Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.[C:20]1([C@@H:26]2[CH2:28][C@H:27]2[C:29](Cl)=[O:30])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:29]([C@@H:27]3[CH2:28][C@H:26]3[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:30])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: O=C(Cl)[C@@H]1C[C@H]1c1ccccc1
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Product: Nc1nc2ccccc2c2c1ncn2CCCCNC(=O)[C@@H]1C[C@H]1c1ccccc1

Procedure:
According to the general method of Example 14, 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin4-amine and trans-2-phenyl-1-cyclopropanecarbonyl chloride were combined to provide N1-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-(trans)-2-phenylcyclopropane-1-carboxamide as an off white solid, m.p. 77.0° C. 1H NMR (300 MHz, DMSO-d6) δ 7.90 (dd, J=8.1, 1.2 Hz, 1H), 7.81 (dd, J=8.1, 1.2 Hz, 1H), 7.78 (s, 1H)? 7.50 (dt, J=8.1, 1.5 Hz, 1H), 7.33-7.15 (m, 4H), 7.05-7.02(m, 2H), 5.84 (broad s, 1H), 5.51 (s, 2H), 4.52 (t, J=7.2 Hz, 2H), 3.32 (q, J=6.6 Hz, 2H), 2.49-2.43 (m, 1H), 2.07-1.95 (m, 3H), 1.64-1.51 (m, 3H), 1.25-1.18 (m, 1H); IR (KBr) 3304, 3179, 2939, 1640, 1582, 1527, 1479, 1396, 1250, 755, 735, 689 cm−1; MS (EI) m/e 399.2059 (399.2059 calcd for C24H25N5O).
Reaction SMILES: [F:1][C:2]1[CH:38]=[CH:37][C:5]([CH2:6][NH:7][C:8](=[O:36])[C:9]2[CH:14]=[CH:13][C:12]([S:15]([N:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20](B4OC(C)(C)C(C)(C)O4)=[CH:19]3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.Br[C:40]1[CH:41]=[CH:42][C:43]([F:46])=[N:44][CH:45]=1.[F-].[Cs+]>CN(C=O)C.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>[F:1][C:2]1[CH:38]=[CH:37][C:5]([CH2:6][NH:7][C:8](=[O:36])[C:9]2[CH:14]=[CH:13][C:12]([S:15]([N:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]([C:40]4[CH:45]=[N:44][C:43]([F:46])=[CH:42][CH:41]=4)=[CH:19]3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(Br)cn1
Reactant: CC1(C)OB(c2cn(S(=O)(=O)c3ccc(C(=O)NCc4ccc(F)cc4)cc3)c3ccccc23)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(F)cc1)c1ccc(S(=O)(=O)n2cc(-c3ccc(F)nc3)c3ccccc32)cc1
Yield: 69.5 %

Procedure:
Combine N-(4-Fluoro-benzyl)-4-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indole-1-sulfonyl]-benzamide (150 mg, 0.28 mmol), 5-Bromo-2-fluoro-pyridine (0.05 mL, 0.56 mmol), CsF (212 mg, 1.4 mmol) and Pd(Ph3P)4 (32 mg, 0.028 mmol) in 1.0 mL DMF and 0.100 mL of water. Evacuate the reaction vessel and place under an atmosphere of nitrogen. Heat the resulting reaction at 90 degrees 12 h. Load the reaction directly onto silica gel and purify by flash column chromatography (EtOAc/Hexanes) to yield 98 mg of white foam (70%) LRMS: MH+ 504.02.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.[N:17]([O-])=[O:18].[Na+]>C(O)(=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:17][OH:18])[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: O=N[O-]
Reactant: O=C(Cc1ccc(F)cc1)c1ccncc1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C(C(=NO)c1ccc(F)cc1)c1ccncc1

Procedure:
2-(4-Fluorophenyl)-1-pyridin-4-ylethanone (0.04 mol/8.6 g) (prepared as described in example 20, steps (a) and (b)) was dissolved in 80 ml of glacial acetic acid. NaNO2 (0.04 mol/2.76 g), dissolved in the smallest amount of H2O possible, was then added dropwise with ice-cooling and stirring. The mixture was then stirred at 0° C. for another 2 h. 500 ml of H2O were then added, and the mixture was stirred at room temperature for another 1 h. The title compound precipitated as a white powder. The precipitate was filtered off, washed with H2O and dried over P2O5 under reduced pressure. Yield: 5.9 g (60%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1B(O)O.C[O:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=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:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:18]1[CH:19]=[CH:20][C:15]([C:14]([OH:22])=[O:13])=[CH:16][CH:17]=1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: COC(=O)c1ccc(I)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: O
Solvent: C1COCCO1
Product: O=C(O)c1ccc(-c2ccc(Cl)cc2Cl)cc1
Yield: 54.5 %

Procedure:
A solution of 2,4-dichlorophenyl boronic acid (3.96 g, 15.11 mmol) and 4-Iodo-benzoic acid methyl ester (2.88 g, 15.11 mmol), K2CO3 (7.31 g, 52.89 mmol) in 1,4-dioxane (85 mL), and water (20 mL) is purged with nitrogen for 10 min. Pd(PPh3)4 (0.87 g, 0.756 mmol) is added and the resulting reaction mixture is refluxed overnight. The reaction is diluted with water and extracted with Et2O. The combined organic layers are washed with water, dried with MgSO4, and concentrated. The crude material is purified by chromatography to give the title compound (2.20 g, 50%). LC/MS (m/z): calcd for C13H18Cl2O2: 267.1; found: 266.9.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([O:11]COC)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.[CH3:16]O>>[CH3:16][O:6][C:4](=[O:5])[C:3]1[CH:7]=[CH:8][C:9]([OH:11])=[CH:10][C:2]=1[F:1]
Reactant: CO
Reactant: COCOc1ccc(C(=O)O)c(F)c1
Agent: Cl
Product: COC(=O)c1ccc(O)cc1F
Yield: 100 %

Procedure:
To a solution of 2-fluoro-4-methoxymethoxybenzoic acid (19.9 g, 100 mmol) in methanol (200 ml) is added conc. hydrochloric acid solution (0.5 ml, catalytic). The solution is heated at reflux overnight. The solution is evaporated in vacuo to give an off-white solid (16.9 g, 100%). δH (300 MHz, CD3OD) 3.83 (3H, s), 6.52 (1H, dd, J=2.3, 12.9 Hz), 6.63 (1H, dd, J=2.1, 8.5 Hz), 7.78 (1H, t, J=8.7 Hz); δC (75 MHz, CD3OD); m/z 170 [(M+), 10%], 139 [(M-OMe)+, 10%]52.34, 104.30, 104.34, 110.78, 112.48, 134.61, 134.96, 163.36, 163.61, 164,93, 165.03, 165.09, 165.19, 166.38, 166.46, 166.79, 167.03, 167.60, 167.65, 205.58.
Reaction SMILES: C(OC([NH:8][CH:9]([C:11]1[S:12][C:13]([C:16]([O:18]C)=[O:17])=[CH:14]N=1)[CH3:10])=O)(C)(C)C.[ClH:20].[CH3:21]O>O1CCOCC1>[ClH:20].[NH2:8][CH:9]([C:11]1[S:12][C:13]([C:16]([OH:18])=[O:17])=[CH:14][CH:21]=1)[CH3:10]
Reactant: COC(=O)c1cnc(C(C)NC(=O)OC(C)(C)C)s1
Reactant: CO
Agent: Cl
Solvent: C1COCCO1
Product: CC(N)c1ccc(C(=O)O)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of methyl 2-(1-(tert-butoxycarbonylamino)ethyl)thiazole-5-carboxylate (0.9 g, 3 mmol) in MeOH (5 mL) was added 4M HCl in dioxane (4 mL). The reaction was stirred overnight at room temperature. The reaction was evaporated to dryness to afford 5-(1-aminoethyl)thiophene-2-carboxylate hydrochloride (0.7 g, 100%).
Reaction SMILES: [C:1]([C:4]1[C:9](=O)[NH:8][C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:5]=1)(=O)[CH3:2].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]([OH:31])=[O:30])=[CH:24][CH:23]=1.C(N(CC)CC)C.[OH-].[NH4+]>C(OC(=O)C)(=O)C>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[C:29](=[O:31])[O:30][C:9]3=[N:8][C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:5]=[C:4]3[C:1]=2[CH3:2])=[CH:26][CH:27]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cc(C(C)=O)c(=O)[nH]c1C(=O)OCC
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc2c(C)c(-c3ccc(Cl)cc3)c(=O)oc2nc1C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.4 %

Procedure:
Diethyl 5-acetyl-1,6-dihydro-6-oxo-2,3-pyridinedicarboxylate, (6.0 g, 0.0213 mol), 4-chlorophenyl acetic acid (3.64 g, 0.0213 mol) and triethylamine (3.0 g, 1.5 eq) are refluxed in 50 mL of acetic anhydride for three and one-half hours and then stirred at room temperature overnight. The reaction mixture is poured into 100 mL of ice cold water and the pH is adjusted to 8 with an ammonium hydroxide solution. The crystalline solid is filtered, washed with water, dried and dissolved in 100 mL of methylene chloride. The solution is dried over anhydrous sodium sulfate and the solvent removed under reduced pressure to give the desired product (8.8 g, 99%), which is crystallized from ethyl acetate to give the pure product having a melting point 179°-181° C.
Reaction SMILES: C(OC(=O)C)(=O)C.[O:8]1[C:13]2[CH:14]=[CH:15][CH:16]=[C:17]([C:18]([OH:20])=[O:19])[C:12]=2[O:11][CH2:10][CH2:9]1.[N+:21]([O-])([OH:23])=[O:22]>C(O)(=O)C>[N+:21]([C:15]1[CH:16]=[C:17]([C:18]([OH:20])=[O:19])[C:12]2[O:11][CH2:10][CH2:9][O:8][C:13]=2[CH:14]=1)([O-:23])=[O:22]
Reactant: O=C(O)c1cccc2c1OCCO2
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C(O)c1cc([N+](=O)[O-])cc2c1OCCO2
Yield: 27 %

Procedure:
160 ml of acetic acid, 160 ml of acetic anhydride and 100 g of 1,4-benzodioxane-5-carboxylic acid were introduced into a balloon flask provided with an agitator and a thermometer. The mixture was heated and a solution of 40 ml of nitric acid in 40 ml of acetic acid was added. The mixture was agitated at 40°-45° C. and then cooled. The crystals were dried off, washed and dried. 34 g of 7-nitro-1,4-benzodioxane-5-carboxylic acid were obtained (M.P.: 246° C.; yield: 27%).
Reaction SMILES: [H][H].C([NH:10][C@H:11]1[CH2:16][CH2:15][C@@H:14]([CH:17]([OH:22])[C:18]([F:21])([F:20])[F:19])[CH2:13][CH2:12]1)C1C=CC=CC=1>CO.[Pd]>[OH:22][CH:17]([C@@H:14]1[CH2:15][CH2:16][C@H:11]([NH2:10])[CH2:12][CH2:13]1)[C:18]([F:19])([F:20])[F:21]
Reactant: [H][H]
Reactant: OC([C@H]1CC[C@@H](NCc2ccccc2)CC1)C(F)(F)F
Agent: [Pd]
Solvent: CO
Product: N[C@H]1CC[C@@H](C(O)C(F)(F)F)CC1

Procedure:
At 50° C. and a hydrogen pressure of 30 bar, 33.6 g of cis-1-benzylamino-4-(1-hydroxy-2,2,2-trifluoroethyl)cyclohexane were hydrogenated in the presence of 2 g of palladium (10% on carbon) in 250 ml of methanol. The catalyst was filtered off and the mixture was concentrated to give the title product as a colourless oil.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[OH:11])([CH3:3])[CH3:2].B(F)(F)F.[CH3:16][CH2:17][O:18]CC.C([O-])(=O)C.[Na+]>C(O)(=O)C>[OH:10][C:7]1[CH:6]=[C:5]([OH:11])[C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][C:8]=1[C:17](=[O:18])[CH3:16]
Reactant: CCOCC
Reactant: CC(C)c1ccc(O)cc1O
Agent: CC(=O)[O-]
Agent: FB(F)F
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)c1cc(C(C)C)c(O)cc1O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
4-Isopropyl-benzene-1,3-diol (5.8 g) and boron trifluoride etherate (28.7 ml) were introduced into a 250 ml single neck RB flask equipped with a reflux condenser and an inlet for nitrogen atmosphere stirred at RT for 10 min. Acetic acid (4.55 ml) was added to the reaction mixture and stirred at 90° C. for 16 h. On completion, 10% sodium acetate (300 ml) was added to the reaction mixture which was stirred at RT for 4 h before. The reaction mixture was extracted with ethyl acetate (300 ml) and washed with sat. sodium bicarbonate (100 ml) and the organic layer was dried over sodium sulphate. The reaction was monitored by TLC (10% EtOAc/n-hexane, product Rf˜0.5). The solvent was removed under reduced pressure to give a residue, which was further purified by column chromatography (SiO2, 10% EtOAc/n-hexane).
Reaction SMILES: CO[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.COC(=O)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C[O-].[Na+].Cl>C(Cl)(Cl)Cl.O>[CH2:14]([C:3]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)=[O:10])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1cccnc1
Reactant: COC(=O)Cc1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(Cc1ccccc1)c1cccnc1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
The mixture of 27.4 g (0.2 mol) of nicotinic acid methyl ester and 30 g (0.2 mol) of phenylacetic acid methyl ester is treated in small amounts under nitrogen with 16.2 g (0.3 mol) of sodium methylate at 20°-25°C. The reaction mixture is stirred for 20 hours at 60°-70°C, in the process of which the alcohol which is formed is blown off. Then 60 ml of concentrated hydrochloric acid is added dropwise to the solid substance and the mixture is boiled for 3 hours under reflux. The still hot yellow solution is treated with 30 ml of water and cooled to 50°C. Then 60 ml of chloroform are added and the reaction mixture is cooled to 5°C. The white crystals which form are collected by suction filtration and washed with chloroform; they melt at 225°C (from ethanol).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[C:9]([C:11]([OH:13])=O)[CH:8]=[CH:7][C:6]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20])[CH3:3].O[N:22]=[C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([S:31]([CH3:34])(=[O:33])=[O:32])[CH:26]=1)[NH2:24]>>[CH3:3][N:2]([CH3:1])[CH2:4][C:5]1[CH:10]=[C:9]([C:11]2[O:13][N:24]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([S:31]([CH3:34])(=[O:33])=[O:32])[CH:26]=3)[N:22]=2)[CH:8]=[CH:7][C:6]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20]
Reactant: Cc1ccccc1-c1ccc(C(=O)O)cc1CN(C)C
Reactant: CS(=O)(=O)c1cccc(C(N)=NO)c1
Product: Cc1ccccc1-c1ccc(-c2nc(-c3cccc(S(C)(=O)=O)c3)no2)cc1CN(C)C

Procedure:
The title compound was prepared following the general procedure 3 starting from Intermediate 8 and Intermediate 19 and was isolated as a white powder. 1H NMR (DMSO-d6, 300 MHz) δ 8.59 (t, J=1.7 Hz, 1H), 8.47 (m, 1H), 8.43 (d, J=1.6 Hz, 1H), 8.21 (m, 1H), 8.15 (dd, J=1.9, 7.9 Hz, 1H), 7.92 (t, J=7.9 Hz, 1H), 7.40 (d, J=8.0 Hz, 1H), 7.35-7.26 (m, 3H), 7.11 (d, J=7.1 Hz, 1H), 3.35 (s, 3H), 3.19 (brs, 2H), 2.09 (s, 6H), 2.02 (s, 3H). LC/MS (Method B): 448.3 (M+H)+. HPLC (Method A) Rt 3.51 min (Purity: 98.5%).
Reaction SMILES: [NH2:1][C:2]1[C:9]([OH:10])=[C:8]([F:11])[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:6]([CH3:18])[C:3]=1[C:4]#[N:5].C(N(CC)CC)C.[CH:26]1([C:31](Cl)=[O:32])[CH2:30][CH2:29][CH2:28][CH2:27]1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(#N)C>[CH:26]1([C:31]([O:10][C:9]2[C:8]([F:11])=[C:7]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:6]([CH3:18])=[C:3]([C:4]#[N:5])[C:2]=2[NH2:1])=[O:32])[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: O=C(Cl)C1CCCC1
Reactant: Cc1c(C#N)c(N)c(O)c(F)c1-c1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1c(C#N)c(N)c(OC(=O)C2CCCC2)c(F)c1-c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 71.2 %

Procedure:
Under nitrogen atmosphere, 2-amino-5-phenyl-4-fluoro-3-hydroxy-6-methylbenzonitrile (I-41) (200 mg, 0.83 mmol) was dissolved in acetonitrile (10 ml), and cooled at 0° C. Triethylamine (138 μl, 1.36 mmol) and cyclopentanecarbonyl chloride (138 μl, 1.36 mmol) were dropwise added to the solution, followed by stirring at room temperature for 2 hours. 10% citric acid was added to the reaction liquid, and the solvent was evaporated away under reduced pressure. Ethyl acetate was added to the resulting residue, followed by washing with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated away under reduced pressure. The resulting residue was purified by preparative TLC (ethyl acetate:n-hexane=1:3, v/v) to obtain the entitled compound (200 mg, 72%) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:12]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:5]([OH:13])=[CH:4][CH:3]=1.Cl[C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][CH:16]=1>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:26][O:25][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][C:21]=1[O:27][CH3:28])[N:18]=[CH:17][CH:16]=[C:15]2[O:13][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:12][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1cc(F)ccc1O
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: CCOC(=O)c1cc(F)ccc1Oc1ccnc2cc(OC)c(OC)cc12
Temperature: 120 °C
Reaction time: 8 h
Yield: 30.8 %

Procedure:
Ethyl 5-fluorosalicylate (191 mg), 4-chloro-6,7-dimethoxyquinoline (125 mg), and 4-dimethylaminopyridine (205 mg) were suspended in o-dichlorobenzene (1 ml), and the suspension was stirred at 120° C. overnight. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give the title compound (64 mg, yield 22%).
Reaction SMILES: C(OC(=O)[NH:10][C:11]1[C:12]([O:26][CH3:27])=[N:13][CH:14]=[C:15]([B:17]2[O:21][C:20]([CH3:23])([CH3:22])[C:19]([CH3:25])([CH3:24])[O:18]2)[CH:16]=1)C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[CH3:27][O:26][C:12]1[C:11]([NH2:10])=[CH:16][C:15]([B:17]2[O:21][C:20]([CH3:23])([CH3:22])[C:19]([CH3:25])([CH3:24])[O:18]2)=[CH:14][N:13]=1
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1NC(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1N
Temperature: 25 °C
Reaction time: 5 h
Yield: 96.6 %

Procedure:
[2-Methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-carbamic acid benzyl ester (506 mg, 1.32 mmol) was dissolved in methanol (10 mL). Pd(OH)2 on carbon (51 mg, 10 mol %) was added and the reaction was degassed with nitrogen. The nitrogen atmosphere was replaced by hydrogen and the reaction mixture was stirred at room temperature for 5 hours. The palladium residue was removed by filtration through a path of Celite, rinsing with more methanol. The filtrate was concentrated in vacuo to give the title compound as an off-white solid (319 mg, 97% yield). MS (ES+) m/e=251. 1H NMR (DMSO-d6) δH 1.27 (12H, s), 3.88 (3H, s), 4.89 (2H, br s), 7.13 (1H, s), 7.64 (1H, s).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:35][CH2:34][CH2:33][C@H:12]1[C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[CH:20]([OH:32])[CH2:21][S:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClCCl.ClC1C=CC=C(C(OO)=[O:47])C=1>>[CH2:1]([O:8][C:9]([N:11]1[CH2:35][CH2:34][CH2:33][C@H:12]1[C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[CH:20]([OH:32])[CH2:21][S:22]([C:23]1[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=1)=[O:47])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(O)CSc1ccc([N+](=O)[O-])cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(O)CS(=O)c1ccc([N+](=O)[O-])cc1

Procedure:
(2S)-1-(N-Benzyloxycarbonyl-L-prolyl)-2-[1-hydroxy-2-(4-nitrophenylthio)ethyl]pyrrolidine (1.50 g) was subjected to oxidation as in Example 2-A) in dichloromethane using 1.1 equivalent of m-chloroperbenzoic acid to give 894 mg of the title compound.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].Cl[CH2:11][C:12]([N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[O:13].C(=O)([O-])O.[Cs+]>CN1C(=O)CCC1>[C:4]([O:6][CH2:11][C:12](=[O:13])[N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])(=[O:5])/[CH:3]=[CH:2]/[C:1]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)/C=C/C(=O)O
Reactant: CCN(CC)C(=O)CCl
Agent: O=C([O-])O
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CCN(CC)C(=O)COC(=O)/C=C/C(=O)OC
Yield: 50.7 %

Procedure:
Following general procedure A, methyl hydrogen fumarate (MHF) (0.39 g, 3.00 mmol) dissolved in NMP was reacted at ca. 55° C. with 2-chloro-N,N-diethylacetamide (0.44 g, 3.00 mmol) in the presence of CsHCO3 (0.69 g, 3.60 mmol) to afford 0.37 g (51% yield) of the title compound (1) after purification by silica gel column chromatography (Biotage) using a mixture of ethyl acetate (EtOAc) and hexanes (1:1) as eluent. M.p.: 53-56° C. 1H NMR (CDCl3, 400 MHz): δ 6.99-6.90 (m, 2H), 4.83 (s, 2H), 3.80 (s, 3H), 3.39 (q, J=7.2 Hz, 2H), 3.26 (q, J=7.2 Hz, 2H), 1.24 (t, J=7.2 Hz, 3H), 1.14 (t, J=7.2 Hz, 3H). MS (ESI): m/z 244.13 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:12]([NH:17][CH2:18][CH:19]3[CH2:24][CH2:23][N:22]([C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)[CH2:21][CH2:20]3)=[N:13][CH:14]=[CH:15][CH:16]=2)=O)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:11]2[C:12]([NH:17][CH2:18][CH:19]3[CH2:20][CH2:21][N:22]([C:25]4[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=4)[CH2:23][CH2:24]3)=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc(Cl)cc1)c1cccnc1NCC1CCN(c2ccncc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: Clc1ccc(NCc2cccnc2NCC2CCN(c3ccncc3)CC2)cc1
Temperature: 65 °C
Yield: 62.3 %

Procedure:
A solution of N-(4-chlorophenyl)-2-[1-(4-pyridyl)piperidin-4-ylmethyl]aminopyridine-3-carboxamide (25 mg, 0.059 mmol) in THF (1 mL) was treated with lithium aluminum hydride (1.0 M in THF, 0.21 mL, 0.21 mmol). The mixture was heated at 65° C. for 4 days, cooled, diluted with methanol (5 m), and loaded onto an SCX ion exchange resin. The resin was eluted with methanol followed by 2 N NH3 in methanol and fractions containing the desired material were concentrated. The residue was triturated with EtOAc, yielding 15 mg (62%) of the title compound.
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(=O)C.C([BH3-])#N.[Na+].[CH2:15]([O:17][C:18](=[O:28])[C:19]([CH:26]=O)([CH3:25])[CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23])[CH3:16]>C(O)C>[CH2:15]([O:17][C:18](=[O:28])[C:19]([CH2:25][NH:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)([CH3:26])[CH2:20][CH2:21][CH:22]([CH3:23])[CH3:24])[CH3:16]
Reactant: CCOC(=O)C(C)(C=O)CCC(C)C
Reactant: NC1CCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C(C)(CCC(C)C)CNC1CCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 39.3 %

Procedure:
Cyclopentylamine (1.49 mL, 15.1 mmol), glacial acetic acid (1.5 mL), and sodium cyanoborohydride (1.90 g, 30.2 mmol) were added sequentially to a solution of crude rac-2-formyl-2,5-dimethyl-hexanoic acid ethyl ester (prepared as described in Example 19c; 3.02 g, 15.1 mmol) in ethanol (45 mL) at 25° C. The mixture was stirred at 25° C. for 18 h, and then was concentrated in vacuo. The residue was partitioned between half-saturated aqueous sodium bicarbonate solution (150 mL) and ethyl acetate (2×150 mL). The combined organic layers were dried over sodium sulfate and were concentrated in vacuo. The residue was purified by flash column chromatography (self-packed glass column, gradient elution: 20-30% ethyl acetate in hexanes) to afford rac-2-cyclopentylaminomethyl-2,5-dimethyl-hexanoic acid ethyl ester (1.60 g, 5.94 mmol, 39%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ: 0.87 (6H, d, J=6.9 Hz), 1.01-1.06 (1H, m), 1.16 (3H, s), 1.27 (3H, t, J=6.9 Hz), 1.27-1.33 (4H, m), 1.43-1.64 (8H, m), 2.51 (1H, d, J=11.7 Hz), 2.79 (1H, d, J=11.7 Hz), 2.96-3.02 (1H, m), 4.12 (2H, q, J=7.2 Hz).