Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.C([O:12][C:13]([C:15]1[N:16]=[C:17]([N:24]2[CH2:29][CH2:28][CH:27]([O:30]C(=O)C(F)(F)F)[CH2:26][CH2:25]2)[N:18]([CH3:23])[C:19](=[O:22])[C:20]=1[OH:21])=O)C>CN(C)C=O>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:13]([C:15]2[N:16]=[C:17]([N:24]3[CH2:29][CH2:28][CH:27]([OH:30])[CH2:26][CH2:25]3)[N:18]([CH3:23])[C:19](=[O:22])[C:20]=2[OH:21])=[O:12])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1nc(N2CCC(OC(=O)C(F)(F)F)CC2)n(C)c(=O)c1O
Reactant: NCc1ccc(F)cc1
Solvent: CN(C)C=O
Product: Cn1c(N2CCC(O)CC2)nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O
Yield: 48.1 %

Procedure:
A solution of 4-fluorobenzylamine (156 mg, 1.25 mmol) and 5-hydroxy-1-methyl-6-oxo-2-[4-(2,2,2-trifluoroacetoxy)piperidin-1-yl]-1,6-dihydropyrimidine-4-carboxylic acid ethyl ester (100 mg, 0.254 mmol) in dimethylformamide (3 mL) was heated at 120° C. for 2 h. Then, cooled and purified by preparative HPLC using MeOH/Water containg 0.1% TFA as an eluent. The fractions containing the product were combined and concentrated to afford title compound as a off-white solid (46 mg, 48%). 1H NMR (500 MHz, CDCl3) δ: 11.62 (s, 1H), 7.75 (br s, 1H), 7.31–7.28 (m, 2H), 7.04 (t, J=8.7 Hz, 2H), 4.56 (d, J=6.4 Hz, 2H), 3.95–3.89 (m, 1H), 3.52 (s, 3H), 3.28–3.23 (m, 2H), 2.88–2.83 (m, 2H), 2.02–1.96 (m, 2H), 1.73–1.66 (m, 2 H), 1.54 (br s, 1H). HRMS (M−H) calcd for C18H20FN4O4: 375.1469. found: 375.1472. Anal cald for C18H21FN4O4: C, 57.44; H, 5.62; N, 14.88. Found: C, 57.19; H, 5.55; N, 14.82.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1([CH3:24])[CH2:8][C:7]2[C:9]([CH3:23])=[C:10]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:11]([CH3:14])=[C:12]([CH3:13])[C:6]=2[O:5]1.[C:25]1([CH:31]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[O:32][CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[C:39]1([CH:31]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[O:32][CH:33]2[CH2:38][CH2:37][N:36]([CH2:2][CH2:3][C:4]3([CH3:24])[CH2:8][C:7]4[C:9]([CH3:23])=[C:10]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:11]([CH3:14])=[C:12]([CH3:13])[C:6]=4[O:5]3)[CH2:35][CH2:34]2)[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: Cc1c(C)c2c(c(C)c1NC(=O)OC(C)(C)C)CC(C)(CCBr)O2
Reactant: c1ccc(C(OC2CCNCC2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(C)c2c(c(C)c1NC(=O)OC(C)(C)C)CC(C)(CCN1CCC(OC(c3ccccc3)c3ccccc3)CC1)O2
Temperature: 60 °C
Reaction time: 15 h
Yield: 90.8 %

Procedure:
A suspension of tert-butyl [2-(2-bromoethyl)-2,3-dihydro-2,4,6,7-tetramethylbenzofuran-5-yl]carbamate (1.2 g), 4-(diphenylmethoxy)piperidine (0.85 g), and potassium carbonate (0.44 g) in N,N-dimethylformamide (20 mL) was stirred at 60° C. for 15 hours. This reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with saturated aqueous NaCl, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol=98:2 to 95:5) to provide 1.6 g of the title compound. Yield 92%.
Reaction SMILES: Br.[NH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:4]1=[O:17].[Cl:18][C:19]1[CH:35]=[CH:34][C:22]([O:23][C:24]2[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=2)=[CH:21][CH:20]=1>C(Cl)Cl.O>[CH2:10]([O:9][N:5]1[CH2:6][CH2:7][CH2:8][C@@H:3]([NH:2][S:30]([C:27]2[CH:28]=[CH:29][C:24]([O:23][C:22]3[CH:34]=[CH:35][C:19]([Cl:18])=[CH:20][CH:21]=3)=[CH:25][CH:26]=2)(=[O:31])=[O:32])[C:4]1=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: N[C@@H]1CCCN(OCc2ccccc2)C1=O
Reactant: O=S(=O)(Cl)c1ccc(Oc2ccc(Cl)cc2)cc1
Agent: Br
Solvent: ClCCl
Solvent: O
Product: O=C1[C@H](NS(=O)(=O)c2ccc(Oc3ccc(Cl)cc3)cc2)CCCN1OCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a suspension of (R)-3-amino-1-benzyloxy-piperidin-2-one hydrogen bromide salt (0.086 g, 0.29 mmol) (synthesized according to Miller's procedure J. Org. Chem. 2002, 67, 4759) and 4-(4-chloro-phenoxy)-benzenesulfonyl chloride (0.095 g, 0.31 mmol) in dry CH2Cl2 (3 mL) was treated with TEA (0.12 mL, 0.86 mmol) under N2. The reaction mixture was stirred at room temperature for 6 h and diluted with CH2Cl2 and water. After the usual work-up, the crude material was purified by chromatography (silica gel, 35% EtOAc/hexanes) to give the desired product, (R)—N-(1-Benzyloxy-2-oxo-piperidin-3-yl)-4-(4-chloro-phenoxy)-benzene-sulfonamide. MS (EI) 487 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](/[CH:7]=[CH:8]/[C:9](=[O:18])/[CH:10]=[CH:11]/[C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=1.[CH3:19][NH2:20]>CN(C=O)C>[CH3:19][N:20]1[CH:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH2:8][C:9](=[O:18])[CH2:10][CH:11]1[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1
Reactant: CN
Reactant: O=C(/C=C/c1cccnc1)/C=C/c1cccnc1
Solvent: CN(C)C=O
Product: CN1C(c2cccnc2)CC(=O)CC1c1cccnc1
Temperature: 0 °C
Reaction time: 6 h
Yield: 95.2 %

Procedure:
A suspension of (1E,4E)-1,5-di(pyridin-3-yl)penta-1,4-dien-3-one (1 g, 3.2 mmol) in DMF (10 mL) was treated with N-methylamine (40% in H2O, 2.8 mL, 32 mmol) at 0° C. The solution was stirred for 6 h at 0° C. The reaction mixture was poured into ice-water (150 mL) and was extracted with DCM. The combined organic layers were dried with MgSO4, filtered and evaporated in vacuo. The crude product was purified by flash-chromatography (CH2Cl2/MeOH 9:1) to obtain NW-B593 as a bright yellow solid (814 mg, 94%). mp: 103-106° C. 1H NMR (300 MHz, CDCl3) δ (ppm): 8.67 (d, 4J=1.8 Hz, 2H, HAr), 8.59 (dd, 3J=4.8 Hz, 4J=1.6 Hz, 2H, HAr), 7.85 (d, 3J=7.9 Hz, 2H, HAr), 7.37 (dd, 3J=7.9 Hz, 3J=4.8 Hz, 2H, HAr), 3.58 (dd, 3J=12.0 Hz, J=2.8 Hz, 2H, CH2), 2.84 (t, 3J=13.0 Hz, 2H, CH), 2.55 (dd, 3, J=13.9 Hz, J=1.8 Hz, 2H, CH2), 1.64 (s, 3H, CH3). 13C NMR (75 MHz, CDCl3) δ (ppm): 204.9 (C), 149.4 (CH), 148.8 (CH), 138.1 (C), 134.8 (CH), 124.1 (CH), 67.5 (CH), 50.2 (CH2), 41.0 (CH3). MS (FAB) m/z: 268.2 (M+). Anal. calcd for C16H17N3O.0.3H2O: C, 70.46; H, 6.50; N, 15.41. Found: C, 70.45; H, 6.38; N, 15.32%.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][C@@H:6]([OH:8])[C@H:5]([C:9]([CH3:11])=[CH2:10])[CH2:4][CH2:3]1.[H][H]>>[CH3:1][C@H:2]1[CH2:7][C@@H:6]([OH:8])[C@H:5]([CH:9]([CH3:11])[CH3:10])[CH2:4][CH2:3]1
Reactant: [H][H]
Reactant: C=C(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O

Procedure:
By means of a centrifugal pump, a circulation was conducted through the main reactor at a rate of about 500 g/h at a feed of L-isopulegol of 24.5 g/h (total amount 588 g) with a purity of 99.8% and 99.8% ee at a constant hydrogen pressure of 30 bar. The main reactor was operated at a temperature of 50° C. and the postreactor at 60° C. All pipelines were provided with electrical trace heating to prevent crystallization of the enantiomerically pure L-menthol (m.p. 44° C.). L-menthol (99.8% ee) was obtained in an amount of 597 g, corresponding to a rate of 24.9 g/h. The product thus obtained was analyzed by gas chromatography. The results are compiled in Table 4.
Reaction SMILES: [N:1]1([C:7]2[N:21]=[C:10]3[N:11]=[CH:12][CH:13]=[C:14]([C:15]4[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=4)[N:9]3[N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[CH:23]([CH2:33][CH3:34])[C:24]([C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)=[O:25].C(N(CC)C(C)C)(C)C>CC(O)C>[F:32][C:29]1[CH:28]=[CH:27][C:26]([C:24](=[O:25])[CH2:23][CH2:33][CH2:34][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[N:21]=[C:10]4[N:11]=[CH:12][CH:13]=[C:14]([C:15]5[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=5)[N:9]4[N:8]=3)[CH2:6][CH2:5]2)=[CH:31][CH:30]=1
Reactant: CCC(Cl)C(=O)c1ccc(F)cc1
Reactant: c1cc(-c2ccnc3nc(N4CCNCC4)nn23)ccn1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCCN1CCN(c2nc3nccc(-c4ccncc4)n3n2)CC1)c1ccc(F)cc1
Yield: 13.5 %

Procedure:
A mixture of 5.6 g (0.02 moles) of 2-(1-piperazinyl)-7-(4-pyridyl)[1,2,4]triazolo[1,5-a]pyrimidine (prepared as described in Example 47), 4.0 g (0.02 moles) of α-chloro-p-fluorobutyrophenone, 3.6 g (0.027 moles) of N,N-diisopropylethylamine and 100 ml of 2-propanol was heated at reflux for 16 hours with stirring. The reaction mixture was evaporated in vacuo to a solid. The solid was dissolved in 100 ml of water and extracted twice with 100 ml of chloroform. The extracts were combined, dried over magnesium sulfate, filtered and evaporated to a dark syrup. The syrup was dissolved in dichloromethane and passed through a pad of magnesium silicate, washing with methylene chloride. This filtrate was collected and set aside. Then acetone was passed through the pad and the acetone filtrate was collected and evaporated to a syrup. The syrup was dissolved in 15 ml of ethanol, 200 ml of ether was added, then hexane until cloudy. Evaporation by boiling caused crystallization. The crude product was collected and washed with ether. Recrystallization from ethanol gave 1.2 g of the desired product as yellow crystals, mp 133°-135° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH:19]([CH3:21])[CH3:20].O>CN(C=O)C>[CH:19]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11])([CH3:21])[CH3:20]
Reactant: CC(C)Br
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C=O)ccc1OC(C)C
Temperature: 65 °C
Reaction time: 2 h

Procedure:
A mixture of 4-hydroxy-3-methoxybenzaldehyde (100 g), anhydrous potassium carbonate (182 g) and 2-bromopropane (81 ml) in DMF (500 ml) was stirred at 65° C. for 2 h. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine. The organic layer was dried (MgSO4), filtered and concentrated in vacuo.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:12](=[O:32])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)=[CH:17][C:16](/[CH:27]=[CH:28]/[C:29]([OH:31])=O)=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C([N:40]=C=NCCCN(C)C)C.[NH4+].ON1C2C=CC=CC=2N=N1.O>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:12](=[O:32])[C:13]2[C:18]([C:19]=1[C:20]1[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=1)=[CH:17][C:16](/[CH:27]=[CH:28]/[C:29]([NH2:40])=[O:31])=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccc(Cl)cc2)c2cc(/C=C/C(=O)O)ccc2c1=O
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccc(Cl)cc2)c2cc(/C=C/C(N)=O)ccc2c1=O
Yield: 88.2 %

Procedure:
A solution of (E)-3-[3-[[(tert-butoxycarbonyl)amino]methyl]-4-(4-chlorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-2-propenic acid (0.20 g, 0.4 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.15 g, 0.8 mmol) and 1-hydroxybenzotriazole ammonium salt (0.12 g, 0.8 mmol) in N,N-dimethylformamide (10 ml) was stirred at room temperature for 2 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was crystallized from ethyl acetate-n-hexane to give (E)-3-[3-[[(tert-butoxycarbonyl)amino]methyl]-4-(4-chlorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-2-propenamide (0.18 g, 90.0%) as crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8](=[O:14])[N:9]([CH2:11][O:12][CH3:13])[N:10]=[C:4]2[C:3]=1[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:2]2[CH:7]=[CH:6][N:5]3[C:8](=[O:14])[N:9]([CH2:11][O:12][CH3:13])[N:10]=[C:4]3[C:3]=2[C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[CH:24][CH:23]=1
Reactant: COCn1nc2c(-c3ccncc3)c(Br)ccn2c1=O
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COCn1nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)ccn2c1=O
Temperature: 20 °C
Yield: 75.1 %

Procedure:
To a degassed mixture of crude 7-bromo-2-(methoxymethyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (620 mg, 1.85 mmol), 4-chlorophenylboronic acid (850 mg, 5.55 mmol) and K2CO3 (1.02 g, 7.4 mmol) in 1,4-dioxane (18 mL) and H2O (6.0 mL) under argon at 20° C. was added Pd(PPh3)4 (107 mg, 0.093 mmol). The reaction mixture was refluxed for 15 h under argon and then cooled to 20° C. The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (3×50 mL). The combined organic extract was washed with saturated aqueous NaHCO3 solution (20 mL), then brine (20 mL), dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography eluting with a 0-60% gradient of EtOAc in hexanes to obtain the title compound as a yellow solid (510 mg, 1.39 mmol). MS: [M+H]+=367.1. 1H NMR (400 MHz, CDCl3) δ 3.46 (s, 3H), 5.32 (s, 2H), 6.62 (d, J=7.1 Hz 1H), 7.01-7.09 (m, 2H), 7.17-7.22 (m, 2H), 7.23-7.29 (m, 2H), 7.85 (d, J=7.1 Hz, 1H), 8.55 (d, J=4.40 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([NH:16][C:17]3[CH:18]=[N:19][C:20]([C:23]4([C:30]#[N:31])[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25][CH2:24]4)=[CH:21][CH:22]=3)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[C:32]1(=[O:38])[O:37][C:35](=[O:36])[CH2:34][CH2:33]1.ClC1C=CC=CC=1Cl>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]4([C:30]#[N:31])[CH2:24][CH2:25][CH:26]([O:29][C:32](=[O:38])[CH2:33][CH2:34][C:35]([OH:37])=[O:36])[CH2:27][CH2:28]4)=[N:19][CH:18]=3)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1c(C(=O)Nc2ccc(C3(C#N)CCC(O)CC3)nc2)cnn1-c1ccc(Cl)cc1
Reactant: O=C1CCC(=O)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Clc1ccccc1Cl
Product: Cc1c(C(=O)Nc2ccc(C3(C#N)CCC(OC(=O)CCC(=O)O)CC3)nc2)cnn1-c1ccc(Cl)cc1
Temperature: 150 °C
Reaction time: 7 h
Yield: 40.7 %

Procedure:
1-(4-Chlorophenyl)-N-[6-(1-cyano-4-hydroxycyclohexyl)pyridin-3-yl]-5-methyl-1H-pyrazole-4-carboxamide (0.42 g), succinic anhydride (0.11 g) and p-toluenesulfonic acid hydrate (5 mg) were added to 1,2-dichlorobenzene (4 ml) and stirred at 150° C. for seven hours. The reaction solution was treated with water and the precipitated solid was recrystallized from aqueous isopropanol to give the titled compound (0.21 g).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([C:23]([CH2:49][O:50][CH2:51][CH2:52][O:53][CH2:54][CH2:55][O:56][CH2:57][CH2:58][O:59][CH2:60][CH2:61][O:62][CH3:63])([CH2:39][O:40][CH2:41][C:42]([O:44]C(C)(C)C)=[O:43])[CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH3:38])[O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH3:22]>ClCCl>[CH2:24]([C:23]([CH2:49][O:50][CH2:51][CH2:52][O:53][CH2:54][CH2:55][O:56][CH2:57][CH2:58][O:59][CH2:60][CH2:61][O:62][CH3:63])([CH2:39][O:40][CH2:41][C:42]([OH:44])=[O:43])[CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH3:22])[O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH3:38]
Reactant: COCCOCCOCCOCCOCC(COCCOCCOCCOCCOC)(COCCOCCOCCOCCOC)COCC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCOCCOCCOCCOCC(COCCOCCOCCOCCOC)(COCCOCCOCCOCCOC)COCC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.6 %

Procedure:
Trifluoroacetic acid (TFA, 0.5 ml) and dichloromethane (0.5 ml) was added to 20 mg of 5. The mixture was shaken at room temperature for 1 h and the volatile materials was then removed at reduced pressure to give 18 mg of 6 as a yellow oil.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.[Br:9]N1C(=O)CCC1=O.C(Cl)Cl.[OH-].[Na+]>C(Cl)(Cl)Cl>[Br:9][C:3]1[CH:4]=[CH:5][C:6]([NH2:8])=[N:7][C:2]=1[F:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1cccc(F)n1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Nc1ccc(Br)c(F)n1
Reaction time: 15 h
Yield: 22.6 %

Procedure:
To a solution of 6-fluoro-2-pyridylamine (1.0 g, 8.93 mmol) in chloroform (55 mL) was added N-bromosuccinimide (1.59 g, 8.93 mmol). The solution was stirred in the dark for 15 hours, at which time it was added to CH2Cl2 (200 mL) and 1N NaOH (50 mL). Upon mixing, the layers were separated and the organic layer was washed with NaCl(sat.) (50 mL), dried over Na2SO4, filtered and concentrated. The crude material was purified by SiO2 chromatography (25% EtOAc/hexanes) yielding 5-bromo-6-fluoro-2-pyridylamine (386 mg, 22%). LCMS (m/z): 190.9/192.9 (MH+); 1H NMR (CDCl3): δ 7.59 (t, J=8.7 Hz, 1H), 6.25 (dd, J=8.1, 1.2 Hz, 1H), 4.58 (bs, 1H).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17](Cl)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[NH2:23][CH2:24][C:25]([CH3:29])([OH:28])[CH:26]=[CH2:27]>C(Cl)Cl>[Cl:8][C:9]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17]([NH:23][CH2:24][C:25]([CH3:29])([OH:28])[CH:26]=[CH2:27])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1
Reactant: C=CC(C)(O)CN
Reactant: O=[N+]([O-])c1c(Cl)nc2ccccc2c1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(C)(O)CNc1c([N+](=O)[O-])c(Cl)nc2ccccc12

Procedure:
Triethyl amine (6.2 mL, 0.045 mole) was added to a solution of 2,4-dichloro-3-nitroquinoline (10.9 g 0.045 mole) in methylene chloride (60 mL). 4-Amino-3-methyl-1-butene-3-ol was added and the reaction mixture was heated at reflux for several hours before being concentrated under vacuum. The residue was chilled in an ice bath to give a solid. The solid was recrystallized from toluene to provide 17.1 g of the desired product as a yellow solid. The structure was confirmed by nuclear magnetic resonance spectroscopy.
Reaction SMILES: O=[C:2]([CH3:10])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[C:11]1([O:21][CH2:22][CH:23]([OH:33])[CH2:24][NH:25]C(C)CCC(O)=O)[C:20]2[C:15](=C[CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1>>[CH2:19]([C:20]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:21][CH2:22][CH:23]([OH:33])[CH2:24][NH:25][CH:2]([CH3:10])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])[CH:18]=[CH2:17]
Reactant: CC(=O)CCCCC(=O)O
Reactant: CC(CCC(=O)O)NCC(O)COc1cccc2ccccc12
Product: C=CCc1ccccc1OCC(O)CNC(C)CCCCC(=O)O

Procedure:
The title compound was synthesized from Compound V (R=2-allylphenyl) and 6-oxoheptanoic acid p-toluide on a 1.5 mmol scale using the general procedure described above for Compound 7.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:23]=[CH:22][CH:21]=[CH:20][C:14]=2[O:15][CH2:16][CH:17]2[CH2:19][O:18]2)=[CH:5][CH:4]=1.[C:24]1([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:23]=[CH:22][CH:21]=[CH:20][C:14]=2[O:15][CH2:16][CH:17]([OH:18])[CH2:19][N:33]2[CH2:34][CH2:35][N:30]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:31][CH2:32]2)=[CH:5][CH:4]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: COc1ccc(CCCCc2ccccc2OCC2CO2)cc1
Solvent: C1CCOC1
Product: COc1ccc(CCCCc2ccccc2OCC(O)CN2CCN(c3ccccc3)CC2)cc1
Yield: 105.4 %

Procedure:
A solution of 185 mg of 2-{2-[4-(4-methoxyphenyl)butyl]phenoxymethyl}oxirane [prepared as described in Example 26(a)] and 96 mg of 1-phenylpiperazine in 5 ml of tetrahydrofuran was stirred at 60° C. for 24 hours. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure. The oily residue thus obtained was purified by column chromatography through silica gel, using a 20:1 by volume mixture of methylene chloride and methanol as the eluent, to give 296 mg (yield 96%) of the title compound as a colorless oil.
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:20])[C:12]1[CH:17]=[CH:16][C:15](Br)=[C:14]([CH3:19])[CH:13]=1.[C:22]1([OH:28])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH3:19][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[O:28][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:11]([NH:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C:3]([OH:2])=[O:21])=[O:20]
Reactant: COC(=O)c1ccccc1NC(=O)c1ccc(Br)c(C)c1
Reactant: Oc1ccccc1
Product: Cc1cc(C(=O)Nc2ccccc2C(=O)O)ccc1Oc1ccccc1

Procedure:
In analogy to example 2,2-(3-Methyl-4-phenoxy-benzoylamino)-benzoic acid was prepared from 2-(4-bromo-3-methyl-benzoylamino)-benzoic acid methyl ester and phenol. MS (m/e): 346.3 (M−H−, 100%).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][NH:9][N:8]=1)=[O:5].Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:21][C:20]=1[Cl:33].N1C(C)=CC=CC=1C>CN1C(=O)CCC1>[Cl:33][C:20]1[CH:21]=[C:22]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:23]=[CH:24][C:19]=1[CH2:18][N:9]1[CH:10]=[CH:11][C:7]([NH:6][C:4](=[O:5])[C:3]2[C:12]([F:16])=[CH:13][CH:14]=[CH:15][C:2]=2[F:1])=[N:8]1
Reactant: O=C(Nc1cc[nH]n1)c1c(F)cccc1F
Reactant: Clc1cc(OCc2ccccc2)ccc1CBr
Solvent: Cc1cccc(C)n1
Solvent: CN1CCCC1=O
Product: O=C(Nc1ccn(Cc2ccc(OCc3ccccc3)cc2Cl)n1)c1c(F)cccc1F
Temperature: 160 °C

Procedure:
To a solution of 2,6-difluoro-N-(1H-pyrazol-3-yl)benzamide (for a preparation see Intermediate 9)(0.961 g, 4.31 mmol) and 1-(bromomethyl)-2-chloro-4-[(phenylmethyl)oxy]benzene (1.21 g, 3.88 mmol) in anhydrous NMP (15 ml) was added 2,6-lutidine (0.5 ml, 4.29 mmol, Aldrich). The reaction vessel (20 ml) was sealed and heated in Biotage Initiator microwave to 160° C. for 30 min. After cooling the reaction mixture was partitioned between saturated aqueous sodium hydrogen carbonate (120 ml) and ethyl acetate (100 ml). The phases were separated and the aqueous phase extracted with ethyl acetate (50 ml). The combined organic extracts were washed with saturated aqueous sodium hydrogen carbonate (50 ml), dried (MgSO4), filtered and the solvent removed in vacuo to leave a red oil (2.84 g). The residue was loaded in dichloromethane and purified on silica (100 g×2) using 0-100% ethyl acetate-cyclohexane. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a white solid (0.778 g); LCMS: (System 4) MH+=454, tRET=3.35 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:31]=[C:32]([F:34])[CH:33]=1)[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[N:10]=[CH:9][C:8]=1[CH2:27][C:28]([NH2:30])=[O:29].C[N+]1([O-])CCOCC1.O>CN(C)C=O.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[F:1][C:2]1[CH:3]=[C:4]([CH:31]=[C:32]([F:34])[CH:33]=1)[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([N:20]3[CH2:21][CH2:22][C:23](=[O:26])[CH2:24][CH2:25]3)=[CH:18][CH:19]=2)[N:10]=[CH:9][C:8]=1[CH2:27][C:28]([NH2:30])=[O:29]
Reactant: NC(=O)Cc1cnc(Nc2ccc(N3CCC(O)CC3)cc2)cc1NCc1cc(F)cc(F)c1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)Cc1cnc(Nc2ccc(N3CCC(=O)CC3)cc2)cc1NCc1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 10 %

Procedure:
120 mg of 4-[(3,5-difluorobenzyl)amino]-6-{[4-(4-hydroxypiperidino)phenyl]amino}pyridine-3-carboxyamide (the compound of Example 191) was dissolved in 1.5 mL of N,N-dimethylformamide, to which 78 mg of 4-methylmorpholine N-oxide, 120 mg of molecular sieve 4A powder and 2.8 mg of tetrapropylammonium perruthenate were added, and stirred at room temperature for 30 minutes. Water was added to the reaction mixture, extracted with ethyl acetate, and the extract was washed with saturated saline. After drying on anhydrous sodium sulfate, the solvent was evaporated, and the residue was purified by silica gel column chromatography (chloroform:methanol=20:1), recrystallized in methanol-ether-hexane to obtain 12 mg (10%) of the title compound as a light brown crystalline powder.