Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@:2]([C:6]([OH:8])=[O:7])([CH2:4][OH:5])[NH2:3].[ClH:9].O1CCOC[CH2:11]1>CO>[ClH:9].[CH3:1][C@@:2]([C:6]([O:8][CH3:11])=[O:7])([CH2:4][OH:5])[NH2:3]
Reactant: C[C@](N)(CO)C(=O)O
Reactant: C1COCCO1
Agent: Cl
Solvent: CO
Product: COC(=O)[C@@](C)(N)CO
Temperature: 25 °C
Reaction time: 16 h
Yield: 96 %

Procedure:
In a three neck 1 L round bottom flask under argon, 2-methylserine (35.0 g, 0.2936 mol) was suspended in methanol (300 mL). To this was added 4N HCl/dioxane (85 mL) and the reaction mixture was stirred at 25° C. for 16 h. The reaction mixture had become a clear colorless solution. Dry HCl gas was bubbled into the reaction mixture for 5 min. and the reaction mixture was then stirred at 60° C. for 4 h. It was then cooled and the excess reagent/solvent was removed under reduced pressure at 65° C. to 70° C. to give the desired product (yield 48.2 g, 96%) as an yellow sticky oil.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].C([Si](C1C=CC=CC=1)(C1C=CC=CC=1)[O:24][CH2:25][CH2:26][CH2:27][N:28]1[C:32]2=[N:33][CH:34]=[CH:35][CH:36]=[C:31]2[C:30]([C:37]2[C:38](=[O:49])[NH:39][C:40](=[O:48])[C:41]=2[C:42]2[O:43][CH2:44][CH2:45][CH2:46][CH:47]=2)=[CH:29]1)(C)(C)C>C1COCC1>[O:43]1[C:42]([C:41]2[C:40](=[O:48])[NH:39][C:38](=[O:49])[C:37]=2[C:30]2[C:31]3[C:32](=[N:33][CH:34]=[CH:35][CH:36]=3)[N:28]([CH2:27][CH2:26][CH2:25][OH:24])[CH:29]=2)=[CH:47][CH2:46][CH2:45][CH2:44]1
Reactant: CC(C)(C)[Si](OCCCn1cc(C2=C(C3=CCCCO3)C(=O)NC2=O)c2cccnc21)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C1NC(=O)C(c2cn(CCCO)c3ncccc23)=C1C1=CCCCO1
Yield: 70 %

Procedure:
Tributyl-(5,6-dihydro-4H-pyran-2-yl)-stannane Compound 15e (0.051 mL, 0.13 mmol) was added to a solution of 3-{1-[3-(tert-butyl-diphenyl-silanyloxy)-propyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-4-chloro-pyrrole-2,5-dione Compound 15d (0.054 g, 0.1 mmol), PdCl2(PPh3)2 (0.007 g, 0.01 mmol) and lithium chloride (0.013 g, 0.3 mmol) in DMF (1.5 mL) at 23° C. under nitrogen. The reaction mixture was heated to 100° C. and stirred for 18 h. After cooling to 23° C., the mixture was diluted with EtOAc (10 mL), washed with H2O (3×10 mL), sat'd KF (1×10 mL) and brine (1×10 mL), then dried (MgSO4) and concentrated. The product was purified by column chromatography (SiO2) to give Compound 15f (0.027 g, 46%) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.34 (dd, J=4.7, 1.5 Hz, 1H), 7.96 (dd, J=8.7, 2.3 Hz, 1H), 7.93 (s, 1H), 7.66 (m, 4H), 7.38 (m, 6H), 7.13 (dd, J=7.9, 4.7 Hz, 1H), 5.78 (t, J=4.3 Hz, 2H), 4.52 (t, J=7.0 Hz, 2H), 3.83 (m, 2H), 3.74 (t, J=5.8 Hz, 2H), 2.29 (m, 2H), 2.16 (m, 2H), 1.86 (m, 2H), 1.08 (s, 9H); MS (ES) m/z: 592 (M+H+). TBAF (0.07 mL, 0.07 mmol; 1 M solution in THF) was added dropwise to a solution of 3-{1-[3-(tert-butyl-diphenyl-silanyloxy)-propyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-4-(5,6-dihydro-4H-pyran-2-yl)-pyrrole-2,5-dione Compound 15f (0.027 g, 0.046 mmol) in THF (2 mL) under nitrogen. After 18 hours the mixture was concentrated and purified by column chromatography (SiO2) to give Compound 23 (0.011 g, 70%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.34 (d, J=4.6 Hz, 1H), 7.99 (d, J=8.1 Hz, 1H), 7.90 (s, 1H), 7.51 (br s, 1H), 7.18 (dd, J=7.9, 4.6 Hz, 1H), 5.87 (t, J=4.2 Hz, 1H), 4.66 (m, 1H), 4.51 (t, J=6.0 Hz, 2H), 3.82 (t, J=4.9 Hz, 2H), 3.43 (m, 2H), 2.31 (m, 2H), 2.04 (m, 2H), 1.85 (m, 2H); MS (ES) m/z: 354 (M+H+).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]([CH2:18][C:19]1([CH3:29])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21][CH2:20]1)([OH:17])[CH:4]=[N:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][C:10]([CH3:16])=[N:11]2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>C(O)(=O)C>[F:31][C:2]([F:1])([F:30])[C:3]([CH2:18][C:19]1([CH3:29])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21][CH2:20]1)([OH:17])[CH2:4][NH:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][C:10]([CH3:16])=[N:11]2
Reactant: Cc1ccc2c(N=CC(O)(CC3(C)CCCc4ccccc43)C(F)(F)F)cccc2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1ccc2c(NCC(O)(CC3(C)CCCc4ccccc43)C(F)(F)F)cccc2n1
Reaction time: 4 h
Yield: 71.3 %

Procedure:
To a solution of 1,1,1-trifluoro-3-[(2-methyl-5-quinolinyl)imino]-2-[(1-methyl-1,2,3,4-tetrahydro-1-naphthalenyl)methyl]-2-propanol (intermediate 8) (130 mg, 0.30 mmol) in glacial acetic acid (4 ml) stirred under nitrogen at 21° C., was added sodium triacetoxyborohydride (254 mg, 1.2 mmol) portionwise over 25 min and the solution was stirred for a further 4 h. The solution was then carefully added to a mixture of saturated aqueous sodium carbonate (50 ml) and ethyl acetate (30 ml) and stirred for 10 min, when effervescence had finished. The layers were separated and the aqueous layer re-extracted with ethyl acetate (30 ml) and the combined organic layers were washed with saturated sodium carbonate (15 ml), water (2×30 ml) and saturated brine (30 ml), dried over anhydrous sodium sulphate and evaporated. The crude product was purified on a 50 g silica cartridge using a Flashmaster 2 system with a 0-100% gradient of ethyl acetate in cyclohexane over 80 min to give the title compound (91.6 mg, 71%) as a mixture of diastereomers.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[CH3:15])[CH2:3][CH2:2]1.[CH3:16][CH:17]([CH3:26])[CH2:18][C@@H:19]([C:21]1[S:22][CH:23]=[CH:24][N:25]=1)[NH2:20]>>[CH3:16][CH:17]([CH3:26])[CH2:18][C@H:19]([NH:20][C:12]([C:10]1[CH:9]=[CH:8][C:7]([CH3:15])=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])[C:21]1[S:22][CH:23]=[CH:24][N:25]=1
Reactant: Cc1ccc(C(=O)O)nc1OCC1CC1
Reactant: CC(C)C[C@H](N)c1nccs1
Product: Cc1ccc(C(=O)N[C@@H](CC(C)C)c2nccs2)nc1OCC1CC1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-methyl-pyridine-2-carboxylic acid (Example 36 d) and (S)-α-(2-methylpropyl)-2-thiazolemethanamine (Example 56 d) as starting materials, MS (EI): m/e=360.2 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([N:14]=[CH:15]N(C)C)=[S:13])([CH3:4])([CH3:3])[CH3:2].[Cl:20][C:21]1[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=1[C:23](=[O:26])[CH2:24]Br>>[C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]1[S:13][C:24]([C:23](=[O:26])[C:22]2[CH:27]=[CH:28][CH:29]=[CH:30][C:21]=2[Cl:20])=[CH:15][N:14]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(CBr)c1ccccc1Cl
Reactant: CN(C)C=NC(=S)NCCCNC(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)NCCCNc1ncc(C(=O)c2ccccc2Cl)s1

Procedure:
The title compound was synthesised from [3-(3-Dimethylaminomethylene-thioureido)-propyl]-carbamic acid tert-butyl ester and 2-chloro phenacylbromide (commercially available) according to the procedure described for Example 25. MS (m/e): 395.8 (MH+, 100%).
Reaction SMILES: CC1(C)[O:6][C@H:5]([C:7]2[N:11]=[C:10]([NH:12][C:13]3[C:18]([O:19][C:20]4[C:21]([CH3:26])=[N:22][CH:23]=[CH:24][CH:25]=4)=[CH:17][C:16]([S:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)=[CH:15][N:14]=3)[S:9][N:8]=2)[CH2:4][O:3]1.Cl>C(O)C>[CH3:26][C:21]1[C:20]([O:19][C:18]2[C:13]([NH:12][C:10]3[S:9][N:8]=[C:7]([C@@H:5]([OH:6])[CH2:4][OH:3])[N:11]=3)=[N:14][CH:15]=[C:16]([S:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)[CH:17]=2)=[CH:25][CH:24]=[CH:23][N:22]=1
Reactant: Cc1ncccc1Oc1cc(Sc2ccccn2)cnc1Nc1nc([C@@H]2COC(C)(C)O2)ns1
Agent: Cl
Solvent: CCO
Product: Cc1ncccc1Oc1cc(Sc2ccccn2)cnc1Nc1nc([C@@H](O)CO)ns1
Temperature: 70 °C
Yield: 82.4 %

Procedure:
A flask was charged with (R)-3-(2,2-dimethyl-1,3-dioxolan-4-yl)-N-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-yl)-1,2,4-thiadiazol-5-amine (3.8 g, 7.683 mmol) and added ethanol (40 mL). 3M HCl (5.122 ml, 15.37 mmol) was added, and the reaction was heated to 70° C. for 1 hour, then cooled to ambient temperature. The ethanol removed in vacuo and saturated sodium bicarbonate solution was added. The aqueous layer was extracted with ethyl acetate. The majority of product crashed out of the aqueous layer and collected by filtration. The solids and residue from organic layer were purified over silica get (10-15% methanol in ethyl acetate) to afford (R)-1-(5-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol (2.877 g, 6.330 mmol, 82.38% yield) as yellow solid. Mass Spectrum (apci) m/z=455.1 (M+H).
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH2:7])(=[O:6])=[O:5].[C:8]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]3[C:33]([CH3:35])([CH3:34])[CH2:32][C:31]4[C:26](=[C:27]([C:37](O)=[O:38])[CH:28]=[C:29]([Cl:36])[CH:30]=4)[NH:25]3)[CH:19]=2)=[CH:14][CH:13]=1)([CH3:11])([CH3:10])[CH3:9].C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[C:8]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]3[C:33]([CH3:35])([CH3:34])[CH2:32][C:31]4[C:26](=[C:27]([C:37]([NH:7][S:4]([CH3:3])(=[O:6])=[O:5])=[O:38])[CH:28]=[C:29]([Cl:36])[CH:30]=4)[NH:25]3)[CH:19]=2)=[CH:14][CH:13]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)c1ccc(-c2cccc(C3Nc4c(cc(Cl)cc4C(=O)O)CC3(C)C)c2)cc1
Reactant: CS(N)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(-c2cccc(C3Nc4c(cc(Cl)cc4C(=O)NS(C)(=O)=O)CC3(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.8 %

Procedure:
To a suspension of 60% sodium hydride (128 mg, 3.2 mmol) in N,N-dimethylformamide (1.5 mL) was added methanesulfonamide (314 mg, 3.3 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h. A solution of 2-(4′-tert-butyl-biphenyl-3-yl)-6-chloro-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (150 mg, 0.33 mmol) and 1,1′-carbonyldiimidazole (136 mg, 0.84 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 70° C. After stirring at 70° C. for 1 h, the above suspension of methanesulfonamide and sodium hydride in N,N-dimethylformamide was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded N-[2-(4′-tert-butyl-biphenyl-3-yl)-6-chloro-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carbonyl]-methanesulfonamide (69 mg, 40%) as a white solid: LC/MS m/e calcd for C29H33ClN2O3S (M+H)+: 526.11, observed: 525.1.
Reaction SMILES: O.ON1C2C=CC=C[C:6]=2N=N1.Cl.CN(C)CCCN=C=NCC.[N:24]1[CH:29]=[CH:28][C:27]([C:30]2[S:34][C:33]([C:35]([O-:37])=[O:36])=[N:32][CH:31]=2)=[CH:26][CH:25]=1.[Li+]>CO>[N:24]1[CH:29]=[CH:28][C:27]([C:30]2[S:34][C:33]([C:35]([O:37][CH3:6])=[O:36])=[N:32][CH:31]=2)=[CH:26][CH:25]=1
Reactant: O=C([O-])c1ncc(-c2ccncc2)s1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Li+]
Solvent: CO
Solvent: O
Product: COC(=O)c1ncc(-c2ccncc2)s1
Reaction time: 96 h
Yield: 53.8 %

Procedure:
1-Hydroxybenzotriazole monohydrate (805 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.71 g) were added to a solution of lithium 5-(4-pyridyl)thiazole-2-carboxylate (632 mg) in methanol (5.0 ml) at room temperature. After stirring for 4 days, the reaction mixture was concentrated under reduced pressure, and dichloromethane (20 ml), a saturated aqueous solution (100 ml) of sodium hydrogencarbonate and water (100 ml) were added to the residue to separate an organic layer. The water layer was then extracted with dichloromethane (2×20 ml). After the resultant organic layers were combined and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was then purified by column chromatography on silica gel (dichloromethane:acetone=5:1→2:1) to obtain the title compound (353 mg) as a colorless solid.
Reaction SMILES: O=[C:2]1[CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[NH:6][CH2:5][CH2:4][NH:3]1.O.[OH-].[Na+]>C1COCC1>[C:8]1([CH:7]2[CH2:2][NH:3][CH2:4][CH2:5][NH:6]2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C1NCCNC1c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: c1ccc(C2CNCCN2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 60 %

Procedure:
2-Oxo-3-phenyl-piperazine (1.76 g, 10 mmol), in 30 mL of anhydrous THF was added dropwise to a 20 mL (20 mmol) of 1M solution of LiAH4 in THF, and the mixture was stirred at room temperature for 24 h. After workup (water, 20% NaOH addition to destroy excess LiAH4), the mixture was filtered and the filter cake was reextracted with ethyl acetate. The combined organic filtrate and extracts were dried over MgSO4, filtered and evaporated to give an slightly yellow solid that was purified by silica gel column chromatography (CHCl3:MeOH:NH4OH/9:1:0.1). The reduced product was isolated as a colorless solid (960 mg, 6 mmol, 60%). 1H NMR (CDCl3): δ 2.69 (1H, t, J=11.3), 2.85-3.10 (7H, m), 3.76 (1H, br d, J=8.9), 7.21-7.38 (5H, m). mp (free base): 79°-81° C.
Reaction SMILES: [CH:1]1([CH2:4][CH:5]=O)[CH2:3][CH2:2]1.[C:7]([O:11][CH2:12][CH3:13])(=[O:10])[NH:8][NH2:9]>CCO>[CH2:12]([O:11][C:7]([NH:8][N:9]=[CH:5][CH2:4][CH:1]1[CH2:2][CH2:3]1)=[O:10])[CH3:13]
Reactant: O=CCC1CC1
Reactant: CCOC(=O)NN
Solvent: CCO
Product: CCOC(=O)NN=CCC1CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 85 %

Procedure:
The solution of 2-cyclopropylethanal was diluted with 50 mL EtOH. Ethyl carbazate (5.14 g, 49.3 mmol) was added and the solution stirred at room temperature for 12 h, upon which it was concentrated in vacuo and the crude material was purified by flash column chromatography (0-5% MeOH in CH2Cl2) to give 7.1 g (85%) of the hydrazone (4a) as a colorless crystalline solid. 1H-NMR (400 MHz, CDCl3): 8.21 (br s, 1H); 7.21 (s, 1H); 4.23 (m, 2H); 2.17 (t, 3H, J=5.9 Hz) 1.06 (m, 2H); 0.80 (m, 1H); 0.1 (d, 2H); 0.48 (m, 2H); 0.13 (m, 2H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH3:21])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.N1C(C)=CC=CC=1C.[CH3:42][O:43][C:44](=[O:58])[C:45]1[CH:50]=[CH:49][CH:48]=[C:47](CN2C=CC(N)=N2)[CH:46]=1>C(Cl)Cl>[CH3:42][O:43][C:44](=[O:58])[C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([CH2:21][N:18]2[CH:19]=[CH:20][C:16]([NH:15][C:13](=[O:14])[C@@H:12]([C:4]3[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[C:2]([Cl:1])[CH:3]=3)[CH2:22][CH:23]3[CH2:24][CH2:25][CH2:26][CH2:27]3)=[N:17]2)[CH:46]=1
Reactant: Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Reactant: COC(=O)c1cccc(Cn2ccc(N)n2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: COC(=O)c1cccc(Cn2ccc(NC(=O)[C@H](CC3CCCC3)c3ccc(S(C)(=O)=O)c(Cl)c3)n2)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 47.4 %

Procedure:
2-(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (250 mg, 0.76 mmol, prepared as in PCT WO 2004/052869 A1, Example 1) was dissolved in methylene chloride (3.8 mL) and a 2.0 M solution of oxalyl chloride in methylene chloride (380 μL, 0.76 mmol) was added and the reaction stirred at 25° C. for 20 min. The solution was chilled to 0° C. and 2,6-lutidine (180 μL, 1.52 mmol) was added. The reaction continued to stir at 0° C. for 20 min. The 3-(3-amino-pyrazol-1-ylmethyl)-benzoic acid methyl ester (176 mg, 0.76 mmol) was added, the ice bath was removed and the reaction continued to stir at 25° C. for 25 min. The reaction was diluted with methylene chloride (40 mL), washed with water (2×10 mL), saturated aqueous brine solution (1×10 mL), dried over magnesium sulfate and concentrated in vacuo to a beige foam. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 0% ethyl acetate/methylene chloride to 15% ethyl acetate/methylene chloride) afforded 3-{3-[2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-ylmethyl}-benzoic acid methyl ester (196 mg, 47%) as a white foam: ESI-LRMS m/e calcd for C27H30ClN3O5S [M+] 543.16, found 544.22 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.05-1.21 (m, 2H, CH2), 1.45-1.94 (m, 8H, 4×CH2), 2.15-2.34 (m, 1H, CH), 3.25 (s, 3H, SO2CH3), 3.52 (t, J=7.5 Hz, 1H, CH), 3.91 (s, 3H, CO2CH3), 5.19 (s, 2H, NCH2), 6.72 (d, J=2.2 Hz, 1H, Ar), 7.34 (m, 2H, Ar), 7.40 (d, Jo=7.7 Hz, 1H, Ar), 7.44 (dd, Jo=8.3, Jm=1.5 Hz. 1H, Ar), 7.58 (d, Jm=1.5 Hz, 1H, Ar), 7.84-7.91 (m, 2H, Ar and NH), 7.97 (d, Jo=7.7 Hz, 1H, Ar), 8.08 (d, Jo=8.3 Hz, 1H, Ar).
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][C:7]2[CH:16]=[C:15]3[C:10]([C:11]([OH:31])=[C:12]([C:26](OCC)=[O:27])[C:13](=[O:25])[N:14]3[CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][C:20]3=[O:24])=[N:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:34][CH:35]([O:37][CH2:38][CH2:39][CH2:40][NH2:41])[CH3:36]>>[F:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][C:7]2[CH:16]=[C:15]3[C:10]([C:11]([OH:31])=[C:12]([C:26]([NH:41][CH2:40][CH2:39][CH2:38][O:37][CH:35]([CH3:36])[CH3:34])=[O:27])[C:13](=[O:25])[N:14]3[CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][C:20]3=[O:24])=[N:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: CC(C)OCCCN
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCC2=O)c1=O
Product: CC(C)OCCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-(4-fluorobenzyl)-4-hydroxy-2-oxo-1-[2-(2-oxopyrrolidin-1-yl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 3-[(1-methylethyl)oxy]-1-propanamine using conditions similar to those employed in Example 563 to provide a white solid: ES+ MS: 525 (M+H+).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][N:12]=1.N#N.C(=O)([O-])[O-].[Cs+].[Cs+]>O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[F:10][C:11]1[N:12]=[CH:13][C:14]([C:2]2[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:15][CH:16]=1
Reactant: N#Cc1cccnc1Cl
Reactant: OB(O)c1ccc(F)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1cccnc1-c1ccc(F)nc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 84.5 %

Procedure:
To an oven-dried, N2-purged, 250-mL, round-bottomed flask containing a magnetic stir bar were added the commercially available 2-chloro-3-cyanopyridine (1.25 g, 9.00 mmol), the commercially available 2-fluoropyridine-5-boronic acid (845 mg, 6.00 mmol), and dichlorobis(triphenylphosphine)palladium(II) (211 mg, 0.300 mmol). The flask was sealed with a septum and purged with N2 atmosphere. Anhydrous dioxane (45 mL) and a N2-purged solution of cesium carbonate (5.86 g, 18.0 mmol) in water (45 mL) were added via syringe. The reaction mixture was heated to ˜90° C. in an oil bath and stirred for 2 hours. The reaction was monitored by LC-MS. After cooling to room temperature, the solvent/volatiles were removed by rotary evaporator to give a thick brown oil. Water (75 mL) was added and the mixture was transferred to a separatory funnel. The mixture was extracted with ethyl acetate (4×30 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated by rotary evaporator to give a brown solid. The product was recrystallized from ethyl acetate/hexanes to give 1.01 g (84%) of the title compound as a tan powder. MS (ESI+) m/z 200.0 (M+H)+; 1H NMR (DMSO-d6) δ 7.43 (dd, J=8.6, 2.9 Hz, 1H), 7.70 (dd, J=8.1, 5.1 Hz, 1H), 8.49 (d, J=1.7 Hz, 1H), 8.51 (d, J=1.7 Hz, 1H), 8.74 (d, J=2.7 Hz, 1H), 8.98 (dd, J=4.7, 1.7 Hz, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:41])[N:10]([C@H:12]([C:14](=[O:40])[NH:15][C:16]1[C:17](=[O:39])[N:18]([CH2:23][C:24]2[CH:25]=[N:26][CH:27]=[C:28]([C:30](=[O:38])[C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[CH:29]=2)[C:19](Br)=[CH:20][CH:21]=1)[CH3:13])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:42]1(B(O)O)[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:8][C:9](=[O:41])[N:10]([C@H:12]([C:14](=[O:40])[NH:15][C:16]1[C:17](=[O:39])[N:18]([CH2:23][C:24]2[CH:25]=[N:26][CH:27]=[C:28]([C:30](=[O:38])[C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[CH:29]=2)[C:19]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[CH:20][CH:21]=1)[CH3:13])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](C(=O)Nc1ccc(Br)n(Cc2cncc(C(=O)c3ccc(F)cc3)c2)c1=O)N(C)C(=O)OCc1ccccc1
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCO
Product: C[C@@H](C(=O)Nc1ccc(-c2ccccc2)n(Cc2cncc(C(=O)c3ccc(F)cc3)c2)c1=O)N(C)C(=O)OCc1ccccc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 89.5 %

Procedure:
A mixture of ((S)-1-{6-bromo-1-[5-(4-fluoro-benzoyl)-pyridin-3-ylmethyl]-2-oxo-1,2-dihydro-pyridin-3-ylcarbamoyl}-ethyl)-methyl-carbamic acid benzyl ester (1D) (79 mg, 0.13 mmol) and phenyl boronic acid (19 mg, 0.15 mmol) in 8 mL of toluene, 3 mL of ethanol and Na2CO3 (0.5 mL, 0.5 mmol, 1 M aqueous solution) is degassed under vacuum. PdCl2(PPh3)2 (5 mg, 0.006 mmol) is added to the mixture. The reaction mixture is stirred at 80° C. for 1 hour, cooled to room temperature and diluted with 20 mL of EtOAc. The organic phase is washed with 2×5 mL of water and concentrated. The crude product is purified by chromatography (heptane 60%, EtOAc 40%) to give ((S)-1-{1-[5-(4-fluoro-benzoyl)-pyridin-3-ylmethyl]-2-oxo-6-phenyl-1,2-dihydro-pyridin-3-ylcarbamoyl}-ethyl)-methyl-carbamic acid benzyl ester (1E) (72 mg, yield 91%) as a light yellow solid. MS (ESI) m/e 619 (M+H+).
Reaction SMILES: [BH4-].[Na+].[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].O.C(=O)(O)[O-].[Na+]>C(O)(=O)C(C)C>[CH3:6][CH:7]([CH3:14])[CH2:8][NH:3][C:4]1[S:5][CH:6]=[C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)c1csc(N)c1C(=O)OCC
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)C(=O)O
Solvent: O
Product: CCOC(=O)c1csc(NCC(C)C)c1C(=O)OCC
Reaction time: 16 h
Yield: 172.4 %

Procedure:
Sodium borohydride (18 g) was added portionwise over 5 hours to a stirred suspension of diethyl 2-aminothiophene-3,4-dicarboxyate (33 g) in isobutyric acid (300 ml) at room temperature. The mixture was stirred for 16 hours then further sodium borohydride (4 g) was added and stirring was continued for 5 hours. Water (1.51) was added, the mixture was neutralised by addition of solid sodium bicarbonate and then extracted with ether (3×500 ml). The organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated to give the subtitle compound (35 g) as a solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]#CC3C=CC(CC(OC)=O)=CC=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(=O)C1C=CC(I)=CC=1)C.C(N([CH2:48][CH3:49])CC)C>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:16]([C:15]1[CH:14]=[CH:13][C:12]([C:9]2([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:11][CH2:10]2)=[C:48]([CH3:49])[CH:18]=1)#[CH:17]
Reactant: COC(=O)Cc1ccc(C#Cc2ccc(C3(OCc4ccccc4)CC3)cc2)cc1
Reactant: CCN(CC)CC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: CCOC(=O)c1ccc(I)cc1
Product: C#Cc1ccc(C2(OCc3ccccc3)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
Using General Procedure F; 1-ethynyl-4-(1-benzyloxycyclopropyl)-3-methyl-benzene (Intermediate 76, 90.0 mg, 0.34 mmol) and ethyl-4-iodo benzoate (Reagent A, 95.0 mg, 0.34 mmol) in triethylamine (6 mL) was treated with copper(I)iodide (23.0 mg, 0.12 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (80 mg, 0.11 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (2-4% EtOAc-hexanes) afforded 68.0 mg (54%) of the title compound.