Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:8]2[CH:9]=[CH:10][C:11](=[O:17])[N:12]([CH2:14][CH2:15][OH:16])[CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N(C(N(C)C)=O)=NC(N(C)C)=O.C(P(CCCC)CCCC)CCC.O[C:50]1[CH:51]=[C:52]([S:56][CH2:57][CH2:58][CH2:59][C:60]([O:62][CH2:63][CH3:64])=[O:61])[CH:53]=[CH:54][CH:55]=1>C1(C)C=CC=CC=1.CCOC(C)=O>[C:18]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:9]=[CH:10][C:11](=[O:17])[N:12]([CH2:14][CH2:15][O:16][C:54]3[CH:53]=[C:52]([S:56][CH2:57][CH2:58][CH2:59][C:60]([O:62][CH2:63][CH3:64])=[O:61])[CH:51]=[CH:50][CH:55]=3)[CH:13]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(=O)CCCSc1cccc(O)c1
Reactant: O=c1ccc(C(c2ccccc2)c2ccccc2)cn1CCO
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCSc1cccc(OCCn2cc(C(c3ccccc3)c3ccccc3)ccc2=O)c1
Temperature: 25 °C
Yield: 84.1 %

Procedure:
To a solution of 5-(diphenylmethyl)-1-(2-hydroxyethyl)pyridin-2(1H)-one (300 mg) in toluene (4.0 mL) were added 1,1′-azobis(N,N-dimethylformamide) (203 mg) and tributylphosphine (291 μL) at ambient temperature. And then to the mixture was added a solution of ethyl 4-[(3-hydroxyphenyl)sulfanyl]butanoate (378 mg) in toluene (2.0 mL) at 0° C. After stirring at ambient temperature for an hour, the reaction mixture was diluted with EtOAc (10 mL). The mixture was washed with water (10 mL) and brine (10 mL). The organic layer was dried over anhydrous MgSO4, filtered and evaporated in vacuo to give crude oil. The oil was purified by silica gel column chromatography(n-hexane:EtOAc=4:1-1:1) to give ethyl 4-[(3-{2-[5-(diphenylmethyl)-2-oxopyridin-1(2H)-yl]ethoxy}phenyl)sulfanyl]butanoate (436 mg) as a colorless oil.
Reaction SMILES: [CH3:1][CH:2]([C:11](=[O:21])[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=O)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[F:22][C:23]1[C:29]([F:30])=[C:28]([F:31])[C:27]([F:32])=[C:26]([F:33])[C:24]=1[NH2:25]>C1(C)C(C)=CC=CC=1>[CH3:1][C:2]1[C:11](=[O:21])[CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:25]([C:24]2[C:26]([F:33])=[C:27]([F:32])[C:28]([F:31])=[C:29]([F:30])[C:23]=2[F:22])[C:3]=1[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: Nc1c(F)c(F)c(F)c(F)c1F
Reactant: CC(C(=O)CC(=O)c1ccccc1)C(=O)c1ccccc1
Solvent: Cc1ccccc1C
Product: Cc1c(-c2ccccc2)n(-c2c(F)c(F)c(F)c(F)c2F)c(-c2ccccc2)cc1=O
Yield: 27.7 %

Procedure:
In 110 ml of xylene were dissolved 3.1 g (0.011 mole) of 2-methyl-1,5-diphenyl-1,3,5-pentanetrione, 20.0 g (0.11 mole) of 2,3,4,5,6-pentafluoroaniline, 3.1 g (0.016 mole) of paratoluenesulfonic acid and 22.0 g of Molecular Sieves 5A, followed by reflux for 1 hours. After cooling the reaction mixture, solid matter was removed by filtration and the filtrate was then concentrated. After 200 ml of chloroform was added, the resultant solution in chloroform was washed first with 50 ml of 10% hydrochloric acid and then with 50 ml of a 10% aqueous solution of sodium hydroxide. After washing the solution in chloroform further with water, it was dried over anhydrous sodium sulfate. Subsequent to removal of the sodium sulfate, the solvent was distilled off and the residue was subjected to column chromatography (eluent: 50.1 mixed solvent of chloroform and methanol). The resulting crystals were recrystallized from a 1:1 mixed solvent of acetone and hexane, thereby affording 1.3 g of 3-methyl-1-(2,3,4,5,6-pentafluorophenyl)-2,6-diphenyl-4(1H)-pyridinone having a melting point of 192°-194° C.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:21])[CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[O:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[N:13][N:14]=1>C1COCC1.CO>[N:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:12]1[O:11][C:10]([CH2:9][CH2:8][CH2:7][CH2:6][C:5]([OH:21])=[O:4])=[N:14][N:13]=1
Reactant: COC(=O)CCCCc1nnc(-c2ccccn2)o1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CCCCc1nnc(-c2ccccn2)o1
Yield: 26.7 %

Procedure:
Add 2 N sodium hydroxide (20 mL) to a solution of 5-(5-pyridin-2-yl[1,3,4]oxadiazol-2-yl)pentanoic acid methyl ester (8.16 g, 31 mmol) in THF (60 mL) and methanol (20 mL) at room temperature under nitrogen and heat the mixture at reflux for 12 hours. Remove the solvent under reduced pressure, dilute the residue with water (500 mL), and wash with ethyl acetate (200 mL). Adjust the pH of the aqueous layer to pH 3 with concentrated HCl and extract with ethyl acetate (3×200 mL). Wash the combined organic extracts with brine (200 mL), dry over sodium sulfate, and remove the solvent under reduced pressure to afford 5-(5-pyridin-2-yl[1,3,4]oxadiazol-2-yl)pentanoic acid (2.05 g, 27%). APCI mass spectrum m/z 246 [C12H13N3O3+H]+.
Reaction SMILES: Br[Si](C)(C)C.[NH2:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[O:16][CH2:17][CH:18]([OH:30])[CH2:19][O:20][CH2:21][P:22]([O:27]CC)([O:24]CC)=[O:23])=[C:9]([O:31]C)[N:8]=1>ClCCl>[OH:30][CH:18]([CH2:19][O:20][CH2:21][P:22]([OH:24])([OH:27])=[O:23])[CH2:17][O:16][N:13]1[CH:12]=[N:11][C:10]2[C:9](=[O:31])[NH:8][C:7]([NH2:6])=[N:15][C:14]1=2
Reactant: CCOP(=O)(COCC(O)COn1cnc2c(OC)nc(N)nc21)OCC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: Nc1nc2c(ncn2OCC(O)COCP(=O)(O)O)c(=O)[nH]1
Temperature: 20 °C
Reaction time: 16 h
Yield: 72.4 %

Procedure:
Bromotrimethylsilane (1.43 ml, 10.9 mmol) was added to a solution of 2-amino-9-[3-(diethoxyphosphorylmethoxy)-2-hydroxypropoxy]-6-methoxypurine (220 mg, 0.54 mmol) in dichloromethane (10 ml) and then stirred at 20° C. for 16 h. The reaction mixture was evaporated in vacuo and co-evaporated with toluene. The residue was recrystallised from water-acetone affording 9-[2-hydroxy-3-(phosphonomethoxy)propoxy]guanine (131 mg, 72%) as a white solid m.p. 245°-247° C., decomp. λmax (H2O) 252 (ε13,200)nm; νmax (KBr) 3400, 3300, 1720, 1640, 1590 and 1380 cm-1 ; δH [(CD3)2SO] 3.58 (2H, m, CH2OCH2P), 3.60 (2H, d, J8.5 Hz, CH2P), 3.91 (1H, m, CHOH), 4.17 (1H, m, CH2ON), 4.30 (1H, m, CH2ON), 6.64 (2H, br.s, D2O exchangeable, NH2), 7.93 (1H, s, H-8), 10.63 (1H, br.s, D2O exchangeable, NH); m/z (FAB+ve Ion), 336 (MH+). Found: C, 32.32; H, 4.08; N, 20.66%; C9H14N5O7P requires C, 32.25; H, 4.21; N, 20.89%.
Reaction SMILES: N1C(C)=CC=CC=1C.[C:9]([S:12][CH:13]1[N:16]([CH:17](Cl)[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)=[O:19])[C:15](=[O:32])[CH2:14]1)(=[O:11])[CH3:10].[C:33]1([P:39]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.CCOCC>O1CCOCC1>[C:9]([S:12][CH:13]1[N:16]([C:17](=[P:39]([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)=[O:19])[C:15](=[O:32])[CH2:14]1)(=[O:11])[CH3:10]
Reactant: CC(=O)SC1CC(=O)N1C(Cl)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1cccc(C)n1
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC(=O)SC1CC(=O)N1C(C(=O)OCc1ccc([N+](=O)[O-])cc1)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 18 h

Procedure:
2,6-Lutidine (2.14 g., 20 mmole) was added to a solution of p-nitrobenzyl 2-(4-acetylthio-2-oxo-1-azetidinyl)-2-chloroacetate (5.9 g., 16 mmole) and triphenylphosphine (5.8 g., 22 mmole) in dioxane (80 ml.). The solution was kept at 55° for 18 hours and then concentrated on a rotary evaporator. The residue was partitioned between brine and ethyl acetate and the organic phase was washed with brine, dried and concentrated. The residue was purified by chromatography over silica gel (ethyl acetate:petroleum ether, 1:2 v/v) to give 4.64 g. (48%) of the title ether.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:42]=[CH:43][CH:44]=1)[O:13][C:14]1[S:18][C:17]([NH:19][C:20](=[O:41])[CH:21]([C:29]2[CH:34]=[CH:33][C:32]([S:35]([CH:38]3[CH2:40][CH2:39]3)(=[O:37])=[O:36])=[CH:31][CH:30]=2)[O:22][CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[N:16][CH:15]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C(OCC)(=O)C>C1COCC1>[CH:38]1([S:35]([C:32]2[CH:33]=[CH:34][C:29]([CH:21]([O:22][CH:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:20]([NH:19][C:17]3[S:18][C:14]([O:13][C:12]4[CH:42]=[CH:43][CH:44]=[C:10]([CH2:9][OH:8])[CH:11]=4)=[CH:15][N:16]=3)=[O:41])=[CH:30][CH:31]=2)(=[O:37])=[O:36])[CH2:40][CH2:39]1
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(Oc2cnc(NC(=O)C(OC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)s2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1ncc(Oc2cccc(CO)c2)s1)C(OC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.4 %

Procedure:
N-[5-[3-[[tert-butyl(dimethyl)silyl]oxymethyl]phenoxy]thiazol-2-yl]-2-(4-cyclopropylsulfonylphenyl)-2-tetrahydropyran-4-yloxy-acetamide (0.05 g, 0.0758 mmol) was taken in 3 mL of dry THF and to it tetra-n-butylammonium fluoride (0.16 mL, 0.16 mmol, 1M solution in THF) was added in inert atmosphere at 0° C. After complete addition the reaction was stirred for overnight at room temperature. TLC showed complete reaction. The reaction mixture was portioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed on vacuo to get the crude product which was purified by preparative TLC to get the solid product (0.020 g).
Reaction SMILES: C[O:2][C:3]1[C:8]([CH2:9][CH2:10][N:11]2[C:15](=[O:16])[C:14]3=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]3[C:12]2=[O:21])=[CH:7][C:6]([CH2:22][CH3:23])=[C:5]([CH3:24])[N:4]=1.Cl.N1C=CC=CC=1>>[C:12]1(=[O:21])[N:11]([CH2:10][CH2:9][C:8]2[C:3](=[O:2])[NH:4][C:5]([CH3:24])=[C:6]([CH2:22][CH3:23])[CH:7]=2)[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]12
Reactant: CCc1cc(CCN2C(=O)c3ccccc3C2=O)c(OC)nc1C
Agent: Cl
Solvent: c1ccncc1
Product: CCc1cc(CCN2C(=O)c3ccccc3C2=O)c(=O)[nH]c1C

Procedure:
2-methoxy-3-(2-phthalimidoethyl)-5-ethyl-6-methyl pyridine is heated at 150° C. for 5-10 minutes in the presence of excess pyridine hydrochloride to give the above titled product.
Reaction SMILES: Cl[C:2]1[N:22]=[C:5]2[C:6]([NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:21][S:18]([CH2:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[NH:10][C:6]1[C:5]2[N:4]([N:3]=[C:2]([NH:36][C:33]3[CH:32]=[CH:31][C:30]([N:27]4[CH2:26][CH2:25][N:24]([CH3:23])[CH2:29][CH2:28]4)=[CH:35][CH:34]=3)[N:22]=2)[CH:9]=[CH:8][CH:7]=1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cc1ccccc1Nc1cccn2nc(Cl)nc12
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2ccc(Nc3nc4c(Nc5ccccc5CS(C)(=O)=O)cccn4n3)cc2)CC1

Procedure:
164 a) A suspension of o-Nitrobenzylbromide (5.71 g, 26.4 mmol) and sodium methanesulfinate (4.0 g, 40.0 mmol) in ethanol (70 mL) was stirred at room temperature for 18 hours. The volatiles were evaporated under reduced pressure. To the residue was added water (50 mL) and stirred for 30 minutes. The suspension was filtered, rinsed with water and air dried. 1-Methanesulfonylmethyl-2-nitro-benzene was isolated as a yellow solid (5.36 g, 94%). MP=115-117° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.10 (d, J=8.1 Hz, 1H), 7.74-7.65 (m, 2H), 7.62-7.58 (m, 1H), 4.80 (s, 2H), 2.91 (s, 3H). 164 b) 2-Methanesulfonylmethyl-phenylamine was prepared from 1-methanesulfonylmethyl-2-nitro-benzene (1.0 g, 4.6 mmol) in a manner analogous to Example 111a. Product isolated as an off-white solid (0.84 g, 98%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.20 (t, J=7.5 Hz, 1H), 7.09 (d, J=7.5 Hz, 1H), 6.86-6.76 (m, 2H), 4.30 (s, 2H), 4.28 (br s, 2H), 2.87 (s, 3H). MS=186 (MH)+. 164 c) (2-Chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(2-methanesulfonylmethyl-phenyl)-amine was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (500.0 mg, 2.151 mmol) and 2-methanesulfonylmethyl-phenylamine (440.0 mg, 2.375 mmol) in a manner analogous to Example 2d. Product isolated as a tan solid (0.62 g, 51%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.02 (d, J=5.9 Hz, 1H), 7.71 (s, 1H), 7.53 (d, J=8.3 Hz, 1H), 7.47-7.41 (m, 3H), 6.89-6.81 (m, 2H), 4.41 (s, 2H), 2.93 (s, 3H). MS=337, 339 (MH)+. 164 d) N(8)-(2-Methanesulfonylmethyl-phenyl)-N(2)-[4-(4-methyl-piperazin-1-yl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridine-2,8-diamine was prepare from (2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(2-methanesulfonylmethyl-phenyl)-amine (75.0 mg, 0.223 mmol) and 4-(4-Methyl-piperazin-1-yl)-phenylamine (47.0 mg, 0.246 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a brown foam (0.013 g, 12%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.96 (d, J=6.8 Hz, 1H), 7.70 (s, 1H), 7.56 (d, J=8.2 Hz, 1H), 7.51 (d, J=8.8 Hz, 2H), 7.43-7.37 (m, 2H), 7.18 (t, J=7.4 Hz, 1H), 6.96 (d, J=8.8 Hz, 2H), 6.83 (d, J=7.8 Hz, 1H), 6.70 (s, 1H), 6.67 (t, J=7.1 Hz, 1H), 4.45 (s, 2H), 3.18-3.13 (m, 4H), 2.94 (s, 3H), 2.62-2.57 (m, 4H), 2.36 (s, 3H). MS=492 (MH)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][C:14]([O:16]C)=[O:15])[CH:8]=[CH:7]2)([O-:3])=[O:2].[OH-].[K+]>>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][C:14]([OH:16])=[O:15])[CH:8]=[CH:7]2)([O-:3])=[O:2]
Reactant: COC(=O)Cn1ccc2cc([N+](=O)[O-])ccc21
Agent: [K+]
Agent: [OH-]
Product: O=C(O)Cn1ccc2cc([N+](=O)[O-])ccc21

Procedure:
(5-Nitro-1H-indol-1-yl)acetic acid was prepared from methyl (5-nitro-1H-indol-1-yl)acetate by KOH hydrolysis: MS (ESI) m/z 219.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=2)=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.CC([O-])=O.[K+].[C:48]([O:52][C:53]([N:55]1[CH2:59][CH2:58][CH2:57][CH:56]1[C:60]1[NH:61][C:62]([C:65]2[CH:74]=[CH:73][C:72]3[C:67](=[CH:68][CH:69]=[C:70](Br)[CH:71]=3)[CH:66]=2)=[CH:63][N:64]=1)=[O:54])([CH3:51])([CH3:50])[CH3:49].[O-]P([O-])([O-])=O.[K+].[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:48]([O:52][C:53]([N:55]1[CH2:59][CH2:58][CH2:57][CH:56]1[C:60]1[NH:61][C:62]([C:65]2[CH:74]=[CH:73][C:72]3[C:67](=[CH:68][CH:69]=[C:70]([C:21]4[CH:20]=[CH:19][C:18]([C:15]5[NH:14][C:13]([CH:9]6[CH2:10][CH2:11][CH2:12][N:8]6[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[N:17][CH:16]=5)=[CH:23][CH:22]=4)[CH:71]=3)[CH:66]=2)=[CH:63][N:64]=1)=[O:54])([CH3:51])([CH3:50])[CH3:49]
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc3cc(Br)ccc3c2)[nH]1
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc(Br)cc2)[nH]1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)OC(C)(C)C)[nH]5)ccc4c3)cc2)[nH]1
Temperature: 85 °C
Yield: 10.4 %

Procedure:
To a solution of 2-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.39 g, 1.0 mmol) and bis(pinacolato)diborane (0.31 g, 1.2 mmol, 1.2 equiv.) in dioxane (5 mL) was added KOAc (0.30 g, 3.0 mmol, 3 equiv.) and Pd(dppf)Cl2 (0.04 g, 0.05 mmol, 0.05 equiv.). The slurry was degassed with argon for 5 minutes and heated to 85° C. for 2.5 hours. The resulting solution was cooled to room temperature and 2-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.45 g, 1.0 mmol, 1 equiv.) and K3PO4 (aqueous, 2 M, 1.75 mL, 3.5 mmol, 3.5 equiv.) was added. The reaction mixture was heated to 85° C. for 6 hours. The slurry was filtered through CELITE and concentrated. The crude product was purified by column chromatography (SiO2, 50→100% EtOAc in Hexanes (2% MeOH)) and preparative HPLC (Gemini, 15→40% MeCN in H2O (0.1% formic acid)) to provide 2-[5-(6-{4-[2-(1-tert-butyloxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]-phenyl}-naphthalen-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.07 g, 10%) as a white powder. LCMS-ESI+: calc'd for C40H46N6O4: 674.4 (M+). Found: 675.6 (M+H+).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([NH:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[O:8])=[CH:5][CH:4]=1.[CH2:17]([CH:20]1[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]1)[CH2:18][CH3:19].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH2:17]([CH:20]1[CH2:25][CH2:24][CH:23]([NH:1][CH2:2][C:3]2[CH:4]=[CH:5][C:6]([C:7]([NH:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[O:8])=[CH:15][CH:16]=2)[CH2:22][CH2:21]1)[CH2:18][CH3:19]
Reactant: CCCC1CCC(=O)CC1
Reactant: NCc1ccc(C(=O)NCCC(=O)O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCCC1CCC(NCc2ccc(C(=O)NCCC(=O)O)cc2)CC1
Temperature: 25 °C

Procedure:
The resulting resin bound 3-(4-aminomethylbenzoylamino)propionic acid was treated with 98 mg 4-propylcyclohexanone (700 μmol) dissolved in 500 μL 1,2-dichloroethane, 50 μL acetic acid and a slurry of 148 mg NaBH(OAc)3 (700 μmol) in 1 mL 1,2-dichloroethane. Over night shaking at 25° C. followed by filtration and washing with 2×1 mL dichloromethane, 2×1 mL CH3OH:DMF 1:1 and 3×1 mL DMF afforded resin bound 3-{4-[(4-propylcyclohexylamino)-methyl]benzoylamino}propionic acid.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([N:11]=[N:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][C:21]=3[NH:23][S:24]([CH3:27])(=[O:26])=[O:25])[C:16]([O:28]CC)=[C:15](C(O)=O)[CH:14]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].Br.[Br:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][NH2:42].N1C(C)=CC=CC=1C>O1CCCC1>[Br:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][NH:42][S:2]([C:5]1[CH:6]=[C:7]([N:11]=[N:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][C:21]=3[NH:23][S:24]([CH3:27])(=[O:26])=[O:25])[C:16]([OH:28])=[CH:15][CH:14]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: NCCCCCCBr
Reactant: CCOc1c(C(=O)O)cc(N=Nc2cccc(S(=O)(=O)Cl)c2)c2c(NS(C)(=O)=O)cccc12
Agent: Br
Solvent: Cc1cccc(C)n1
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1cccc2c(O)ccc(N=Nc3cccc(S(=O)(=O)NCCCCCCBr)c3)c12

Procedure:
A suspension of 4-[3-chlorosulfonylphenylazo]-1-ethoxycarboxy-5-methanesulfonamidonaphthalene (20.4 g), 6-bromohexylamine hydrobromide (14.4 g), 2,6-lutidine (600 ml) and tetrahydrofuran (30 ml) was reacted for one hour at 50°-55° C. The mixture was cooled and filtered; the filtrate was concentrated to an oil which was dissolved in a minimum amount of acetonitrile and chromatographed on silica gel using acetonitrile as the eluant. The orange colored eluate was concentrated and cooled to obtain the product; yield 7.3 g (32%), m.p. 163°-5° C.
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH:9][C@H:10]2[CH2:15][CH2:14][C@@H:13]([C:16]([CH3:21])([CH3:20])[CH:17]([CH3:19])[CH3:18])[CH2:12][CH2:11]2)[C:4]=1I)[CH3:2].[Cu][C:24]#[N:25]>>[C:24]([C:4]1[C:5]([NH:9][C@H:10]2[CH2:15][CH2:14][C@@H:13]([C:16]([CH3:21])([CH3:20])[CH:17]([CH3:19])[CH3:18])[CH2:12][CH2:11]2)=[N:6][CH:7]=[N:8][C:3]=1[CH2:1][CH3:2])#[N:25]
Reactant: N#C[Cu]
Reactant: CCc1ncnc(N[C@H]2CC[C@@H](C(C)(C)C(C)C)CC2)c1I
Product: CCc1ncnc(N[C@H]2CC[C@@H](C(C)(C)C(C)C)CC2)c1C#N

Procedure:
Prepared as in Example 2 from 6-ethyl-5-iodo-4-[cis-4-(1,1,2-trimethylpropyl)cyclohexylamino]pyrimidine and copper(I) cyanide.
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:15])[CH2:8][CH2:9][CH2:10][C:11]=3[NH:12]2)=[CH:4][CH:3]=1.[CH3:16]N(C=O)C>>[F:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:15])[CH2:8][CH2:9][CH2:10][C:11]=3[N:12]2[CH3:16])=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: O=C1CCCc2[nH]c3cc(F)ccc3c21
Product: Cn1c2c(c3ccc(F)cc31)C(=O)CCC2
Reaction time: 1.5 h

Procedure:
A solution of 7-fluoro-1,2,3,9-tetrahydro-4H-carbazol-4-one (1.0 g) in dry DMF (8 ml) was added dropwise to a stirred, ice-cooled suspension of pre-washed (hexane: 2×10 ml) sodium hydride (78% dispersion in oil; 175 mg) in dry DMF (5 ml) under nitrogen and stirring was continued at room temperature for 1.5 h. The solution was cooled to 0°, iodomethane (0.35 ml) was added dropwise and stirring was continued at 0° for 2 h. The suspension was poured into 8% aqueous sodium bicarbonate (30 ml) extracted with dichloromethane (2×30 ml) and the combined, dried organic extracts were evaporated and dried in vacuo at 100° for 18 h to give the title compound (1.03 g) as a solid, m.p. 174°-175°.
Reaction SMILES: [CH2:1]1[C:6](=[O:7])[S:5][CH2:4][C:2]1=[O:3].C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.[C:27](O)(=[O:45])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]/[CH:35]=[CH:36]\[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44].Cl>CN(C)C=O>[OH:3][C:2]1[CH2:4][S:5][C:6](=[O:7])[C:1]=1[C:27](=[O:45])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]/[CH:35]=[CH:36]\[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]
Reactant: O=C1CSC(=O)C1
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCCCCC/C=C\CCCCCCCC(=O)C1=C(O)CSC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 33 %

Procedure:
To a stirring solution of 1.71 g (14.75 mmol) of thiotetronic acid in 10 mL of dimethylformamide is added 2.22 mL (17.2 mmol) of triethylamine and 592 mg (4.85 mmol) of 4-diemthylaminopyridine at 0° C. Next, 3.38 g (17.6 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 5.0 g (17.7 mmol) of oleic acid are added and the reaction mixture is stirred overnight at room temperature. The reaction is acidified with 1.0N HCl and extracted three times with diethyl ether. The combined organic layers are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue is subjected to HPLC chromatography (2 inch Dynamax silica gel column, 25 mL/min) eluting with 100% ethyl acetate to give 1.85 g (33%) of 4-hydroxy-3-[(Z)-1-oxo-9-octadecenyl]-2(5H)-thiophenone as an oil.
Reaction SMILES: [F:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@:9]1([CH2:20][F:21])[CH2:14][C@@H:13]([C:15]([F:18])([F:17])[F:16])[O:12][C:11]([NH2:19])=[N:10]1.[N+:22]([O-])([O-:24])=[O:23].[K+].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(O)=O.[Na+].[OH-].[Na+]>OS(O)(=O)=O.O.C(Cl)Cl>[F:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:22]([O-:24])=[O:23])=[CH:4][C:3]=1[C@:9]1([CH2:20][F:21])[CH2:14][C@@H:13]([C:15]([F:17])([F:18])[F:16])[O:12][C:11]([NH2:19])=[N:10]1
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1cccc([C@]2(CF)C[C@@H](C(F)(F)F)OC(N)=N2)c1F
Agent: O=C([O-])O
Agent: O=P([O-])([O-])[O-]
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: O
Product: Cc1cc([N+](=O)[O-])cc([C@]2(CF)C[C@@H](C(F)(F)F)OC(N)=N2)c1F
Reaction time: 0.08 h
Yield: 97.3 %

Procedure:
(4S,6S)-4-(2-fluoro-3-methylphenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (1.13 g, 3.67 mmol) was dissolved in conc. H2SO4 (20 mL) and cooled in an ice-bath. Then potassium nitrate (0.264 ml, 5.50 mmol) was added in one portion and the reaction was stirred for 5 min, removed from the ice-bath and after 5 min at room temperature LCMS showed the reaction went to completion and ice was added. The reaction mixture was poured into a mixture of DCM, water, ice and potassium phosphate tribasic (61.5 g, 290 mmol) and stirred for 5 min followed by the slowly addition of saturated NaHCO3. The mixture was neutralized with 5 N NaOH and extracted with DCM. The combined organics were dried over Na2SO4, filtered and concentrated to afford a pale yellow foam as (4S,6S)-4-(2-fluoro-3-methyl-5-nitrophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (1.26 g, 3.57 mmol, 97% yield). MS m/z=353.9 [M+H]+. Calculated for C13H12F5N3O3: 353.08.