Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-].[Na+].[H-].[Na+].[CH2:5]([O:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl[CH2:22][CH2:23][CH2:24][CH2:25][C:26]#[N:27]>CN(C=O)C>[C:17]([O:16][C:14]([N:13]([CH2:22][CH2:23][CH2:24][CH2:25][C:26]#[N:27])[O:12][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: N#CCCCCCl
Reactant: CC(C)(C)OC(=O)NOCc1ccccc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CCCCC#N)OCc1ccccc1
Reaction time: 0.25 h

Procedure:
N-(tert-Butoxycarbonyl)-N-(4-cyanobutyl)-O-benzylhydroxylamine (4) was synthesized by adding sodium iodide (84 mg, 0.56 mmol) and then sodium hydride (80% oil dispersion, 0.49 g, 16.3 mmol) to O-benzyl-N-tert-butoxycarbonyl hydroxylamine (2.68 g, 12.0 mmol) in dry DMF (40 ml). After stirring for 15 minutes, 5-chlorovaleronitrile (1.5 mL, 13.3 mmol) was added and the suspension heated at 80°-85° C. for 4 hours under argon. After cooling, the reaction was quenched with H2O (100 mi), then extracted with ether (4×75 mL). The combined organic layers were washed with 100 mL each of 1% aqueous Na2SO3, H2O and brine and then concentrated to give 4.39 g crude product. Column chromatography with 4.5% EtOAc/CHCl3 produced 3.17 g of O-benzyl-N-(tert-butoxycarbonyl)-N-(4-cyanobutyl)hydroxylamine (4) (87% yield): NMR δ 1.5-1.75 (s+m, 13 H), 2.3 (t, 2 H), 3.4 (t, 2 H), 4.77 (s, 2 H), 7.3 (s, 5 H). Anal. calcd. for C17H24N2O3 : C, 67.08; H, 7.95; N, 9.20. Found: C, 67.19; H, 7.99; N, 9.11.
Reaction SMILES: C([N:4]1[CH:8]=[C:7]([CH3:9])[N:6]=[C:5]1[CH3:10])(=O)C.[O:11]1CC[CH2:13][CH2:12]1>>[C:12]([C:8]1[NH:4][C:5]([CH3:10])=[N:6][C:7]=1[CH3:9])(=[O:11])[CH3:13]
Reactant: CC(=O)n1cc(C)nc1C
Reactant: C1CCOC1
Product: CC(=O)c1[nH]c(C)nc1C
Yield: 41 %

Procedure:
A solution of 6.9 g (0.05 M) of 1-acetyl-2,4-dimethylimidazole in 700 ml of dry tetrahydrofuran was photolyzed in a quartz flask with a short wave ultraviolet light source (254 nm) for 40 hours. The tetrahydrofuran solution was concentrated in vacuo to give an oil which was chromatographed on silica gel using 5% methanol in chloroform as eluent to give 2.8 g (41%) of 5-acetyl-2,4-dimethylimidazole as a white solid, mp 83°-87°. Recrystallization from isopropyl ether gave analytically pure material, mp 87°-88°. nmr (CDCl3) (δ): 2.53 (s, 6H); 2.40 (s, 3H). Anal. Calcd. for C7H10N2O: C, 60.85; H, 7.30; N, 20.27; found: C, 60.66; H, 7.26; N, 20.09.
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][C:9](=O)[CH2:8][CH2:7]1)=O)C.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[O:16]1[CH2:17][CH2:18][N:13]([CH:9]2[CH2:8][CH2:7][NH:6][CH2:11][CH2:10]2)[CH2:14][CH2:15]1
Reactant: CCOC(=O)N1CCC(=O)CC1
Reactant: C1COCCN1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: C1CC(N2CCOCC2)CCN1
Temperature: 25 °C
Reaction time: 10 h
Yield: 67.6 %

Procedure:
1-Ethoxycarbonyl-4-piperidone (250 g), morpholine (152.0 g) and p-toluenesulfonic acid (5 g) were added to toluene (600 ml) and the mixture was heated under reflux for 15 hr with dehydration. Then, the solvent was evaporated and the obtained oily component was added to a suspension of ethanol (1L) containing sodium borohydride (58 g) under ice-cooling. The mixture was further stirred at room temperature for 10 hr. The reaction mixture was treated with diluted hydrochloric acid and the solvent was evaporated under reduced pressure. Thereto were added 2-propanol (2 L) and potassium hydroxide (365 g) and the mixture was heated under reflux at 80° C. for 15 hr. The solvent was evaporated under reduced pressure. The obtained oily component was purified by distillation to give the title compound (168 g).
Reaction SMILES: [NH2:1][C@H:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].[OH-].[Na+].[N+:15]([C:18]1[CH:19]=[C:20]([CH:42]=[C:43]([N+:45]([O-:47])=[O:46])[CH:44]=1)[C:21]([NH:23][C@H:24]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:25][C:26](ON1C(=O)CCC1=O)=[O:27])=[O:22])([O-:17])=[O:16].Cl>O.O1CCCC1>[N+:15]([C:18]1[CH:19]=[C:20]([CH:42]=[C:43]([N+:45]([O-:47])=[O:46])[CH:44]=1)[C:21]([NH:23][C@H:24]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:25][C:26]([NH:1][C@H:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5])=[O:27])=[O:22])([O-:17])=[O:16]
Reactant: N[C@@H](CC(=O)O)c1ccccc1
Reactant: O=C(C[C@H](NC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1)c1ccccc1)ON1C(=O)CCC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C[C@H](NC(=O)C[C@H](NC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
5.65 g of (S)-3-amino-3-phenylpropionic acid were suspended in 70 ml of water, the pH of the suspension was adjusted to 10.5-11 by adding sodium hydroxide solution, and 70 ml of tetrahydrofuran were added. The mixture was cooled to 0-5° C. in an icebath and 13 g of 2,5-dioxopyrrolidin-1-yl(S)-3-(3,5-dinitrobenzamido)-3-phenylpropionate were added in portions with stirring over a period of 15 min. On completion of addition, the pH of the reaction mixture was kept between 9-9.5 by adding sodium hydroxide solution. On attainment of a constant pH with virtually full conversion (HPLC monitoring; <0.5 area % of reactant), the solution was diluted to a volume of about 800 ml with water, a pH of 1.5-2 was established by addling 4 N hydrochloric acid and the mixture was stirred for a further 30 min. The solid was filtered off with suction, washed with water and dried at 50° C. under reduced pressure. The dried solid was digested in 250 ml of tetrahydrofuran at 40° C. for 20 min, the suspension was cooled and the solid (product fraction 1) was filtered off with suction. The mother liquor was concentrated at a water bath temperature of 40° C. to a volume of about 70-80 ml, the resulting suspension was cooled to room temperature, and the solid (product fraction 2) filtered off with suction. The product fractions were combined and dried at 50° C. under reduced pressure. The yield was 11.1 g; HPLC purity >99.5 area %; 1H NMR (DMSO) δ (ppm): 2.64 (d, 2H), 2.77 (m, 2H), 5.15 (m, 1H), 5.52 (m, 1H), 7.10-7.20 (m, 5H), 7.25 (t, 1H), 7.31 (t, 2H), 7.39 (d, 2H), 8.44 (d, 1H), 8.95 (m, 1H), 9.01 (m, 2H), 9.53 (d, 1H), 12.17 (s, 1H, CO2H).
Reaction SMILES: [C:1](=[O:16])([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)OC1C=CC=CC=1.[NH2:17][C@H:18]([C:26]([O-:28])=[O:27])[CH2:19]C1C=CC=CC=1.C([N+](CCCC)(CCCC)CCCC)CCC.Cl>C(#N)C>[O:9]([C:1]([NH:17][C@H:18]([C:26]([OH:28])=[O:27])[CH3:19])=[O:16])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Reactant: N[C@@H](Cc1ccccc1)C(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Solvent: CC#N
Product: C[C@H](NC(=O)Oc1ccccc1)C(=O)O
Temperature: 25 °C

Procedure:
Under a nitrogen atmosphere, 428 mg (2 mmol) of diphenyl carbonate and 5 mL of acetonitrile were loaded into a round bottom flask having a volume of 100 mL, and then the mixture was stirred at room temperature. Next, 813 mg (2 mmol) of tetrabutylammonium phenylalanine salt and 15 mL of acetonitrile were dropped to the solution, and then the mixture was stirred for 15 minutes. After that, a 1M aqueous HCl solution was added to the reaction solution to terminate the reaction, and then the resultant was concentrated with an evaporator. Next, water was added to the concentrated product, and then the resultant was extracted with ethyl acetate. The resultant organic layer was washed with water and brine, and was then dried with sodium sulfate. After that, the dried product was concentrated with an evaporator. Thus, a crude product was obtained. Next, the crude product was purified by column chromatography. Thus, N-phenoxycarbonyl-L-alanine was obtained. An isolation amount and an isolation yield were 445.0 mg and 78%, respectively.
Reaction SMILES: [Cl:1][CH2:2]/[CH:3]=[CH:4]/[C:5](Cl)=[O:6].[CH2:8]([NH:10][CH2:11][CH3:12])[CH3:9]>CCOCC>[Cl:1][CH2:2]/[CH:3]=[CH:4]/[C:5]([N:10]([CH2:11][CH3:12])[CH2:8][CH3:9])=[O:6]
Reactant: CCNCC
Reactant: O=C(Cl)/C=C/CCl
Solvent: CCOCC
Product: CCN(CC)C(=O)/C=C/CCl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
4-Chlorocrotonyl chloride (1.36 g, 9.80 mmol) in ether (20 ml) is combined with diethylamine in ether (5 ml) at -15° C. in a flame dried flask. The reaction is warmed to ambient temperature, stirred for 1 to 2 hours, quenched with water (30 ml), extracted with ethyl acetate (2×30 ml), washed with saline (30 ml), dried over sodium sulfate, and concentrated in vacuo to yield the crude 4-chloro-N,N-diethylcrotonamide.
Reaction SMILES: [CH2:1]([O:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH:2]=[CH2:3].[OH:13]NC(=O)OC(C)(C)C.[H-].[Na+].C(Br)C=C.ClC1C=CC=C(C(OO)=O)C=1>ClCCl>[O:13]1[CH2:3][CH:2]1[CH2:1][O:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)OC(=O)NO
Reactant: C=CCONC(=O)OC(C)(C)C
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C=CCBr
Product: CC(C)(C)OC(=O)NOCC1CO1
Temperature: 25 °C
Reaction time: 24 h
Yield: 62 %

Procedure:
According to (16-1) described in Reference Example 16, 659 mg (3.80 mmol) of tert-butyl N-(allyloxy)carbamate prepared from tert-butyl N-hydroxycarbamate, sodium hydride and allyl bromide was dissolved in 10 ml of dichloromethane, and the thus prepared solution was mixed with 886 mg (4.67 mmol) of m-chloroperbenzoic acid and stirred at room temperature for 24 hours. The reaction solution was filtered, mixed with a 1 N sodium hydroxide aqueous solution and extracted with chloroform. The chloroform layer was washed with saturated brine and dried with anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=4/1) to obtain 447 mg (yield, 62%) of tert-butyl N-(2,3-epoxypropoxy)carbamate.
Reaction SMILES: [CH3:1][S:2]([N:5]([S:7]([NH2:10])(=[O:9])=[O:8])[CH3:6])(=[O:4])=[O:3].[CH3:11][O:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[N:16]=[C:15]([NH:21][C:22](=O)[O:23]C2C=CC=CC=2)[N:14]=1>C(#N)C>[CH3:1][S:2]([N:5]([S:7]([NH:10][C:22]([NH:21][C:15]1[N:14]=[C:13]([O:12][CH3:11])[CH:18]=[C:17]([O:19][CH3:20])[N:16]=1)=[O:23])(=[O:9])=[O:8])[CH3:6])(=[O:4])=[O:3]
Reactant: CN(S(C)(=O)=O)S(N)(=O)=O
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Solvent: CC#N
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)N(C)S(C)(=O)=O)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.4 %

Procedure:
37.6 g of (N-methylsulfonyl-N-methylamino)sulfonamide are dissolved in 500 ml of acetonitrile, 55.0 g of phenyl 4,6-dimethoxy-2-pyrimidylcarbamate are added dropwise at room temperature, and the mixture is stirred for 18 hours at room temperature. Approx. 400 ml of acetonitrile are distilled off, and then 200 ml of water are added at 0° C., and the mixture is brought to pH 2-3 using 2N HCl. The product which has precipitated is filtered off with suction and washed with water. 72.6 g of the desired product of a purity of 98.4% are obtained, which corresponds to a yield of 96.8% of theory. The melting point of the product is 185-186° C.
Reaction SMILES: C(O[C:6]([C:8]1[N:13]=[C:12](O)[C:11]2[CH:15]=[C:16]([S:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[S:17][C:10]=2[C:9]=1[OH:25])=[O:7])CCC.C([O:30][C:31]([C:33]1C(O)=C2C=C(SC3C=CC=CC=3)SC2=C(O)[N:38]=1)=[O:32])CCC>>[OH:25][C:9]1[C:10]2[S:17][C:16]([S:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][C:11]=2[CH:12]=[N:13][C:8]=1[C:6]([NH:38][CH2:33][C:31]([OH:32])=[O:30])=[O:7]
Reactant: CCCCOC(=O)c1nc(O)c2sc(Sc3ccccc3)cc2c1O
Reactant: CCCCOC(=O)c1nc(O)c2cc(Sc3ccccc3)sc2c1O
Product: O=C(O)CNC(=O)c1ncc2cc(Sc3ccccc3)sc2c1O

Procedure:
The title compound was prepared from a mixture of 4,7-dihydroxy-2-phenylsulfanyl-thieno[3,2-c]pyridine-6-carboxylic acid n-butyl ester and 4,7 dihydroxy-2-phenylsulfanyl-thieno[2,3-c]pyridine-5-carboxylic acid n-butyl ester, example 17.a, under conditions analogous to experimental conditions 5.a. The products were obtained as a mixture of the two isomers; MS: (+) m/z 437.91, 439.91 (M+1, 79Br/81Br).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1>[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=2)[C:5]([O:7][CH3:8])=[O:6])=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccnc(Cl)c1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccnc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 150 °C
Yield: 80 %

Procedure:
Methyl 2-chloroisonicotinate (427 mg), 4-(trifluoromethyl)phenylboronic acid (474 mg), potassium phosphate (800 mg), 1,1-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (102 mg), in PhMe (5 ml) were placed in a microwave tube and the contents were heated in the microwave oven for 20 min at 150° C. The cooled mixture was filtered through Hyflo® to remove inorganic material, the Hyflo® was washed with EtOAc and the combined organic extracts were dispersed between H2O and EtOAc. The organic extracts were washed with brine, dried (MgSO4) and evaporated. The crude oil was purified by chromatography on silica using 10-25% EtOAc in hexane to yield the product as a crystalline solid (560 mg, 85%). 1H NMR (400 MHz, CDCl3) δ: 4.01 (3H, s), 7.76 (2H, d, J 8.3), 7.84 (1H, dd, J 1.4, 4.9), 8.18 (2H, d, J 8.2), 8.33 (1H, t, J 1.1), 8.87 (1H, dd, J 0.6, 4.8).
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[S:13][C:12]([CH2:14][N:15]3[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[N:16]3)=[CH:11][CH:10]=2)[O:8][CH2:7][CH2:6][O:5]1.[NH4+].[Cl-]>CCO.O.[Fe]>[CH3:3][C:4]1([C:9]2[S:13][C:12]([CH2:14][N:15]3[CH:19]=[CH:18][C:17]([NH2:20])=[N:16]3)=[CH:11][CH:10]=2)[O:8][CH2:7][CH2:6][O:5]1
Reactant: CC1(c2ccc(Cn3ccc([N+](=O)[O-])n3)s2)OCCO1
Agent: [Fe]
Agent: N#N
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: CC1(c2ccc(Cn3ccc(N)n3)s2)OCCO1
Temperature: 75 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a mixture of 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-ylmethyl]-3-nitro-1H-pyrazole (230 mg, 0.78 mmol), iron powder (132 mg, 2.34 mmol) and NH4Cl (210 mg, 3.85 mmol) in a mixture of EtOH (4.0 mL) and water (2.0 mL) was stirred at 75° C. for 30 min. The reaction mixture was filtered while hot and concentrated under reduced pressure. CH2Cl2 (40 mL) was added followed by 1M NaOH (40 mL). The aq. layer was extracted with CH2Cl2 (2×20 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a red oil. LC-MS-conditions 02: tR=0.69 min; [M+H]+=266.38.
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][CH2:9][CH2:10][S:11][S:12][CH2:13][CH2:14][NH:15][C:16](=[O:24])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[OH:23].[C:25](O)(=[O:47])[CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30]/[CH:31]=[CH:32]\[CH2:33]/[CH:34]=[CH:35]\[CH2:36]/[CH:37]=[CH:38]\[CH2:39]/[CH:40]=[CH:41]\[CH2:42]/[CH:43]=[CH:44]\[CH2:45][CH3:46].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CC#N.CCOC(C)=O>[C:25]([NH:8][CH2:9][CH2:10][S:11][S:12][CH2:13][CH2:14][NH:15][C:16](=[O:24])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[OH:23])(=[O:47])[CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30]/[CH:31]=[CH:32]\[CH2:33]/[CH:34]=[CH:35]\[CH2:36]/[CH:37]=[CH:38]\[CH2:39]/[CH:40]=[CH:41]\[CH2:42]/[CH:43]=[CH:44]\[CH2:45][CH3:46]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)O
Reactant: NCCSSCCNC(=O)c1ccccc1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NCCSSCCNC(=O)c1ccccc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.5 %

Procedure:
The TFA salt of N-(2-(2-(2-aminoethyl)-disulfanyl)-ethyl)-2-hydroxybenzamide (1.08 mmol) was taken up in anhydrous CH3CN (15 mL) along with (4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoic acid (DHA, 352 mg, 1.08 mmol), HATU (450 mg, 1.2 mmol) and DIEA (0.550 mL). The resulting reaction mixture was stirred at room temperature for 2 h. It was then diluted with EtOAc and washed successively with saturated aqueous NaHCO3 and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. Purification by chromatography (60% EtOAc, 40% pentane) afforded N-(2-(2-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoethyl)disulfanyl)ethyl)-2-hydroxybenzamide (280 mg, 44%). Mass calculated for C33H46N2O3S2: 582.3; found: [M+H]+=583.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:17]=[CH:18][C:19]4[O:23][C:22]([C:24]5([NH:32]C(=O)OC(C)(C)C)[CH2:29][O:28]C(C)(C)[O:26][CH2:25]5)=[CH:21][C:20]=4[CH:40]=3)[N:12]=2)=[CH:7][C:6]=1[O:41][CH3:42])[CH2:2][CH3:3].ClC1C=C(C2ON=C(C3C=CC4OC(C5(NC(=O)OC(C)(C)C)COC(C)(C)OC5)=CC=4C=3)N=2)C=CC=1OCCC>>[NH2:32][C:24]([C:22]1[O:23][C:19]2[CH:18]=[CH:17][C:16]([C:13]3[N:12]=[C:11]([C:8]4[CH:9]=[CH:10][C:5]([O:4][CH2:1][CH2:2][CH3:3])=[C:6]([O:41][CH3:42])[CH:7]=4)[O:15][N:14]=3)=[CH:40][C:20]=2[CH:21]=1)([CH2:25][OH:26])[CH2:29][OH:28]
Reactant: CCCOc1ccc(-c2nc(-c3ccc4oc(C5(NC(=O)OC(C)(C)C)COC(C)(C)OC5)cc4c3)no2)cc1OC
Agent: CCCOc1ccc(-c2nc(-c3ccc4oc(C5(NC(=O)OC(C)(C)C)COC(C)(C)OC5)cc4c3)no2)cc1Cl
Product: CCCOc1ccc(-c2nc(-c3ccc4oc(C(N)(CO)CO)cc4c3)no2)cc1OC
Yield: 57 %

Procedure:
When the product of Step C was substituted for tert-butyl 5-(5-(5-(3-chloro-4-propoxyphenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate in Example 36, Step E, the similar procedure afforded the title compound in 57% yield, as colourless solid. 1H-NMR (DMSO-d6) 8.28 (s, 1H); 7.92 (d, 1H, J=2.82 Hz); 7.61 (m, 3H); 7.16 (d, 1H, J=8.53 Hz); 6.88 (s, 1H); 4.78 (b, 2H); 4.01 (t, 2H, J=6.03 Hz); 3.99 (s, 3H); 3.77-3.57 (m, 4H); 1.78-1.71 (m, 2H); 0.96 (t, 3H, J=7.29 Hz).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[Cl:10][C:11]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14]>C(OCC)(=O)C>[Cl:10][C:11]1[CH:19]=[C:18]([F:20])[C:17]([N+:1]([O-:4])=[O:2])=[CH:16][C:12]=1[C:13]([OH:15])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1ccc(F)cc1Cl
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: O=C(O)c1cc([N+](=O)[O-])c(F)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.2 %

Procedure:
A blend of 70% nitric acid (64.5 gm) and concentrated sulfuric acid (65 mL) was added dropwise over an hour period to a suspension of 2-chloro-4-fluoro-benzoic acid (125.0 gm, 716 mL). The white suspension was stirred mechanically for 30 minutes at ambient temperature. The thick white suspension was carefully poured into ice-water (100 mL). Ethyl acetate (800 mL) was added. The organic layer was separated, dried (MgSO4) and evaporated to dryness under vacuum to give the title compound of Step A as a white solid (156.0 gm, 99%); m.p. 134°-136° C.; IR (cm-1), C=O (1719.8). This intermediate was used without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[C:14]([CH2:16][OH:17])[CH:13]=[C:12]([C:18]([OH:20])=O)[CH:11]=1)#[N:2].Cl.Cl.[CH3:23][C:24]1[N:29]=[CH:28][C:27]([C@H:30]([NH2:32])[CH3:31])=[CH:26][CH:25]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[C:14]([CH2:16][OH:17])[CH:13]=[C:12]([C:18]([NH:32][C@@H:30]([C:27]2[CH:28]=[N:29][C:24]([CH3:23])=[CH:25][CH:26]=2)[CH3:31])=[O:20])[CH:11]=1)#[N:2]
Reactant: Cc1ccc([C@@H](C)N)cn1
Reactant: Cc1ccc(-c2cc(CO)cc(C(=O)O)c2)c(C#N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(CO)cc(C(=O)N[C@H](C)c3ccc(C)nc3)c2)c(C#N)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 2′-cyano-5-(hydroxymethyl)-4′-methylbiphenyl-3-carboxylic acid (40 mg, 0.15 mmol) in N,N-dimethylformamide (1 mL) were added (R)-1-(6-methylpyridin-3-yl)ethanamine dihydrochloride (60 mg, 0.29 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (120 mg, 0.32 mmol), and N,N-diisopropylethylamine (400 μL, 2.3 mmol). The reaction mixture was stirred for 16 hours at 25° C., and then purified by preparative HPLC to afford the final product as a light color solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14](Br)=[CH:15][N:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:19]([C:21]1[CH:22]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:24]=[N:25][CH:26]=1)=[O:20].C(=O)([O-])[O-].[Na+].[Na+]>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:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:23]3[CH:24]=[N:25][CH:26]=[C:21]([CH:19]=[O:20])[CH:22]=3)=[CH:15][N:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(c2cncc(C=O)c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCCc2cc(Br)cnc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCCc2cc(-c3cncc(C=O)c3)cnc21
Temperature: 100 °C
Yield: 79.9 %

Procedure:
A vial containing 6-bromo-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester (3.35 g, 10.7 mmol), 5-formylpyridine-3-boronic acid pinacol ester (2.74 g, 11.8 mmol), 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium (II) (870 mg, 1.1 mmol), and aqueous sodium carbonate solution (2M, 7.5 mL, 15.0 mmol) in 1,4-dioxane (75 mL) is flushed with Ar, sealed tightly and heated to 100° C. for 1 h. The reaction mixture is cooled to room temperature and partitioned between water and EtOAc. The layers are separated and the aqueous is further extracted with EtOAc. The combined organic layers are washed with brine and filtered through diatomaceous earth, rinsing well with EtOAc. The filtrate is dried (Na2SO4) and concentrated. The crude product is purified on silica gel column (25-100% EtOAc in heptane) to afford 6-(5-formyl-pyridin-3-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester (2.9 g).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.C[Si]([C:28]#[C:29][C:30]1[CH:31]=[N:32][CH:33]=[C:34]([CH:37]=1)[C:35]#[N:36])(C)C>C(N(CC)CC)C.C(OCC)(=O)C>[C:29]([C:30]1[CH:31]=[N:32][CH:33]=[C:34]([CH:37]=1)[C:35]#[N:36])#[CH:28]
Reactant: C[Si](C)(C)C#Cc1cncc(C#N)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C#Cc1cncc(C#N)c1
Reaction time: 0.08 h
Yield: 74.1 %

Procedure:
Add a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (50.0 mL, 50.0 mmol) to a suspension of 5-trimethylsilanylethynyl-nicotinonitrile (10.0 g, 50.0 mmol), (prepared as described in PREPARATION 3), in triethylamine (98 mL) at 0° C. After 5 min, dilute the reaction mixture with ethyl acetate and wash twice with water. Back-extract the combined aqueous washes twice with ethyl acetate. Wash the combined organic layers with a saturated aqueous solution of sodium chloride, dry (sodium sulfate), filter, and concentrate. Purify the residue by silica gel chromatography, eluting with a gradient from 98:2 to 90:10 dichloromethane:ethyl acetate, to give the title compound as a white crystalline solid (4.75 g, 74%).