Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:27]2[S:31][C:30]([C:32]3([NH2:36])[CH2:35][CH2:34][CH2:33]3)=[N:29][CH:28]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[N:8]([S:17]([C:20]3[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[C:5]2=[N:6][CH:7]=1.C[Si]([N:41]=[C:42]=[O:43])(C)C>O1CCCC1.O>[Cl:1][C:2]1[C:3]([C:27]2[S:31][C:30]([C:32]3([NH:36][C:42]([NH2:41])=[O:43])[CH2:33][CH2:34][CH2:35]3)=[N:29][CH:28]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[N:8]([S:17]([C:20]3[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[C:5]2=[N:6][CH:7]=1
Reactant: C[Si](C)(C)N=C=O
Reactant: Cc1ccc(S(=O)(=O)n2c(-c3cnn(C)c3)cc3c(-c4cnc(C5(N)CCC5)s4)c(Cl)cnc32)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2c(-c3cnn(C)c3)cc3c(-c4cnc(C5(NC(N)=O)CCC5)s4)c(Cl)cnc32)cc1
Temperature: 70 °C

Procedure:
A mixture of 1-(5-(5-chloro-2-(1-methyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)thiazol-2-yl)cyclobutanamine (40 mg, 0.074 mmol) (Example 121A) in anhydrous tetrahydrofuran (1 mL) was treated with trimethylsilyl isocyanate (0.049 ml, 0.371 mmol), and the reaction mixture was heated to 70° C. for 5 hours. Additional trimethylsilyl isocyanate (0.025 ml, 0.185 mmol) was added, and the reaction solution was heated for 16 hours at 70° C. The reaction was cooled, diluted with water, and extracted with dichloromethane. The organic extracts were combined and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with 5% methanol in dichloromethane, to provide the title compound. MS ESI(+) m/z 582.3 [M+H]+.
Reaction SMILES: CC1C=CC=C(C)N=1.[Cl:9][C:10](=[N:19][OH:20])[C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:18].[Cl:21][CH2:22][CH2:23][CH2:24]S(Cl)(=O)=O>C1C=CC=CC=1>[Cl:21][CH2:22][CH2:23][CH2:24][O:20][N:19]=[C:10]([Cl:9])[C:11]1[C:12]([Cl:18])=[CH:13][CH:14]=[CH:15][C:16]=1[Cl:17]
Reactant: ON=C(Cl)c1c(Cl)cccc1Cl
Reactant: O=S(=O)(Cl)CCCCl
Solvent: c1ccccc1
Solvent: Cc1cccc(C)n1
Product: ClCCCON=C(Cl)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.6 %

Procedure:
A 3.6 g (0.034 mol) sample of 2,6-dimethylpyridine was added dropwise to a cooled solution (ice bath) of 7.4 g (0.033 mol) alpha-chloro-2,6-dichlorobenzaldoxime and 5.9 g (0.03 mol) 3-chloropropylsulfonyl chloride in 75 ml benzene. The reaction mixture was allowed to warm to 25° C., stirred for 2 hours (a red solid formed) and allowed to stand overnight. The reaction mixture was evaporated under reduced pressure and the residue was chromatographed through a silica gel column with dichloromethane. A semi-crystalline yellow product was eluted from the column. The product was recrystallized from ether/hexane to give 4.3 g of O-(3-chloropropyl)-alpha-chloro-2,6-dichlorobenzaldoxime as a white solid, m.p. 69°-71° C. Elemental analysis for C10H9Cl4NO3S showed: %S, calc. 8.8, found 9.2; %Cl, calc. 38.8, found 37.9.
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].[CH2:29]([O:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=1)[CH3:30]>C1COCC1>[CH2:29]([O:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=[CH:9][CH2:8][CH2:7][CH2:6][CH2:5][C:2]([OH:4])=[O:3])=[CH:34][CH:33]=1)[CH3:30]
Reactant: O=C(O)CCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOc1ccc(C=O)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CCOc1ccc(C=CCCCCC(=O)O)cc1
Yield: 64 %

Procedure:
This compound was synthesized from 5-carboxypentyltriphenylphosphonium bromide (9.50 g, 20 mmol) and p-ethoxybenzaldehyde (3.00 g, 20 mmol) in THF (100 mL) by a Wittig reaction. Crystallization (hexanes-ethyl acetate) afforded the product (3.18 g, 64%) as white crystals (mp 62-63° C.), IR: 3450-2500, 1720 cm-1 ; 1H-NMR: 1.40 (t, 3H), 1.50 (m, 2H), 1.70 (m, 2H), 2.38 (m, 4H), 4.00 (q, 2H), 5.72+6.05 (m, 1H), 6.32 (t, 1H), 7.05 (q, 4H), 10.10 (bs, 1H). Anal. Calcd. for C15H20O3 : C, 72.55, H, 8.12% Found: C, 72.53, H, 8.15%. Z:E=45:55.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10]C)=[O:9])=[CH:6][N:5]=[C:4]([Cl:12])[CH:3]=1.CO.[OH-].[Na+].Cl>C1COCC1.O>[Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[C:4]([Cl:12])[CH:3]=1
Reactant: COC(=O)c1cnc(Cl)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cnc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 69 %

Procedure:
To a solution of methyl 4,6-dichloronicotinate in a mixture of THF (400 ml), MeOH (100 ml) and H2O (100 ml) was added a solution of NaOH (10 g) in 40 ml H2O. The mixture was stirred for 40 min. at room temp. Then, the solvents were reduced and it was acidified with conc. HCl to a pH of about 2. It was extracted using a mixture of Et2O/EtOAc and the organic layer was dried with Na2SO4. The solvents were removed and the residue dried in vacuo to obtain the title compound as a white solid (12.3 g, 69%). Rf (CHCl3/MeOH 10:1)=0.85. 1H-NMR (300 MHz, DMSO-D6): δ=8.80 (s, 1H), 7.90 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N+:3]=1[O-:10].[CH2:11]([NH:13][CH2:14][CH3:15])[CH3:12].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[N+:3]([O-:10])=[CH:4][C:5]([CH2:8][N:13]([CH2:14][CH3:15])[CH2:11][CH3:12])=[CH:6][CH:7]=1
Reactant: [O-][n+]1cc(CCl)ccc1Cl
Reactant: CCNCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN(CC)Cc1ccc(Cl)[n+]([O-])c1
Reaction time: 16 h
Yield: 88.5 %

Procedure:
2-Chloro-5-chloromethylpyridine 1-oxide (1.78 g, 10.0 mmol; described in: Tilley, J. W. et al, J. Heterocyclic Chem. 1979, 16, 333), diethyl amine (1.46 g, 20.0 mmol), and potassium carbonate (1.38 g, 10.0 mmol) were mixed in acetonitrile (50 mL) at room temperature. The mixture was stirred for 16 h, the solvent was removed in vacuo, and the residue was purified on a silica gel column using chloroform/methanol, (9:1), as the eluent to give 1.90 g (88% yield) of the title compound as a pale orange oil: MS (EI) m/z 215 and 217 (M++1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[O:9][C:8](=[O:10])[C:7]2[C:11]([CH3:15])=[CH:12][CH:13]=[CH:14][C:6]=2[N:5]=1)[CH3:2].Cl.[O:17]1CCCC1>>[CH2:1]([O:3][C:4]([NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:7]=1[C:8]([OH:17])=[O:10])=[O:9])[CH3:2]
Reactant: C1CCOC1
Reactant: CCOc1nc2cccc(C)c2c(=O)o1
Agent: Cl
Product: CCOC(=O)Nc1cccc(C)c1C(=O)O
Yield: 74 %

Procedure:
2-Ethoxy-5-methyl-4H-3,1-benzoxazin-4-one (20 g., 97.56 mmol) of Preparation III herein, and 4N HCl (10 ml), were stirred in tetrahydrofuran (THF, 200 ml) at room temperature for 15 minutes. The reaction mixture was evaporated to dryness under reduced pressure. The residue was dissolved in ethyl acetate (250 ml), washed with water (3×150 ml), and evaporated to give a pale yellow solid. Recrystallization from ethyl acetate/ pet. ether afforded 2-ethoxycarbonylamino-6-methylbenzoic acid (16.18 g, 74%) as colorless crystals; m.p. 123.5°-125° C.; analysis for C11H13NO4 : C, 59.19; H, 5.87; N, 6.27. Found: C, 59.32; H, 5.95; N, 6.25.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15](=O)[CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[NH2:23][OH:24].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15](=[N:23][OH:24])[CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)CCC(=O)c1ccc(-c2ccc(Cl)c(Cl)c2)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C(O)CCC(=NO)c1ccc(-c2ccc(Cl)c(Cl)c2)cc1
Yield: 97.6 %

Procedure:
In a manner similar to Example 4, Step (c), 4-(3′,4′-dichloro-biphenyl-4-yl)-4-oxo-butyric acid (1.23 g, 0.00381 mol) was allowed to react with hydroxylamine hydrochloride (0.2994 g, 0.00431 mol) in the presence of sodium carbonate (0.4567 g, 0.00431 mol) in absolute ethanol (20 mL) to give 1.257 g of 4-(3′,4′-dichloro-biphenyl-4-yl)-4-hydroxyimino-butyric acid as a white solid; mp 165.5-166.5° C.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[C:11]([C:12]([OH:14])=[O:13])=[C:10]([C:15]([OH:17])=[O:16])[C:9]3[CH2:18][O:19][CH2:20][CH2:21][C:8]2=3)=[CH:4][CH:3]=1.[C:24](OC(C(F)(F)F)=O)(C(F)(F)F)=O>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:11]([C:12]([OH:14])=[O:13])=[C:10]([C:15]([O:17][CH3:24])=[O:16])[C:9]3[CH2:18][O:19][CH2:20][CH2:21][C:8]2=3)=[CH:22][CH:23]=1
Reactant: O=C(O)c1c2c(n(Cc3ccc(F)cc3)c1C(=O)O)CCOC2
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1c2c(n(Cc3ccc(F)cc3)c1C(=O)O)CCOC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
An ice cooled suspension of 1-(4-fluorobenzyl)-1,4,6,7-tetrahydropyrano[4,3-b]pyrrole-2,3-dicarboxylic acid (3.1 g, 9.71 mmol) in Dichloromethane (DCM) (50 mL) was treated with TFAA (2.70 mL, 19.42 mmol) and warmed to ambient temperature. After 2 h, the reaction mixture was concentrated in vacuo, dissolved in MeOH (5 mL) and heated to reflux (90° C. bath). After 2 h, the reaction mixture was concentrated in vacuo to afford 1-(4-fluorobenzyl)-3-(methoxycarbonyl)-1,4,6,7-tetrahydropyrano[4,3-b]pyrrole-2-carboxylic acid. The crude acid was dissolved in DMF (25 mL) and treated with N-methyl sarcosine methyl ester HCl (2.033 g, 14.56 mmol), DIPEA (2.54 mL, 14.56 mmol) and HATU (4.43 g, 11.65 mmol). After 20 min, the reaction mixture was partitioned between water and EtOAc. The layers were separated and the organic phase was washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by ISCO (0-50% EtOAc-hexanes) to afford methyl 1-(4-fluorobenzyl)-2-((2-methoxy-2-oxoethyl)(methyl)carbamoyl)-1,4,6,7-tetrahydropyrano[4,3-b]pyrrole-3-carboxylate (3.2 g, 7.65 mmol, 79% yield) as a white solid. LCMS (m/z) ES+=419 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:40])[C:10]3([CH:15]([C:16]4[C:17]([O:23][C:24]([C:27]([O:29]C)=[O:28])([CH3:26])[CH3:25])=[N:18][CH:19]=[C:20]([Cl:22])[CH:21]=4)[CH2:14][C:13](=[O:31])[NH:12][CH:11]3[C:32]3[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=3[CH3:39])[C:5]2=[CH:4][CH:3]=1.O[Li].O.O.Cl>CO>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:40])[C:10]3([CH:15]([C:16]4[C:17]([O:23][C:24]([C:27]([OH:29])=[O:28])([CH3:25])[CH3:26])=[N:18][CH:19]=[C:20]([Cl:22])[CH:21]=4)[CH2:14][C:13](=[O:31])[NH:12][CH:11]3[C:32]3[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=3[CH3:39])[C:5]2=[CH:4][CH:3]=1
Reactant: COC(=O)C(C)(C)Oc1ncc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12
Agent: Cl
Agent: [Li]O
Solvent: CO
Solvent: O
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)cnc2OC(C)(C)C(=O)O)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 80 °C
Yield: 90.6 %

Procedure:
A mixture of racemic (2′S, 3S, 4′R)-6-chloro-4′-[5-chloro-2-(1-methoxycarbonyl-1-methyl-ethoxy)-pyridin-3-yl]-2′-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (160 mg, 0.27 mmol), LiOH.H2O (250 mg, 5.94 mol), H2O (5 mL) and methanol (15 mL) was heated at 80° C. for 40 min. After cooled to room temperature, the solution was acidified to “pH” 1 by addition of 1N HCl solution. The aqueous layer was extracted with EtOAc. The organic layer was washed with water, brine, dried over anhydrous Na2SO4 and concentrated to give the title compound as a light yellow solid (140 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][CH:8]([CH2:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[C:25]([F:30])[CH:24]=1)[CH:9]([OH:21])[CH2:10][NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][CH3:20])[CH:14]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH2:39]([O:46][C:47](Cl)=[O:48])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.CCCCCCC.CCOC(C)=O>C1COCC1>[CH2:39]([O:46][C:47](=[O:48])[N:11]([CH2:10][CH:9]([OH:21])[CH:8]([NH:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:31])[CH2:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[C:25]([F:30])[CH:24]=1)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][CH3:20])[CH:14]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CCc1cccc(CNCC(O)C(Cc2cc(F)cc(F)c2)NC(=O)OC(C)(C)C)c1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCc1cccc(CN(CC(O)C(Cc2cc(F)cc(F)c2)NC(=O)OC(C)(C)C)C(=O)OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.3 %

Procedure:
To a solution of [1-(3,5-difluoro-benzyl)-3-(3-ethyl-benzylamino)-2-hydroxy-propyl]-carbamic acid tert-butyl ester (16.1 g, 37 mmol) and triethylamine (6.2 mL, 44 mmol) in 80 mL of anhydrous THF under N2 at 0° C. is added benzylchloroformate (5.8 mL, 41 mmol). The solution is warmed to ambient temperature and stirred for 16 h. The solution is quenched with brine and concentrated to remove most of the THF. The residue is diluted with ethyl acetate and separated. The organic phase is washed with 1 M KH2PO4, saturated NaHCO3 and dried over Na2SO4. The mixture is filtered and concentrated to a white solid which is purified on a BIOTAGE 40M column eluting with 400 mL of heptane followed by 4/1:heptane/EtOAc to obtain [3-tert-butoxycarbonylamino-4-(3,5-difluoro-phenyl)-2-hydroxy-butyl]-(3-ethyl-benzyl)-carbamic acid benzyl ester as a white solid (15 g, 26 mmol, 71%), (MS:M+H: 569.4). This compound (6.0 g, 11 mmol) is dissolved in 10 mL of anhydrous CH2Cl2 at 0° C. and 10 mL of TFA is added. The solution is warmed to ambient temperature and stirred for 3 h. The solution is concentrated, diluted with EtOAc and washed with 1M NaOH. The combined organics are dried (Na2SO4) and the mixture is filtered and concentrated to give desired compound as a white solid (5.0 g, 11 mmol, quant. yield), (MS:M+H, 469.5).
Reaction SMILES: [O:1]1[CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:2]1.[C:21]([CH2:24][N:25]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32][N:31]([CH2:37][C:38]([OH:40])=[O:39])[CH2:30][CH2:29][N:28]([CH2:41][C:42]([OH:44])=[O:43])[CH2:27][CH2:26]1)([OH:23])=[O:22].[OH-].[K+]>O1CCOCC1.O>[OH:1][CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:2][N:34]1[CH2:35][CH2:36][N:25]([CH2:24][C:21]([OH:23])=[O:22])[CH2:26][CH2:27][N:28]([CH2:41][C:42]([OH:44])=[O:43])[CH2:29][CH2:30][N:31]([CH2:37][C:38]([OH:40])=[O:39])[CH2:32][CH2:33]1
Reactant: c1ccc(COCCCCCCCCCC2CO2)cc1
Reactant: O=C(O)CN1CCNCCN(CC(=O)O)CCN(CC(=O)O)CC1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)CN1CCN(CC(=O)O)CCN(CC(O)CCCCCCCCCOCc2ccccc2)CCN(CC(=O)O)CC1
Temperature: 70 °C
Reaction time: 24 h

Procedure:
28.73 g (103.92 mmol) of 1,2-epoxy-11-benzyloxyundecane and 10 g (28.86 mmol) of 1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyclododecane (=D03A) are dissolved in a mixture of 50 ml of dioxane/80 ml of water and the pH is brought to pH 10 with 6N potassium hydroxide solution. It is stirred for 24 hours at 70° C. It is evaporated to dryness, the residue is taken up with 200 ml of water/50 ml of methanol and extracted twice with 100 ml of tert-butyl methyl ether. The aqueous solution is adjusted to pH 3 with 5N hydrochloric acid and evaporated to dryness. The residue is boiled out (extracted) with 200 ml of methanol/80 ml of methylene chloride. It is cooled in an ice bath and filtered off from precipitated potassium chloride. The filtrate is concentrated by evaporation in a vacuum, the residue is dissolved in 45 ml of water/20 ml of ethanol and then added to a column of poly-(4-vinylpyridine). The product is eluted with a solution of ethanol/water 1:3. After concentration by evaporation in a vacuum, the residue is chromatographed on a reversed-phase column (RP 18/mobile solvent=gradient of water/tetrahydrofuran). After concentration by evaporation of the main fraction, 12.22 g (68% of theory) of a strongly hygroscopic, vitreous solid is obtained.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[N:4]=1)#[CH:2].Br[C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[C:14]#[N:15].C(N(CC)CC)C.O>CN(C)C=O>[CH3:9][C:5]1[N:4]=[C:3]([C:1]#[C:2][C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=2)[C:14]#[N:15])[CH:8]=[CH:7][CH:6]=1
Reactant: N#Cc1cccc(Br)c1
Reactant: C#Cc1cccc(C)n1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1cccc(C#Cc2cccc(C#N)c2)n1
Temperature: 90 °C
Reaction time: 3 h
Yield: 28.4 %

Procedure:
A mixture of 1 g (8.54 mMol) 2-ethynyl-6-methyl-pyridine (prepared in analogy to D. E. Ames et al., Synthesis, 1981, p. 364-5), 2.3 g (12.8 mMol) 3-bromo-benzonitrile, 0.47 g (0.7 mMol) bis-(triphenylphosphine)-palladium-II-chloride, 80 mg (0.41 mMol) cuprous iodide and 1.53 ml (15 mMol) triethylamine in 10 ml dimethylformamide is stirred for 3 hours at 90° C. The reaction mixture is cooled to ambient temperature, poured into water and extracted with dichloromethane. The organic layer is dried over sodium sulfate, filtered, evaporated to dryness and the residue is purified by chromatography on silica gel with hexane/ethyl acetate (4:1) as eluant. Crystallization from hexane of the obtained product affords 0.53 g (28.4%) of the title compound as brown crystals, melting point 120-3° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[C:13]([C:15]([NH:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][C:23]=2[C@H:24]2[CH2:29][C@@H:28]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[C@@H:27]([S:38][CH3:39])[C@@H:26]([CH3:40])[CH2:25]2)=[O:16])[CH:12]=[CH:11][C:10]=1[F:41].C1C=C(Cl)C=C(C(OO)=[O:50])C=1.C1CCCCC=1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[C:13]([C:15]([NH:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][C:23]=2[C@H:24]2[CH2:29][C@@H:28]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:36])[CH3:34])[C@@H:27]([S@@:38]([CH3:39])=[O:50])[C@@H:26]([CH3:40])[CH2:25]2)=[O:16])[CH:12]=[CH:11][C:10]=1[F:41]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CS[C@H]1[C@@H](C)C[C@@H](c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C[C@H]1NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: C1=CCCCC1
Product: C[C@H]1C[C@@H](c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1[S@@](C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 31 %

Procedure:
To a solution of tert-butyl (1R,2S,3S,5R)-5-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-3-methyl-2-(methylthio)cyclohexylcarbamate (1.0 equiv.) in CH2Cl2 (0.10 M) in a 0° C. bath was added mCPBA (1.2 equiv.). The capped solution was left stirring at rt for 1 hr. cyclohexene (10.0 equiv.) was added to quench any remaining mCBPA and after stirring for 5 minutes the solution was directly loaded onto ISCO SiO2 column and purified to yield tert-butyl (1R,2S,3S,5R)-5-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-3-methyl-2-((R)-methylsulfinyl)cyclohexylcarbamate in 31% yield, LC/MS=603.2 (MH+), Rt=0.66 min; and tert-butyl (1R,2S,3S,5R)-5-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-3-methyl-2-(methylsulfonyl)cyclohexylcarbamate in 37% yield. LC/MS (m/z)=619.2 (MH+), Rt=0.88 min.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=2)[C:6]([OH:20])=[C:5]([C:21](OC)=[O:22])[N:4]=1)#[N:2].[NH2:25][CH2:26][C@H:27]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:28]([OH:30])=[O:29].C[O-].[Na+]>COCCO>[CH2:31]([C@@H:27]([CH2:26][NH:25][C:21]([C:5]1[N:4]=[C:3]([C:1]#[N:2])[C:12]2[C:7]([C:6]=1[OH:20])=[CH:8][CH:9]=[C:10]([O:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH:11]=2)=[O:22])[C:28]([OH:30])=[O:29])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: NC[C@H](Cc1ccccc1)C(=O)O
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: COCCO
Product: N#Cc1nc(C(=O)NC[C@H](Cc2ccccc2)C(=O)O)c(O)c2ccc(Oc3ccccc3)cc12
Temperature: 25 °C

Procedure:
Methyl 1-cyano-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate (20 mg, 0.06 mmol), (S)-3-amino-2-benzyl-propionic acid (crude as TFA salt, 0.38 mmol) and sodium methoxide (40 mg, 0.74 mmol) were suspended in 2-methoxyethanol (3 mL). The resulting mixture was heated to reflux for 3 hours and then cooled to room temperature. The solvent was removed in vacuo and the residue was dissolved in H2O (15 mL) and EtOAc (15 mL). To the stirred mixture was added 1 N hydrochloric acid until pH was 1. The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO4, concentrated, and purified by flash chromatography (0-50% EtOAc/CH2Cl2 with 0.5% formic acid) to give the title compound in 17 mg. MS: (−) m/z 465.96 (M−1).
Reaction SMILES: [NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:2]([C:6]([OH:8])=O)[CH:3]([CH3:5])[CH3:4].[NH:16]1[CH2:28][CH2:27][CH2:26][C@H:17]1[C:18]([NH:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[O:19].Cl>>[NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:2]([C:6]([N:16]1[CH2:28][CH2:27][CH2:26][C@H:17]1[C:18]([NH:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[O:19])=[O:8])[CH:3]([CH3:4])[CH3:5]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)CNC(=O)[C@@H]1CCCN1
Agent: Cl
Product: COC(=O)CNC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C

Procedure:
Boc-Val-OH (52.1 g, 240 mmol) was reacted with II (53.4 g, 240 mmol) by the mixed anhydride method as described for the preparation of I in part (a). The resulting oil showed a single spot on TLC; yield 64.0 g (69%), Rf1 0.69.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([O:12][CH3:13])=[CH:4][CH:3]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[O:22][C:23]3[CH:33]=[C:32]([N:34]([CH3:39])[S:35]([CH3:38])(=[O:37])=[O:36])[C:31](B4OC(C)(C)C(C)(C)O4)=[CH:30][C:24]=3[C:25]=2[C:26]([NH:28][CH3:29])=[O:27])=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>O1CCOCC1.O.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]>[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[O:22][C:23]3[CH:33]=[C:32]([N:34]([CH3:39])[S:35]([CH3:38])(=[O:36])=[O:37])[C:31]([C:2]4[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([O:12][CH3:13])=[CH:4][CH:3]=4)=[CH:30][C:24]=3[C:25]=2[C:26](=[O:27])[NH:28][CH3:29])=[CH:17][CH:16]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: COC(=O)c1nc(Br)ccc1OC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(OC)c(C(=O)OC)n3)cc12
Temperature: 60 °C
Reaction time: 5 h
Yield: 91.2 %

Procedure:
To a stirring mixture of methyl 6-bromo-3-methoxypicolinate (200 mg, 0.81 mmol), 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (408 mg, 0.81 mmol) and K2CO3 (146 mg, 1.06 mmol) in dioxane/H2O (4 mL/0.2 mL) was added Pd(dppf)Cl2 (20 mg) under N2 protection. The mixture was stirred at 60° C. for 5 h, and after concentrated in vacuo, the residue was extracted with EtOAc. The organic phase was washed with brine, dried over Na2SO4 and evaporated. The residue was purified by column chromatography (PE:EtOAc=2:1, then 1:1) to give the product of methyl 6-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)-3-methoxypicolinate (400 mg, yield: 90%). 1H-NMR (CDCl3, 400 MHz) δ 7.88˜7.92 (m, 3H), 7.70 (d, J=8.8 Hz, 1H), 7.56 (s, 1H), 7.40 (d, J=8.8 Hz, 1H), 7.14 (t, J=8.8 Hz, 2H), 5.85 (d, J=3.2 Hz, 1H), 3.91 (s, 3H), 3.89 (s, 3H), 3.15 (s, 3H), 2.92 (d, J=4.8 Hz, 3H), 2.72 (s, 3H). MS (M+H)+: 542.