Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:3]1.[CH:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH2:16]([NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:4][CH2:3]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](NCc2ccccc2)CC1

Procedure:
The title compound was prepared by a similar method to example 5 from tert-butyl trans-4-aminocyclohexylcarbamate (1.0 g, 4.7 mmol) (J. Org. Chem. 8811, 61, 1996), benzaldehyde (530 mg, 5 mmol) and sodium triacetoxyborohydride (2.0 g, 9.4 mmol). The product was purified by column chromatography on silica gel eluting with a solvent system of dichloromethane:methanol:ammonia (95:5:0.5) to give the title compound (0.73 g) as a solid.
Reaction SMILES: [O:1]=[C:2]([CH3:13])[CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5]1.[Cl:14]N1C(=O)CCC1=O.C(OCC)(=O)C>C1COCC1>[Cl:14][C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:4]([CH2:3][C:2](=[O:1])[CH3:13])[CH:5]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(=O)Cn1ccc2ccccc21
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)Cn1cc(Cl)c2ccccc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 1-(2-oxopropyl)indole from Example 3, Step 1 (800 mg, 4.6 mmol) in dry THF (20 mL) was added in one portion at r.t. N-chlorosuccinimide (680 mg, 5.1 mmol). The resulting reaction mixture was stirred at room temperature for 1.5 hours. Ethyl acetate was then added (200 mL) and the organic phase was washed successively with 1N HCl, saturated NaHCO3, brine, dried and evaporated. The crude product was purified by flash chromatography eluting with 25% EtOAc in hexanes to yield the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][S:5]([C:8]1[N:12]=[CH:11][NH:10][N:9]=1)(=[O:7])=[O:6].C(N(CC)CC)C.[CH2:20]([N:22]([CH:26]([CH3:28])[CH3:27])[C:23](Cl)=[O:24])[CH3:21]>O1CCCC1>[CH2:20]([N:22]([CH:26]([CH3:28])[CH3:27])[C:23]([N:10]1[CH:11]=[N:12][C:8]([S:5]([CH2:4][CH2:3][O:2][CH3:1])(=[O:6])=[O:7])=[N:9]1)=[O:24])[CH3:21]
Reactant: CCN(C(=O)Cl)C(C)C
Reactant: COCCS(=O)(=O)c1nc[nH]n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCN(C(=O)n1cnc(S(=O)(=O)CCOC)n1)C(C)C

Procedure:
A solution of 0.03 mole of 3-(2-methoxyethylsulphonyl)-1,2,4-triazole, 6 ml. of triethylamine and 0.033 mole of N-ethyl-N-isopropylcarbamoyl chloride in 40 ml. of dry tetrahydrofuran was heated under reflux for 15 hours. The cooled reaction mixture was filtered to remove triethylamine hydrochloride and the filtrate was evaporated to remove solvent. The product crystallized on cooling and treatment with 100 ml. of petroleum ether (b.p. 62°-68° C.). Thin solid was collected and recrystallized from 100 ml. benzene petroleum ether (b.p. 40°-60° C.) to give 1-(N-ethyl-N-isopropylcarbamoyl)-3-(2-methoxyethylsulphonyl)-1,2,4-triazole, m.p. 64°-65° C. Elemental analysis satisfactory.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])[C:5]([Cl:8])=[N:6][CH:7]=1.[C:14](=O)([O-])[O-].[K+].[K+].IC.O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([N:9]([CH3:14])[S:10]([CH3:13])(=[O:12])=[O:11])[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: CS(=O)(=O)Nc1cc(Br)cnc1Cl
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: CN(c1cc(Br)cnc1Cl)S(C)(=O)=O
Yield: 89.4 %

Procedure:
A solution of N-(5-bromo-2-chloropyridin-3-yl)methanesulfonamide (96 mg, 0.34 mmol, reagent preparation 24) in DMF (1 mL) was treated with potassium carbonate (93 mg, 0.68 mmol) and iodomethane (33 uL, 0.51 mmol) at rt for 18 h. Water was then added, and the resulting aqueous mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with aqueous lithium chloride (10%) followed by water, dried over magnesium sulfate, filtered, and concentrated in vacuo to provide N-(5-bromo-2-chloropyridin-3-yl)-N-methylmethanesulfonamide (91.2 mg, 0.304 mmol, 90% yield) as a light yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.46 (d, 1H), 8.00 (d, 1H), 3.32 (s, 3H), 3.07 (s, 3H); MS (EI) for C7H8BrClN2O2S: 299, 301, 303 (Br+Cl isotopes, MH+).
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]([F:15])[F:14].CN([CH:19]=[O:20])C>C1COCC1>[F:14][CH:13]([F:15])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[CH:19]=[O:20]
Reactant: CN(C)C=O
Reactant: FC(F)c1ccccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1ccccc1C(F)F
Reaction time: 0.5 h
Yield: 112.3 %

Procedure:
A solution of n-BuLi (4.2 mL, 10.6 mmol) in THF was added to a solution of 1-bromo-2-(difluoromethyl)benzene 51 (2.0 g, 9.7 mmol) in THF (50 mL) at −78° C. The reaction mixture was stirred for 30 min and DMF (1.4 g, 19.3 mmol) was added. Stirring was continued for 1 h at −40° C. and the reaction was quenched by the addition of sat. aq NH4Cl. The crude mixture was extracted with Et2O, dried (MgSO4) and concentrated to give 52 (1.7 g, 94% yield).
Reaction SMILES: [F:1][C:2]1[CH:38]=[C:37]([NH:39][C:40]([NH:42][C:43](=[O:51])[CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[S:41])[CH:36]=[CH:35][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][N:21]([CH2:29][CH:30]4[CH2:34][CH2:33][CH2:32][O:31]4)C(=O)OC(C)(C)C)=[CH:16][CH:15]=3)[S:13][C:6]=12>C1(C)C=CC=CC=1.C(O)(C(F)(F)F)=O>[F:1][C:2]1[CH:38]=[C:37]([NH:39][C:40]([NH:42][C:43](=[O:51])[CH2:44][C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)=[S:41])[CH:36]=[CH:35][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][NH:21][CH2:29][CH:30]4[CH2:34][CH2:33][CH2:32][O:31]4)=[CH:16][CH:15]=3)[S:13][C:6]=12
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccccc5)cc4F)c3s2)cc1)CC1CCCO1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc3cc(-c4ccc(CNCC5CCCO5)cc4)sc23)c(F)c1
Reaction time: 8 h

Procedure:
To a solution of 80 (200 mg, 0.28 mmol) in toluene (5 mL), TFA (excess) was added. The reaction mixture was allowed to stir overnight, the solvent was removed under reduced pressure and the remained solid was triturated with diethyl ether to afford title compound 81 as the di-TFA salt (130 mg, 57% yield). 1H NMR (DMSO) δ (ppm): 12.47 (s, 1H), 11.83 (s, 1H), 9.06 (s, 2H), 8.53 (dd, J=2.0 and 5.5 Hz, 1H), 8.13 (s, 1H), 8.0 (d, J=12.1 Hz, 1H), 7.97 (d, J=8.7 Hz, 2H), 7.63 (d, J=8.2 Hz, 2H), 7.53 (m, 2H), 7.32 (m, 4H), 7.27 (m, 1H), 6.68 (d, J=5.8 Hz, 1H), 4.23 (m, 1H), 3.82 (s, 2H), 3.78 (m, 1H), 3.71 (m, 1H), 3.11 (m, 1H), 2.95 (m, 1H), 2.0 (m, 1H), 1.98 (m, 2H), 1.56 (m, 1H). MS (m/z) 627.3 (M+H).
Reaction SMILES: [CH3:1][C:2]([CH3:12])=[CH:3][C:4]([CH2:7][C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:6])[CH3:5].[PH3:13]>>[CH3:12][CH:2]([CH2:3][C:4]([CH3:6])([CH3:5])[CH2:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH2:1][P:13]([CH2:1][CH:2]([CH3:12])[CH2:3][C:4]([CH3:5])([CH3:6])[CH2:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH2:1][CH:2]([CH3:12])[CH2:3][C:4]([CH3:5])([CH3:6])[CH2:7][C:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: P
Reactant: CC(C)=CC(C)(C)CC(C)(C)C
Product: CC(CP(CC(C)CC(C)(C)CC(C)(C)C)CC(C)CC(C)(C)CC(C)(C)C)CC(C)(C)CC(C)(C)C

Procedure:
Triisobutylene is reacted with phosphine according to Example 1 and the reaction mixture is subjected to vacuum stripping to remove unreacted triisobutylene and mono 2,4,4,6,6-pentamethylheptylphosphine. The residue is reacted with 1-dodecene according to Example 1 and a mixture is obtained of predominantly bis(2,4,4,6,6-pentamethylheptyl)-ndodecylphosphine and tris(2,4,4,6,6-pentamethylheptyl) phosphine. The above mixture is oxidized with hydrogen peroxide and the corresponding mixture of symmetrical branched and unsymmetrical branched tertiary phosphine oxides is obtained, useful as a metal extractant commposition.
Reaction SMILES: Cl.C([O:9][NH:10][C:11](=[O:41])[CH:12]([N:16]([CH2:28][CH2:29][C:30]([N:32]1[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][OH:40])[CH2:34][CH2:33]1)=[O:31])[S:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH:13]([CH3:15])[CH3:14])C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:9][NH:10][C:11](=[O:41])[CH:12]([N:16]([CH2:28][CH2:29][C:30]([N:32]1[CH2:33][CH2:34][N:35]([CH2:38][CH2:39][OH:40])[CH2:36][CH2:37]1)=[O:31])[S:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH:13]([CH3:15])[CH3:14]
Reactant: [H][H]
Reactant: COc1ccc(S(=O)(=O)N(CCC(=O)N2CCN(CCO)CC2)C(C(=O)NOCc2ccccc2)C(C)C)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COc1ccc(S(=O)(=O)N(CCC(=O)N2CCN(CCO)CC2)C(C(=O)NO)C(C)C)cc1

Procedure:
To a solution of N-benzyloxy-2-[{3-[4-(2-hydroxyethyl)piperazin-1-yl]-3-oxopropyl}-(4-methoxybenzenesulfonyl)amino]-3-methylbutyramide hydrochloride (0.39 grams, 0.63 mmol) in methanol (30 mL) was added 5% palladium on barium sulfate (0.19 grams). The mixture was agitated under 3 atmospheres hydrogen in a Parr shaker for 2.25 hours. The catalyst was removed by filtration through nylon (pore size 0.45 μm) and the solvent was evaporated to a tan foam which was chromatographed on silica gel eluting with 15% methanol in chloroform containing 0.5% ammonium hydroxide. Clean fractions containing the desired product were taken up in saturated sodium bicarbonate solution. The resulting mixture was extracted several times with ethyl acetate and the combined extracts were concentrated to afford N-hydroxy-2-[{3-[4-(2-hydroxyethyl)piperazin-1-yl]-3-oxopropyl}-(4-methoxybenzenesulfonyl)amino]-3-methyl-butyramide as an oil. The hydrochloride salt (0.20 grams, 61%) was formed using anhydrous hydrochloric acid in cold (0° C.) methanol. MS: 487 (M+1). Analysis calculated for C21H34N4O7S.circle-solid.HCl.circle-solid.0.5H2O: C, 47.41; H, 6.82; N, 10.53. Found: C, 47.41; H, 7.11; N, 9.91.
Reaction SMILES: B(F)(F)F.CCOCC.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.[CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]=1>C1(C)C=CC=CC=1>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:13][CH:12]=1
Reactant: Oc1ccc(Br)cc1
Reactant: C1=CCCCC1
Agent: FB(F)F
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: Brc1ccc(OC2CCCCC2)cc1
Temperature: 40 °C
Reaction time: 5 h

Procedure:
Boron trifluoride etherate (5.83 mL) was added to a mixture of 4-bromophenol (39.8 g) and cyclohexene (187 mL) in toluene (160 mL) to form bright orange-red solution. The mixture was stirred at 40° C. under nitrogen for 5 hr. The mixture was quenched with 2N NaOH aq. (40 mL) and water at room temperature and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with hexane) to give the title compound (46.3 g) as pale yellow oil.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.C(N(CC)CC)C.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>C(Cl)Cl>[O:8]=[C:6]1[NH:7][CH:3]([CH2:2][O:1][S:22]([C:19]2[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=2)(=[O:24])=[O:23])[CH2:4][CH2:5]1
Reactant: O=C1CC[C@@H](CO)N1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2CCC(=O)N2)cc1
Yield: 70.5 %

Procedure:
To of (S)-(+)-5-(Hydroxymethyl)-2-pyrrolidinone (1.0 g 8.69 mmol) and triethylamine (1.21 ml, 8.69 mmol) in 50 mL of methylene chloride was added 1.66 g (8.69 mmol) of p-toluenesulfonyl chloride. The resultant solution was stirred at room temperature for 3 days. The organic solution was washed 1× with water, dried over MgSO4, filtered, and concentrated. Silica gel chromatography (95:5 ethyl acetate/methanol) gave 1.65 g (71%) of toluene-4-sulfonic acid 5-oxo-pyrrolidin-2-ylmethyl ester as a white powder that was used in the next step. Rf=0.29 (95:5 ethyl acetate/methanol). 1H NMR (400 MHz, CDCl3): δ 1.65–1.80 (m, 1H), 2.15–2.35 (m, 3H), 2.42 (s, 3H), 3.80–3.90 (m, 2H), 3.95–4.05 (m, 1H), 6.53 (bs, 1H), 7.30–7.35 (d, J=8.4 Hz, 2H), 7.74–7.76 (d, J=8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ 21.7, 22.8, 29.3, 52.6, 72.0, 127.9, 130.1, 132.4, 145.4, 178.0. To 150 mg (0.40 mmol) of 6-Methoxy-1-methyl-7-[(2S,3S)-(2-phenyl-piperidin-3-ylamino)-methyl]-3,4-dihydro-1H-quinolin-2-one, potassium carbonate (55 mg, 0.40 mmol), and catalytic KI in 4 mL of DMF was added toluene-4-sulfonic acid 5-oxo-pyrrolidin-2-ylmethyl ester (107 mg, 0.40 mmol) The suspension was heated to 60° C. for 16 hours. The reaction was diluted with methylene chloride and washed 3× with water, 2× with brine, dried over MgSO4, filtered, and concentrated. Silica gel chromatography using (85:15 ethyl acetate/methanol) gave 19 mg (10%) of the title compound, a white foam. Rf=0.10 (85:15 ethyl acetate/methanol). MS (M+H)+=477.2; 1H NMR (400 MHz, CDCl3): δ 1.30–1.60 (m, 3H), 1.78–1.82 (dd, J=12.6, 3.0 Hz, 1H), 1.98–2.16 (m, 6H), 2.20–2.30 (m, 1H), 2.50–2.52 (dd, J=12.6, 11.0 Hz, 1H), 2.54–2.58 (t, J=7.4 Hz, 2H), 2.68 (bs, 1H), 2.76–2.80 (t, J=7.4 Hz, 2H), 3.14 (s, 3H), 3.25–3.29 (m, 1H), 3.30 (bs, 1H), 3.37–3.40 (d, J=13.9 Hz, 1H), 3.49 (s, 3H), 3.62–3.66 (d, J=13.9 Hz, 1H), 3.86–3.91 (m, 1H), 6.49 (s, 1H), 6.50–6.55 (bs, 1H), 6.60 (s, 1H), 7.20–7.30 (m, 5H); 13C NMR (100 MHz, CDCl3): δ 20.1, 25.0, 25.5, 27.3, 29.6, 29.9, 31.8, 45.6, 50.8, 53.7, 55.5, 56.3, 61.1, 72.4, 109.9, 116.28, 127.1, 128.3, 128.9, 133.6, 140.6, 152.9, 170.0, 177.5. The dihydrochloride salt was prepared by the addition of 2 M HCl in ether to a solution of the product in ethyl acetate. Concentration gave a white solid (Mp=203–207° C.).
Reaction SMILES: [Cl:1][CH2:2][CH:3]([CH2:26][Cl:27])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][S:12]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[C:6]=1[NH2:25].[N:28]([O-])=O.[Na+].C(=O)(O)[O-].[Na+]>C1COCC1.Cl.O>[Cl:27][CH2:26][CH:3]([CH2:2][Cl:1])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:6]=1[NH:25][N:28]=[C:11]2[S:12]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1)(=[O:13])=[O:14]
Reactant: O=N[O-]
Reactant: Nc1c(CS(=O)(=O)c2cccc3ccccc23)cccc1OC(CCl)CCl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=S(=O)(c1cccc2ccccc12)c1n[nH]c2c(OC(CCl)CCl)cccc12
Temperature: 3 °C

Procedure:
A mixture of 2-(2-chloro-1-chloromethyl-ethoxy)-6-(naphthalene-1-sulfonylmethyl)-phenylamine (4) (2 g, 4.77 mmoles) in THF and 4M HCl (15 ml) was stirred, under nitrogen, at 3° C., treated dropwise with a solution of sodium nitrite (0.34 g, 5 mmoles) in H2O (2 ml). The reaction mixture was poured into a cold solution of saturated sodium bicarbonate and extracted with EtOAc. The extracts were combined, dried over Na2SO4 and concentrated under vacuum to afford the title compound as an off white solid (1.76 g, 4.05 mmoles), identified by HNMR analysis.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:24]=[C:23]([Cl:25])[C:20]([C:21]#[N:22])=[C:19]([C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:28][CH:27]=3)[N:18]=2)=[CH:13][CH:12]=1.CCN(C(C)C)C(C)C>ClCCl>[Cl:25][C:23]1[C:20]([C:21]#[N:22])=[C:19]([C:26]2[CH:27]=[CH:28][C:29]([O:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:30][CH:31]=2)[N:18]=[C:17]([C:14]2[CH:13]=[CH:12][C:11]([NH:10][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:16][CH:15]=2)[CH:24]=1
Reactant: N#Cc1c(Cl)cc(-c2ccc(N)cc2)nc1-c1ccc(Oc2ccccc2)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1c(Cl)cc(-c2ccc(NC(=O)c3ccccc3)cc2)nc1-c1ccc(Oc2ccccc2)cc1
Reaction time: 16 h
Yield: 100 %

Procedure:
Benzoyl chloride (10 μL, 0.086 mmol was added to a mixture of 6-(4-aminophenyl)-4-chloro-2-(4-phenoxyphenyl)nicotinonitrile (13 mg, 0.033 mmol, from Step 3 of Example 199) and Hunig's base (30 μL, 0.172 mmol) in dichloromethane (0.6 mL). After 16 h at room temperature, the reaction was complete as judged by LCMS analysis. Silica gel chromatography, eluting with 0-50% ethyl acetate in hexanes, gave N-(4-(4-chloro-5-cyano-6-(4-phenoxyphenyl)pyridin-2-yl)phenyl)benzamide as yellow solid (17.6 mg, 100% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.18 (2H, δ, J=8.53 Hz), 8.02-8.06 (2H, m), 7.97 (1H, s), 7.91 (2H, δ, J=7.28 Hz), 7.80-7.87 (3H, m), 7.57-7.63 (1H, m), 7.53 (2H, t, J=7.40 Hz), 7.38-7.44 (2H, m), 7.19 (1H, t, J=7.40 Hz), 7.09-7.17 (4H, m); MS (ES+) m/z: 502 (M+H); LC retention time: 4.923 min (analytical HPLC Method A).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH2:10])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH:11]([O:14][C:15](Cl)=[O:16])([CH3:13])[CH3:12]>>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:15](=[O:16])[O:14][CH:11]([CH3:13])[CH3:12])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: CC(C)OC(=O)Cl
Product: CC(C)OC(=O)Nc1ccc2[nH]ccc2c1

Procedure:
The title compound was prepared by following the similar procedure as described in Intermediate-52, using 1H-indol-5-amine and isopropyl-chloro-formate (0.72 g, 52%); MS: 219(M+1).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH3:11][CH:12]1OC(C)OC(C)O1>>[CH3:11][CH:12]1[NH:6][C:4](=[O:5])[C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[O:1]1
Reactant: CC1OC(C)OC(C)O1
Reactant: NC(=O)c1ccccc1O
Product: CC1NC(=O)c2ccccc2O1

Procedure:
2-Hydroxybenzamide was transformed by Method G (using paraldehyde). M.p. 124-126° C.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].CN(C)C(=N)N(C)C.[CH2:12]([C@@H:19]1[CH2:23][O:22][C:21](=[O:24])[N:20]1[C:25](=[O:37])[C@H:26](Br)[CH:27]([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:28][CH2:29][CH2:30][CH3:31])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CCOC(C)=O.CCCCCC>C(#N)C>[N:1]([C@@H:26]([CH:27]([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:28][CH2:29][CH2:30][CH3:31])[C:25]([N:20]1[C@H:19]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:23][O:22][C:21]1=[O:24])=[O:37])=[N+:2]=[N-:3]
Reactant: CCCCC(CCCC)[C@@H](Br)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: CN(C)C(=N)N(C)C
Solvent: CC#N
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCCC(CCCC)[C@H](N=[N+]=[N-])C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reaction time: 96 h

Procedure:
Tetramethylguanidine azide (TMGA) (5.398 g, 37.70 mmol) was added dropwise (5 min) to a 25° C. solution of (4R)-4-benzyl-3-[(2R)-2-bromo-3-butylheptanoyl]-1,3-oxazolidin-2-one (4.0 g, 9.42 mmol) in acetonitrile (50 mL). The reaction was stirred for 4 days. An aliquot was taken and TLC (1:4 EtOAc-hexane) indicated that reaction was complete. The solvent was removed in vacuo. The resulting black semi-solid was dissolved in CH2Cl2 (200 mL) and quenched with 1N HCl (30 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to obtain (4R)-3-[(2S)-2-azido-3-butylheptanoyl]-4-benzyl-1,3-oxazolidin-2-one as a crude yellow oil (3.61 g, 99.1%). Mass Spectrum (−ESI): 385 (M−H)−.
Reaction SMILES: [F:1][CH:2]([F:27])[CH2:3][N:4]1[C:8]([N:9]2[CH2:15][CH:14](O)[CH2:13][N:12]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:11][CH2:10]2)=[C:7]([N+:24]([O-:26])=[O:25])[CH:6]=[N:5]1.COCCN(S(F)(F)[F:38])CCOC.C([O-])(O)=O.[Na+]>C(Cl)Cl.C1COCC1>[F:1][CH:2]([F:27])[CH2:3][N:4]1[C:8]([N:9]2[CH2:15][CH:14]([F:38])[CH2:13][N:12]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:11][CH2:10]2)=[C:7]([N+:24]([O-:26])=[O:25])[CH:6]=[N:5]1
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCN(c2c([N+](=O)[O-])cnn2CC(F)F)CC(O)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2c([N+](=O)[O-])cnn2CC(F)F)CC(F)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74 %

Procedure:
To a solution of tert-butyl 4-(1-(2,2-difluoroethyl)-4-nitro-1H-pyrazol-5-yl)-6-hydroxy-1,4-diazepane-1-carboxylate (370 mg, 0.95 mmol) in DCM (10 mL) was added deoxo-Fluor® (50% solution in THF, 1.0 mL, 2.37 mmol) and the mixture was stirred at room temperature for 18 hr. Saturated aqueous NaHCO3 solution (10 mL) was added slowly and the mixture was stirred for 15 min. The aqueous layer was extracted with DCM (10 mL), the combined organic layers were passed through a phase separation cartridge and the solvent was removed under reduced pressure. Purification via silica gel column chromatography gave tert-butyl 4-(1-(2,2-difluoroethyl)-4-nitro-1H-pyrazol-5-yl)-6-fluoro-1,4-diazepane-1-carboxylate as a pale green gum (366 mg, 74%). 1H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 6.34-6.00 (m, 1H), 5.08-2.75 (m, 11H), 1.48 (s, 9H).
Reaction SMILES: [C:1]1([S:7][C:8]([CH3:18])([CH3:17])[C:9]([CH2:11][C:12]([O:14]CC)=O)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:19][C:20]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:49])[CH2:29][CH2:30][CH2:31][O:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]([CH2:42][CH3:43])([CH3:41])[CH3:40])=[CH:35][C:34]=2[C:44]([CH2:47][CH3:48])([CH3:46])[CH3:45])=[CH:23][C:21]=1[NH2:22]>C1(C)C(C)=CC=CC=1>[Cl:19][C:20]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:49])[CH2:29][CH2:30][CH2:31][O:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]([CH2:42][CH3:43])([CH3:41])[CH3:40])=[CH:35][C:34]=2[C:44]([CH2:47][CH3:48])([CH3:46])[CH3:45])=[CH:23][C:21]=1[NH:22][C:12](=[O:14])[CH2:11][C:9](=[O:10])[C:8]([S:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([CH3:17])[CH3:18]
Reactant: CCOC(=O)CC(=O)C(C)(C)Sc1ccccc1
Reactant: CCC(C)(C)c1ccc(OCCCC(=O)Nc2ccc(Cl)c(N)c2)c(C(C)(C)CC)c1
Solvent: Cc1ccccc1C
Product: CCC(C)(C)c1ccc(OCCCC(=O)Nc2ccc(Cl)c(NC(=O)CC(=O)C(C)(C)Sc3ccccc3)c2)c(C(C)(C)CC)c1
Yield: 85 %

Procedure:
A mixture of 5.2 g of ethyl (2-Phenylthio-2-methylpropionyl)acetate and 8.8 g of 2-chloro-5-[4-(2,4-di-tert-amylphenoxy)butyramido]aniline in 30 ml of xylene was refluxed for five hours. From the reaction mixture xylene was distilled off, and the residue was recrystallized from acetonitrile to obtain 11.5 g (yield 85%) of Coupler (16) having a melting point of 144° to 145° C.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1.Cl[CH2:15][CH:16]1[O:21][CH2:20][CH2:19][N:18]([CH3:22])[CH2:17]1>>[CH3:22][N:18]1[CH2:19][CH2:20][O:21][CH:16]([CH2:15][N:1]2[CH:5]=[C:4]([C:6]3[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][N:7]=3)[N:3]=[CH:2]2)[CH2:17]1
Reactant: N#Cc1ccnc(-c2c[nH]cn2)c1
Reactant: CN1CCOC(CCl)C1
Product: CN1CCOC(Cn2cnc(-c3cc(C#N)ccn3)c2)C1

Procedure:
The title compound was prepared from 2-(1H-imidazol-4-yl)pyridine-4-carbonitrile and 2-(chloromethyl)-4-methylmorpholine according to the procedure for the preparation of Example 43, part A (heating to 120°). [M+H] Calc'd for C15H17N5O, 284. Found, 284.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:14]2([O:18][CH2:19][CH2:20][OH:21])[CH2:17][CH2:16][CH2:15]2)[NH:9][C:10](=[O:13])[C:11]=1[OH:12])=[O:5])[CH3:2].[CH3:22][S:23](Cl)(=[O:25])=[O:24]>O1CCCC1>[CH3:22][S:23]([N:9]1[C:10](=[O:13])[C:11]([O:12][S:23]([CH3:22])(=[O:25])=[O:24])=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[N:7]=[C:8]1[C:14]1([O:18][CH2:19][CH2:20][O:21][S:23]([CH3:22])(=[O:25])=[O:24])[CH2:15][CH2:16][CH2:17]1)(=[O:25])=[O:24]
Reactant: CCOC(=O)c1nc(C2(OCCO)CCC2)[nH]c(=O)c1O
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(C2(OCCOS(C)(=O)=O)CCC2)n(S(C)(=O)=O)c(=O)c1OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A cold (0° C.) solution of 5-hydroxy-2-[1-(2-hydroxy-ethoxy)-cyclobutyl]-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (7.23 g, 25 mmol) in anhydrous tetrahydrofuran was treated with methanesulfonylchloride (Aldrich) by dropwise addition. The solution was warmed to room temperature and stirred for 4 hrs. The reaction was concentrated in-vacuo, and the crude product was dissolved in ethyl acetate (75 mL) and washed with saturated sodium bicarbonate solution. The organic solution was dried (sodium sulfate), filtered to remove solids, and concentrated in vacuo to give the title compound as a brown oil. 1H NMR (500 MHz, CDCl3) δ: 4.49 (2H, q, J=7.0 Hz), 4.35-4.38 (2H, m), 3.93-4.00 (1H, m), 3.66-3.67 (3H, s), 3.62-3.65 (2H, m), 3.44-3.46 (3H, s), 3.05-3.07 (3H, s), 2.74-2.82 (1H, m), 2.60-2.67 (2H, m), 2.41-2.49 (2H, m), 1.43 (3H, t, J=7.0 Hz). LCMS (M+H): 532.94.