1 h. Isolation of the free base from the mixture by addition of saturated aq. NaHCO3 and extraction with 10% MeOH/DCM, followed by drying of the organic extract over Na2SO4, filtration, and concentration under reduced pressure afforded 2-(3-(((3R)-1-acetyl-3-piperidinyl)amino)-2-methyl-5-quinoxalinyl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (34 mg, 30%). 1H NMR (DMSO-d6) δ: 7.85-7.91 (m, 1H), 7.77-7.83 (m, 1H), 7.54-7.63 (m, 2H), 7.30-7.40 (m, 2H), 7.05-7.11 (m, 1H), 4.45-4.55 (m, 1H), 4.27-4.39 (m, 1H), 4.13-4.27 (m, 1H), 3.96-4.10 (m, 1H), 3.86-3.95 (m, 1H), 3.76-3.86 (m, 1H), 3.39-3.46 (m, 3H), 2.87-2.97 (m, 1H), 2.07 (s, 3H), 1.59 (s, 3H), 1.10-1.22 (m, 3H). m/z (ESI, +ve) 419.1 (M+H)+.
Reaction SMILES: NC1C=CC=CC=1NC(=O)C1C=CC(CNC2N=C(C3C=CC(OCCN(C)C)=CC=3)C=CN=2)=CC=1.NC1C=CC=CC=1NC(C1C=CC2N=C(C3C=CC(OC(F)(F)F)=CC=3)SC=2C=1)=O.C(OC(=O)[NH:73][C:74]1[CH:79]=[CH:78][CH:77]=[CH:76][C:75]=1[NH:80][C:81](=[O:96])[C:82]1[CH:87]=[CH:86][C:85]([CH:88]=[C:89]2[S:93][C:92](=[O:94])[NH:91][C:90]2=[O:95])=[CH:84][CH:83]=1)(C)(C)C>>[NH2:73][C:74]1[CH:79]=[CH:78][CH:77]=[CH:76][C:75]=1[NH:80][C:81](=[O:96])[C:82]1[CH:83]=[CH:84][C:85]([CH:88]=[C:89]2[S:93][C:92](=[O:94])[NH:91][C:90]2=[O:95])=[CH:86][CH:87]=1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C=C2SC(=O)NC2=O)cc1
Agent: CN(C)CCOc1ccc(-c2ccnc(NCc3ccc(C(=O)Nc4ccccc4N)cc3)n2)cc1
Agent: Nc1ccccc1NC(=O)c1ccc2nc(-c3ccc(OC(F)(F)F)cc3)sc2c1
Product: Nc1ccccc1NC(=O)c1ccc(C=C2SC(=O)NC2=O)cc1
Yield: 37 %

Procedure:
Following the procedure described for the synthesis of compound 117 (scheme 28) but substituting the amide 116 by the amide 348, title compound was obtained in 37% yield. 1H NMR: (400 MHz, DMSO-d6, δ (Ppm): 9.72 (s, 1H), 8.06 (d, j=8.2 Hz, 2H), 7.79 (s, 1H), 7.69 (d, J=8.4, 2H), 7.14 (d (dd) J=7.8, 1H), 6.95 (d (dd), J=1.6 Hz, J=9.0, 1H), 6.75 (dd, J=1.2 Hz, J=8.0 Hz, 1H), 6.56 (t (dd), J=7.2 Hz 1H). LRMS: 339.4 (calcd.), 340.4 [MH]+ (found).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([C@@H:13]([OH:28])[CH2:14][C@H:15]([CH2:19][O:20]CC2C=CC=CC=2)[CH:16]([CH3:18])[CH3:17])[CH2:11][C@@H:10]([CH:29]([CH3:31])[CH3:30])[C@@H:9]1[C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[C:34]([O:40][CH2:41][CH2:42][CH2:43][O:44][CH3:45])[CH:33]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Na].[Cl-].[NH4+].C1(C)C=CC=CC=1>O1CCCC1.N.O.C(O)(=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:12]([CH2:11][C@H:10]([CH2:9][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[C:34]([O:40][CH2:41][CH2:42][CH2:43][O:44][CH3:45])[CH:33]=1)[CH:29]([CH3:31])[CH3:30])[C@@H:13]([OH:28])[CH2:14][C@H:15]([CH2:19][OH:20])[CH:16]([CH3:17])[CH3:18])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCCOc1cc([C@H]2[C@H](C(C)C)C[C@@H]([C@@H](O)C[C@H](COCc3ccccc3)C(C)C)N2C(=O)OC(C)(C)C)ccc1OC
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)C[C@H](CO)C(C)C)C(C)C)ccc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.4 %

Procedure:
A solution of 1.0 g of the pyrrolidine 8 in 2.5 mL of tetrahydrofuran is added to a mixture of 0.37 g of sodium in 5 mL of ammonia and 2.5 mL of tetrahydrofuran at −50° C. The mixture is stirred for 3 h then 2.56 g of ammonium chloride is added and the mixture allowed to warm to r.t. To the mixture is then added 40 mL of toluene, 1.9 g of acetic acid and 25 mL of water. The phases are separated and the aqueous phase is back-extracted with 25 mL of toluene. The combined organic phases are then washed with 4×120 mL of 1:1 water-brine, dried over sodium sulfate and the solvent removed in vacuum, affording e.g. 0.76 g of the product 9a as an oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[NH:7][CH:8]([C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29](=[O:40])[NH:30][O:31]C(=O)C3C=CC=CC=3)=[CH:23][CH:22]=2)=[CH:16][CH:15]=1)[C:9](=[O:13])[N:10]([CH3:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6](=[O:41])[NH:7][CH:8]([C:9](=[O:13])[N:10]([CH3:12])[CH3:11])[C:14]1[CH:15]=[CH:16][C:17]([O:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29](=[O:40])[NH:30][OH:31])=[CH:23][CH:22]=2)=[CH:18][CH:19]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: [H][H]
Reactant: CN(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Oc2ccc(CCC(=O)NOC(=O)c3ccccc3)cc2)cc1
Agent: [Pd]
Solvent: CO
Product: CN(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Oc2ccc(CCC(=O)NO)cc2)cc1
Yield: 90 %

Procedure:
Palladium (5% on BaSO4, 2.0 g) was added to a degassed solution of the benzyl hydroxamate 34 (1.5 g) in MeOH (100 mL) and the suspension was treated with hydrogen at atmospheric pressure for 6 h. The suspension was filtered over a Celite® bed and concentrated to yield the desired hydroxamate 35 (1.1 g, 90%). 1H NMR (400 MHz, DMSO-d6): 10.42 (s, 1H), 7.33 (d, J=8.4 Hz, 2H), 7.22 (d, J=8.4 Hz, 2H), 7.12 (d, J=8.4 Hz, 1H), 6.93 (overlapped d, J=8.8 Hz, 2H), 6.92 (overlapped d, J=8.4 Hz, 2H), 5.50 (d, J=8.0 Hz, 1H), 2.90 (s, 3H), 2.84 (s, 3H), 2.80 (t, J=8.0 Hz, 2H), 2.25 (t, J=7.6 Hz, 2H), 1.37 (s, 9H).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[C:19]([C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1)#[N:20]>>[C:19]([C:21]1[CH:26]=[C:25]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)[CH:24]=[CH:23][CH:22]=1)#[N:20]
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCCNC1=O
Product: N#Cc1cccc(-c2cc(C#N)cc3cc4n(c23)CCCNC4=O)c1

Procedure:
The title compound, light grey solid (78 mg, 96%), MS (ISP) m/z=327.5 [(M+H)+], mp 225.5° C., was prepared in accordance with the general method of example 1 from 7-bromo-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 20) (76.0 mg, 0.25 mmol) and commercially available 3-cyanophenylboronic acid (47.8 mg, 0.325 mmol).
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:20])[CH3:19])[CH:14]=[CH:15][CH:16]=2)=[N:8][CH:9]=1)([O-])=O.[H][H]>CO.ClCCl.[Pd]>[NH2:1][C:4]1[C:5]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:20])[CH3:19])[CH:14]=[CH:15][CH:16]=2)=[N:8][CH:9]=1
Reactant: CC(=O)Nc1cccc(Oc2cc(Nc3ccccc3)c([N+](=O)[O-])cn2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: CC(=O)Nc1cccc(Oc2cc(Nc3ccccc3)c(N)cn2)c1

Procedure:
The product of Step 5 (37.7 g, 103.5 mmol) in MeOH (350 mL) and dichloromethane (350 mL) was hydrogenated for overnight with a balloon of hydrogen gas in the presence of 10% palladium on carbon (3.5 g). After filtration of the catalyst through a pad of Celite, the filtrate was concentrated in vacuo to afford the title compound as a crude foam (˜35 g, quantitative). 1H NMR (400 MHz, MeOD) δ ppm 7.56 (s, 1H), 7.39-7.40 (m, 1H), 7.19-7.34 (m, 5H), 7.07-7.11 (m, 1H), 6.73 (dt, 1H, 1.8 Hz, 7.1 Hz), 6.48 (s, 1H), 3.32-3.34 (m, 3H), 2.12 (s, 3H). MS (ES+) m/e 335 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:43])[C@@H:4]([NH:20][C:21](=[O:42])[C:22]1[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=1[NH:29][S:30]([C:33]1[C:38]2=[N:39][S:40][N:41]=[C:37]2[CH:36]=[CH:35][CH:34]=1)(=[O:32])=[O:31])[CH:5]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1.[Li+].[OH-]>Cl.C1COCC1>[N:41]1[S:40][N:39]=[C:38]2[C:33]([S:30]([NH:29][C:23]3[CH:24]=[C:25]([I:28])[CH:26]=[CH:27][C:22]=3[C:21]([NH:20][C@@H:4]([CH:5]([C:6]3[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=3)[C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[C:3]([OH:43])=[O:2])=[O:42])(=[O:31])=[O:32])=[CH:34][CH:35]=[CH:36][C:37]=12
Reactant: COC(=O)[C@@H](NC(=O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nsnc12)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(N[C@H](C(=O)O)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1)c1ccc(I)cc1NS(=O)(=O)c1cccc2nsnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.7 %

Procedure:
A mixture of (S)-2-[2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3,3-bis-(4-chloro-phenyl)-propionic acid methyl ester (49 mg, 0.064 mmol), THF (2 mL), and LiOH (1 M in water, 1 mL) was stirred vigorously overnight at rt. The mixture was acidified with conc. HCl (4 drops), diluted with THF to 3.5 mL, and purified by preparative reverse phase HPLC to provide 37 mg (77%) of the acid as a white solid. HPLC: RT=10.62 min. MS (ESI−): mass calcd. for C28H19Cl2IN4O5S2, 753.42; m/z found, 751/753 [M−H]−. 1H NMR (500 MHz, MeOD): 8.32 (dd, J=7.1, 0.9, 1H), 8.24 (dd, J=8.8, 0.8, 1H), 7.95 (d, J=1.5, 1H), 7.76 (dd, J=8.8, 7.1, 1H), 7.38-7.21 (m, 9H), 6.72 (d, J=8.3, 1H), 5.37 (d, J=11.5, 1H), 4.50 (d, J=11.5, 1H).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([CH3:8])=[C:6]([CH:9]=[O:10])[N:5]=[CH:4]1)[CH3:2].[BH4-].[Na+].O>CO>[CH2:1]([N:3]1[C:7]([CH3:8])=[C:6]([CH2:9][OH:10])[N:5]=[CH:4]1)[CH3:2]
Reactant: CCn1cnc(C=O)c1C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCn1cnc(CO)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 49 %

Procedure:
To a 0° C. solution of 1-ethyl-5-methyl-1H-imidazole-4-carbaldehyde (700 mg, 5.1 mmol) in anhydrous methanol (75 mL) was added sodium borohydride (380 mg, 10.0 mmol). The reaction mixture was stirred at room temperature for 2 hours. Water (20 mL) was added. The mixture was evaporated. The resultant residue was treated with EtOAc (30 mL) and water (5 mL). The mixture was dried over MgSO4, filtered, evaporated, and dried in vacuo, affording (1-ethyl-5-methyl-1H-imidazol-4-yl)methanol (350 mg, 49% yield). The product was used without further purification.
Reaction SMILES: [OH-].[Li+].[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C@@H:11]1[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][C@H:12]1[C:23]([O:25]C)=[O:24]>O1CCCC1>[C:19]([O:18][C:16]([N:14]1[CH2:15][C@@H:11]([C:5]2[CH:6]=[CH:7][C:8]([F:10])=[CH:9][C:4]=2[F:3])[C@H:12]([C:23]([OH:25])=[O:24])[CH2:13]1)=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: COC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1c1ccc(F)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@H](C(=O)O)[C@H](c2ccc(F)cc2F)C1
Reaction time: 48 h

Procedure:
Lithium hydroxide (130 mg, 23.5 mmol) was added dropwise to a stirred solution of 1-tert-butyl 3-methyl (3S,4R)-4-(2,4-difluorophenyl)pyrrolidine-1,3-dicarboxylate, from preparation 52 (930 mg, 2.72 mmol) in tetrahydrofuran (10 mL) at room temperature. The reaction mixture was stirred for 48 hours, concentrated in vacuo and diluted with water (15 mL). The phases were separated and the aqueous phase was extracted with ethyl acetate (1×25 mL). The aqueous layer was acidified with 2M hydrochloric acid solution (2.7 mL) and further extracted with ethyl acetate (2×40 mL). The combined organic extracts were dried over magnesium sulfate, filtered, concentrated in vacuo and azeotroped with dichloromethane to give the desired product, 775 mg (87%).
Reaction SMILES: Cl.[N:2]1([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[C:14]3[CH:20]=[C:19]([C:21]([OH:23])=O)[NH:18][C:15]3=[N:16][CH:17]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[N:24]1([C:21]([C:19]2[NH:18][C:15]3=[N:16][CH:17]=[C:12]([O:11][CH2:10][CH2:9][CH2:8][N:2]4[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]4)[CH:13]=[C:14]3[CH:20]=2)=[O:23])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: C1CCNCC1
Reactant: O=C(O)c1cc2cc(OCCCN3CCCCC3)cnc2[nH]1
Agent: Cl
Product: O=C(c1cc2cc(OCCCN3CCCCC3)cnc2[nH]1)N1CCCCC1
Yield: 75 %

Procedure:
The title compound was synthesized in analogy to example 1 from 5-(3-piperidin-1-yl-propoxy)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid hydrochloride and piperidine to give the desired product as a light brown solid (75%).
Reaction SMILES: [C:1]([CH2:9][NH:10][CH2:11][C:12]1[CH:13]=[C:14]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH:25]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:26]([O:28]CC3C=CC=CC=3)=[O:27])=[CH:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OCC)(=O)C.[Pd]>[C:1]([CH2:9][NH:10][CH2:11][C:12]1[CH:13]=[C:14]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH:25]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:26]([OH:28])=[O:27])=[CH:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(-c2cccc(CNCC(=O)c3ccccc3)c2)cc1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC(Cc1ccc(-c2cccc(CNCC(=O)c3ccccc3)c2)cc1)C(=O)O
Yield: 61.3 %

Procedure:
58 mg (10% by mass) of 10% palladium-on-charcoal are introduced into a solution containing 580 mg of benzyl 3-{3′-[(benzoylmethylamino)methyl]biphenyl-4-yl}-2-tert-butoxycarbonylaminopropionate in 8 ml of ethyl acetate. After bubbling hydrogen into the solution for 16 h at ambient temperature and 2 h at 50° C., the reaction medium is filtered through Celite and the solvents are evaporated off. The residue obtained is purified by chromatography on a column of silica and eluted with a 3/7 heptane/ethyl acetate mixture. 300 mg of 3-{3′-[(benzoylmethylamino)methyl]biphenyl-4-yl}-2-tert-butoxycarbonylaminopropionic acid are obtained with a 61% yield.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=O.[C:12](OC)(=[O:15])[CH2:13][CH3:14].CC(C)([O-])C.[Na+]>C1COCC1>[CH3:14][C:13]1[C:12]([OH:15])=[N:1][C:2]2[C:3]([C:4]=1[OH:6])=[CH:8][CH:9]=[CH:10][N:11]=2
Reactant: COC(=O)c1cccnc1N
Reactant: CCC(=O)OC
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(O)nc2ncccc2c1O
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a stirred solution of methyl 2-aminonicotinate (1.3 g, 8.54 mmol) and methyl propionate (20.08 mL, 214 mmol) in THF (20 mL) was added sodium tert-butoxide (2.053 g, 21.36 mmol) portion wise over 1 min. The reaction was stirred at rt for 40 min and then at 100° C. for 4 h. After this time the reaction was cooled to rt and evaporated in vacuo. The resulting solid was dissolved in water (20 mL) and neutralized to pH 7 with 1.0M aqueous HCl. The resulting solid was filtered and dried under vacuum overnight to give 3-methyl-1,8-naphthyridine-2,4-diol as a tan solid. Mass Spectrum (ESI) m/e=177.2 (M+1).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=[C:8]([C:9]([NH:11][C:12]2[NH:16][N:15]=[N:14][N:13]=2)=[O:10])[CH:7]=1.[CH3:24]OCCN>>[O:2]1[CH2:1][CH2:24][N:5]([C:6]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=[C:8]([C:9]([NH:11][C:12]3[NH:16][N:15]=[N:14][N:13]=3)=[O:10])[CH:7]=2)[CH2:4][CH2:3]1
Reactant: COCCN
Reactant: COCCNc1cc(C(=O)Nc2nnn[nH]2)nc2ccccc12
Product: O=C(Nc1nnn[nH]1)c1cc(N2CCOCC2)c2ccccc2n1

Procedure:
In a similar way, 4(2-Methoxyethylamino)-N(1H-tetrazol-5-yl)quinaldamide, m.p. 260° (d) was prepared from 2-methoxyethylamine.