Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-])=O)[C:4]=1[CH2:12][C:13]([OH:15])=O>[Pd].C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:4]=1[CH2:12][C:13](=[O:15])[NH:9]2
Reactant: COc1cccc([N+](=O)[O-])c1CC(=O)O
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1cccc2c1CC(=O)N2
Yield: 36.8 %

Procedure:
A mixture of 2-methoxy-6-nitrophenylacetic acid (31 g, 150 mmol), and 3.0 g of 10% palladium on carbon in 200 mL of glacial acetic acid was stirred under an atmosphere of H2 gas until uptake ceased. The catalyst was filtered and the solvent evaporated in vacuo. The crude product was crystallized from methanol to give 9.0 g of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([CH:19]1[O:21][CH2:20]1)Cl>>[O:21]1[CH2:20][CH:19]1[CH2:17][N:14]1[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:12][CH2:13]1
Reactant: ClCC1CO1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Product: O=C(OCc1ccccc1)N1CCN(CC2CO2)CC1

Procedure:
By using 1-benzyloxycarbonylpiperazine (6 ml) and (±)-epichlorohydrin (2.4 ml) as starting materials, the title compound (7.80 g) was obtained in the same manner as that of Reference Example 33.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[C:13]([F:14])=[C:12]([F:15])[C:11]([F:16])=[C:10]([F:17])[C:9]=2[F:18])=[C:6]([F:19])[C:5]([F:20])=[C:4](F)[C:3]=1[F:22].[CH2:23]([OH:26])[C:24]#[CH:25].C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>C1(C)C=CC=CC=1>[CH2:23]([O:26][C:4]1[C:5]([F:20])=[C:6]([F:19])[C:7]([C:8]2[C:13]([F:14])=[C:12]([F:15])[C:11]([F:16])=[C:10]([F:17])[C:9]=2[F:18])=[C:2]([F:1])[C:3]=1[F:22])[C:24]#[CH:25]
Reactant: C#CCO
Reactant: Fc1c(F)c(F)c(-c2c(F)c(F)c(F)c(F)c2F)c(F)c1F
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: C#CCOc1c(F)c(F)c(-c2c(F)c(F)c(F)c(F)c2F)c(F)c1F
Temperature: 25 °C
Yield: 48 %

Procedure:
A mixture of decafluorobiphenyl (1.67 g, 5 mmol), propargyl alcohol (0.58 ml), potassium carbonate (7.5 g), and 18-crown-6 (0.1 g) in 30 ml of toluene was stirred under reflux for 8 hours. After cooling to room temperature, 2 g of celite was added and the reaction mixture was filtered. The filtrate was evaporated on a rotavapor to remove most of the solvent and then the product was purified by preparative gas chromatography, giving 0.93 g (48%) of 4-propargyloxynonafluorobiphenyl which was used in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]([CH2:12][CH3:13])C(=O)[O:8][C:9](=[O:10])[C:4]=2[CH:3]=1.Cl>[OH-].[K+]>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([NH:6][CH2:12][CH3:13])=[C:4]([CH:3]=1)[C:9]([OH:10])=[O:8]
Reactant: CCn1c(=O)oc(=O)c2cc(Cl)ccc21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: CCNc1ccc(Cl)cc1C(=O)O
Temperature: 95 °C
Yield: 69.5 %

Procedure:
150 mg (0.67 mmol) of 6-chloro-1-ethyl-1H-benzo[d][1,3]oxazine-2,4-dione were suspended in 1.33 ml of 2N KOH and the mixture was heated to 95° C. for 2 h. After cooling to RT the pH was adjusted to 5-6 by careful addition of 1N HCl. The precipitate was then filtered off, washed with water and dried to give 93 mg (71%) of 5-chloro-2-ethylamino-benzoic acid as a yellow solid. 1HNMR (DMSO-d6, 300 MHz): δ 1.13 (t, J=7.2 Hz, 3H), 3.12 (q, J=7.2 Hz, 2H), 6.68 (d, J=9.1 Hz, 1H), 7.31 (dd, J=9.1 and 2.7 Hz, 1H), 7.64 (d, J=2.7 Hz, 1H).
Reaction SMILES: C(OC([N:8]1[C@H:12]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:25]4[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][N:26]=4)[N:19]=3)=[CH:16][N:17]=2)[CH2:11][O:10]C1(C)C)=O)(C)(C)C>O1CCCC1.C(OCC)(=O)C.Cl>[NH2:8][C@H:12]([C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:25]3[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][N:26]=3)[N:19]=2)=[CH:16][N:17]=1)[CH2:11][OH:10]
Reactant: Cc1ccnc(Nc2cccc(-c3cnc([C@@H]4COC(C)(C)N4C(=O)OC(C)(C)C)s3)n2)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccnc(Nc2cccc(-c3cnc([C@@H](N)CO)s3)n2)c1
Temperature: 60 °C
Reaction time: 5 h
Yield: 44.2 %

Procedure:
To a solution of (S)-2,2-dimethyl-4-{5-[6-(4-methylpyridin-2-ylamino)pyridin-2-yl]thiazol-2-yl}oxazolidine-3-carboxylic acid tert-butyl ester (1.90 g, 4.06 mmol) obtained in Example 12 in tetrahydrofuran (10 ml), 4N hydrogen chloride-ethyl acetate solution (10 ml) was added and stirred at 60° C. for 5 hours. After the reaction solution was concentrated, it was neutralized with a saturated aqeous sodium bicarbonate, and extracted with ethyl acetate. After the organic layer was washed with a saturated brine and dried over magnesium sulfate, it was concentrated and the residue was purified by flash chromatography on silica gel (chloroform:methanol=20:1) and the title compound (588 mg, 44%) was obtained.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][C:20]=1[N:26]1[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]1>S(Cl)(Cl)=O>[Br:1][C:2]1[S:6][C:5]([C:7]([NH:25][C:22]2[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[C:20]([N:26]3[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]3)[CH:21]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: COc1ccc(N)cc1N1CCN(C)CC1
Reactant: O=C(O)c1ccc(Br)s1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: COc1ccc(NC(=O)c2ccc(Br)s2)cc1N1CCN(C)CC1
Reaction time: 18 h

Procedure:
5-Bromo-2-thiophenecarboxylic acid (0.375;1.8 mmol) was heated at reflux in thionyl chloride (8 ml) for 30 minutes, cooled, evaporated in vacuo and the residue azeotroped with toluene. The residue was redissolved in CH2Cl2 (10 ml) and treated with dry triethylamine (0.25 ml;1.81 mmol) and 4-methoxy-3-(4-methyl-1-piperazinyl)benzenamine (0.4 g;1.81 mmol). The solution was stirred under Ar (18 hours), evaporated in vacuo and partitioned satd. K2CO3 (aq)/EtOAc. The organic phases were combined, dried over Na2SO4, filtered and the filtrate evaporated in vacuo to a brown gum. The gum was purified by flash silica-gel chromatography and eluted with 3%MeOH/CHCl3 to yield the title compound as a brown gum which crystallised on standing (0.388 g;52%), and was converted to the oxalate salt, mp=114°-115° C.
Reaction SMILES: C=O.[C:3](O)(=O)C.[Cl-].[NH2+:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1.C([BH3-])#N.[Na+]>C1COCC1.O>[CH3:3][N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1
Reactant: CC(=O)O
Reactant: COC(=O)c1ccc(C2CC[NH2+]CC2)cc1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(C2CCN(C)CC2)cc1
Temperature: 60 °C
Reaction time: 18 h
Yield: 54.4 %

Procedure:
Water (0.4 mL), paraformaldehyde (0.742 g, 24.71 mmol) and acetic acid (1.415 mL, 24.71 mmol) were added to a stirred suspension of methyl 4-piperidin-1-ium-4-ylbenzoate chloride (1.58 g, 6.18 mmol) in THF (40 mL) under nitrogen. Sodium cyanoborohydride (0.582 g, 9.27 mmol) was added portion wise over a period of 10 mins. The resulting mixture was stirred at 60° C. for 18 h. The reaction mixture was evaporated to dryness and mixed with water (30 mL) and 1M HCl (10 mL). The solution was washed with ethyl acetate (2×25 mL), basified with solid potassium carbonate and extracted ethyl acetate (2×25 mL). The organic layer was washed with saturated brine and dried over MgSO4, filtered and evaporated to afford pure methyl 4-(1-methylpiperidin-4-yl)benzoate (0.784 g, 54.4%) as a colourless oil which solidified on standing.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.[CH3:11][C:12]1[CH:13]=[CH:14][C:15]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)=[N:16][CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1.O>[Br:1][C:2]1[C:3]([O:25][C:22]2[CH:21]=[CH:20][C:19]([NH:18][C:15]3[CH:14]=[CH:13][C:12]([CH3:11])=[CH:17][N:16]=3)=[CH:24][CH:23]=2)=[N:4][CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: Cc1ccc(Nc2ccc(O)cc2)nc1
Reactant: COc1cnc(Cl)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1cnc(Oc2ccc(Nc3ccc(C)cn3)cc2)c(Br)c1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
3-Bromo-2-chloro-5-methoxypyridine (0.30 g, 1.35 mmol), 4-(5-methylpyridin-2-ylamino)phenol (0.68 g, 3.37 mmol), and cesium carbonate (1.32 g, 4.05 mmol) were mixed in NMP (4 mL) under a nitrogen atmosphere. The reaction mixture was stirred at 120° C. for 16 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc (2×). The combined organic layers were washed with sat. sodium chloride (1×), dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting crude product was purified by silica gel chromatography. The isolated product contained a significant impurity. The impurity was removed by reverse phase HPLC. The desired product was partitioned between DCM and sat. aqueous sodium bicarbonate. The organic layers were separated, dried over magnesium sulfate, filtered, and concentrated in vacuo to give N-(4-(3-bromo-5-methoxypyridin-2-yloxy)phenyl)-5-methylpyridin-2-amine. MS (ESI, pos. ion) m/z: 386.1 and 388.1 (M+1).
Reaction SMILES: [NH2:1][C@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[N:32][CH:31]=1>>[C:18]([NH:17][C:13]1[CH:12]=[C:11]([CH:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][C@H:2]([NH:1][C:29](=[O:36])[C:30]3[CH:35]=[CH:34][CH:33]=[N:32][CH:31]=3)[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:6][CH2:7]2)[CH:16]=[CH:15][CH:14]=1)(=[O:22])[CH:19]([CH3:21])[CH3:20]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](N)c3ccccc3)CC2)c1
Reactant: O=C(Cl)c1cccnc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](NC(=O)c3cccnc3)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure Q1 and Scheme AC using N-(3-{1-[(3S)-3-amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and nicotinoyl chloride: ESMS m/e: 485.3 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH:8]([C:19]1[C:27]2[C:22](=[C:23]([CH2:28][S:29][CH3:30])[CH:24]=[CH:25][CH:26]=2)[NH:21][CH:20]=1)[C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)[C:3](OCC)=[O:4].BrC1SC(C(C2C3C(=C(CSC)C=CC=3)NC=2)CCO)=CN=1>>[CH3:1][CH:2]([CH:8]([C:19]1[C:27]2[C:22](=[C:23]([CH2:28][S:29][CH3:30])[CH:24]=[CH:25][CH:26]=2)[NH:21][CH:20]=1)[C:9]1[CH:10]=[CH:11][C:12]([C:15]([F:17])([F:18])[F:16])=[CH:13][CH:14]=1)[CH2:3][OH:4]
Reactant: CCOC(=O)C(C)C(c1ccc(C(F)(F)F)cc1)c1c[nH]c2c(CSC)cccc12
Agent: CSCc1cccc2c(C(CCO)c3cnc(Br)s3)c[nH]c12
Product: CSCc1cccc2c(C(c3ccc(C(F)(F)F)cc3)C(C)CO)c[nH]c12

Procedure:
The title compound was prepared starting from 0.97 g (2.23 mmol) of the compound from Example 28A in analogy to the synthesis of the compound from Example 19. 0.66 g (75% of theory) of the title compound was obtained as mixture of diastereomers.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH2:13][CH2:14][CH2:15][Cl:16])=[CH:6][C:5]=1[N+:17]([O-])=O>C(OCC)(=O)C.CO.[Pd]>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH2:13][CH2:14][CH2:15][Cl:16])=[CH:6][C:5]=1[NH2:17]
Reactant: COC(=O)c1cc(OC)c(OCCCCl)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(OC)c(OCCCCl)cc1N
Reaction time: 12 h
Yield: 92.3 %

Procedure:
To a solution of the intermediate from Step 2 (29.14 g, 95.8 mmol) in ethyl acetate: methanol (3:1, 1 L) was added 10% Pd/C (3 g). The mixture was stirred under H2 for 12 hours. Completion of the reaction was monitored by LCMS. The reaction mixture was filtered using a celite pad and washed with excess ethyl acetate. The filtrate was evaporated to dryness to afford the pure 2-amino-4-(3-chloro-propoxy)-5-methoxy-benzoic acid methyl ester (24.2 g, 94%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 7.13 (s, 1H), 6.43 (s, 2H), 6.39 (s, 1H), 4.04 (t, 2H), 3.80 (t, 2H), 3.74 s, 3H), 3.65 (s, 3H), 2.19 (m, 2H), LC-MS (ESI)m/z 274 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5](N)=[CH:4][CH:3]=1.[OH-].[Na+].N([O-])=O.[Na+].Cl.N([O-])=O.C([O-])(=O)C.[K+].O(CC)C([S-])=[S:29].[K+]>O>[I:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([SH:29])=[CH:4][CH:3]=1
Reactant: CCOC(=S)[S-]
Reactant: Nc1ccc(I)cc1C(=O)O
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=N[O-]
Solvent: O
Product: O=C(O)c1cc(I)ccc1S
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80.5 %

Procedure:
A solution of 5-iodoanthranilic acid (71.1 g; 0.272 mole), sodium hydroxide (11.5 g; 0.275 mole) and sodium nitrite (18.75 g; 0.275 mole) in water (325 ml) was added slowly with stirring to a mixture of concentrated hydrochloric acid (75 ml) and ice (100 g) while the temperature was maintained between 0° and 5° by external cooling and by the addition of ice. After completion of the addition of the nitrite solution, the mixture was stirred for an additional 30 minutes and adjusted to pH 7 with dilute sodium hydroxide solution and potassium acetate. The cold diazonium mixture was added to a vigorously stirred solution of potassium ethyl xanthate (125 g; 0.775 mole) in water (400 ml) preheated to 75°-80°. When the evolution of nitrogen ceased, the reaction mixture was cooled and acidified to pH 3 with concentrated hyrochloric acid. After decanting the aqueous phase, the resulting sludge was dissolved in 10 percent sodium hydroxide solution (200 ml) and heated on a steam bath for two hours. The solution was cooled, filtered, acidified to pH 4-5 with concentrated hydrochloric acid, and the solid collected, washed and dried. The resulting disulfide was refluxed for 16 hours with zinc dust (25 g) in glacial acetic acid (750 ml). The solid was collected, washed with cold water, digested with concentrated hydrochloric acid for 30 minutes, filtered, washed with water and dried to give 5-iodothiosalicyclic acid (61.3 g), m.p. 208°-210°. Treatment of 5-iodothiosalicyclic acid (60 g) with acetic anhydride (300 ml) and concentrated sulfuric acid (1 ml) at 100° for one hour yielded 5-iodoacetylthiosalicylic acid (35.1 g), m.p. 163°14 165°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([C:16]2[N:17]=[C:18](Cl)[S:19][CH:20]=2)=[O:15])[CH:8]=1)[CH3:2].[F:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1>>[CH2:1]([O:3][C:4](=[O:22])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([C:16]2[N:17]=[C:18]([C:28]3[CH:27]=[CH:26][CH:25]=[C:24]([F:23])[CH:29]=3)[S:19][CH:20]=2)=[O:15])[CH:8]=1)[CH3:2]
Reactant: OB(O)c1cccc(F)c1
Reactant: CCOC(=O)C=Cc1cccc(NC(=O)c2csc(Cl)n2)c1
Product: CCOC(=O)C=Cc1cccc(NC(=O)c2csc(-c3cccc(F)c3)n2)c1

Procedure:
The chloro thiazole (114)(80 mg, 0.24 mmol) was coupled to 3-fluoro-phenylboronic acid (42 mg, 0.30 mmol) using Method E, except that the reaction mixture was heated for a total of 12 h. The crude residue was purified by column chromatography eluting with 20% EtOAc in heptane to give the title compound.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([N:9]2[CH2:13][CH2:12][NH:11][C:10]2=[O:14])=[N:6][C:5]=1[CH3:15])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH:22]1([CH2:25]Br)[CH2:24][CH2:23]1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>[C:1]([C:4]1[S:8][C:7]([N:9]2[CH2:13][CH2:12][N:11]([CH2:25][CH:22]3[CH2:24][CH2:23]3)[C:10]2=[O:14])=[N:6][C:5]=1[CH3:15])(=[O:3])[CH3:2]
Reactant: CC(=O)c1sc(N2CCNC2=O)nc1C
Reactant: BrCC1CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: C1CCOC1
Product: CC(=O)c1sc(N2CCN(CC3CC3)C2=O)nc1C
Yield: 33 %

Procedure:
To a solution of 1-(5-acetyl-4-methylthiazol-2-yl)imidazolidin-2-one (2.25 g, 10.00 mmol), tetrabutylammonium iodide (0.10 g) and potassium carbonate (3.50 g, 25.27 mmol) in tetrahydrofuran (100 mL) was added cyclopropylmethyl bromide (2.0 mL, 20.88 mmol). The reaction mixture was heated to reflux for 50 hours. The solvent was removed in vacuo, and the residue was washed with water and hexanes to afford the title compound in 33% yield (0.94 g): mp 103-104° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 4.14-4.05 (m, 2H), 3.72-3.69 (m, 2H), 3.19 (d, J=6.0 Hz, 2H), 2.57 (s, 3H), 2.44 (s, 3H), 0.99-0.89 (m, 1H), 0.59-0.55 (m, 2H), 0.27-0.22 (m, 2H); MS (ES+) m/z 280.2 (M+1).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[CH2:12][CH2:11][C:10]3([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[C:9]2=[O:18])[CH2:4][CH2:3]1.Cl[C:20]1[C:25]([CH3:26])=[CH:24][C:23]([N+:27]([O-:29])=[O:28])=[CH:22][N:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[OH:1][C@@H:2]1[CH2:3][CH2:4][C@H:5]([N:8]2[CH2:12][CH2:11][C:10]3([CH2:17][CH2:16][N:15]([C:20]4[C:25]([CH3:26])=[CH:24][C:23]([N+:27]([O-:29])=[O:28])=[CH:22][N:21]=4)[CH2:14][CH2:13]3)[C:9]2=[O:18])[CH2:6][CH2:7]1
Reactant: Cc1cc([N+](=O)[O-])cnc1Cl
Reactant: O=C1N([C@H]2CC[C@@H](O)CC2)CCC12CCNCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc([N+](=O)[O-])cnc1N1CCC2(CC1)CCN([C@H]1CC[C@@H](O)CC1)C2=O
Temperature: 90 °C

Procedure:
A mixture of 2-(cis-4-hydroxycyclohexyl)-2,8-diazaspiro[4.5]decan-1-one (0.10 g, 0.40 mmol), 2-chloro-3-methyl-5-nitropyridine (0.0718 g, 0.416 mmol) and potassium carbonate (0.11 g, 0.79 mmol) in N,N-dimethylformamide (2.0 mL) was heated at 90° C. overnight. After cooled to room temperature, the mixture was diluted with ethyl acetate, washed with water and brine. The organic phase was dried over Na2SO4, filtered, and concentrated. The residue was used directly in next step without further purification.
Reaction SMILES: Cl[C:2]1[C:3]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[CH:12][S:11][C:4]=2[N:5]=[C:6]([CH2:8][CH2:9][OH:10])[N:7]=1.C(N(CC)CC)C.Cl.[CH3:29][O:30][CH2:31][CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>C(O)C>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]2[C:3]3[C:2]([N:35]4[CH2:36][CH2:37][CH:32]([CH2:31][O:30][CH3:29])[CH2:33][CH2:34]4)=[N:7][C:6]([CH2:8][CH2:9][OH:10])=[N:5][C:4]=3[S:11][CH:12]=2)=[CH:15][CH:16]=1
Reactant: OCCc1nc(Cl)c2c(-c3ccc(F)cc3)csc2n1
Reactant: COCC1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COCC1CCN(c2nc(CCO)nc3scc(-c4ccc(F)cc4)c23)CC1
Temperature: 55 °C
Yield: 89.7 %

Procedure:
2-[4-Chloro-5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-2-yl]ethanol (150 mg, 0.0005 mol), triethylamine (0.214 mL, 0.00154 mol) and 4-(methoxymethyl)piperidine hydrochloride (0.091 g, 0.00055 mol) were dissolved in ethanol (5 mL) and warmed to 55° C. for 2 hrs. The reaction was then poured over ice and extracted with DCM. The organics were dried by passage through a PTFE frit and concentrated in vacuo to give 2-[5-(4-fluorophenyl)-4-[4-(methoxymethyl)-1-piperidyl]thieno[2,3-d]pyrimidin-2-yl]ethanol (180 mg). LCMS RT=4.33 min. M+1=402.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23](O)=[O:24].[N:37]1[CH:42]=[CH:41][CH:40]=[C:39]([CH2:43][NH2:44])[CH:38]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:23]([NH:44][CH2:43][C:39]1[CH:38]=[N:37][CH:42]=[CH:41][CH:40]=1)=[O:24]
Reactant: NCc1cccnc1
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)O)c2ccccc2)cc1OC
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)NCc2cccnc2)c2ccccc2)cc1OC

Procedure:
prepared by reaction of [1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-acetic acid with 3-picolylamine.
Reaction SMILES: C[O:2][C:3](=[O:28])[C@H:4]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1)[NH:5][C:6]([C:8]1([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7].[Cl:29][C:30]1[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:31]=1[C:32](Cl)=[O:33].N1C(C)=CC=CC=1C>ClCCl.CCOCC>[Cl:29][C:30]1[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:31]=1[C:32]([NH:27][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][C@@H:4]([C:3]([OH:2])=[O:28])[NH:5][C:6]([C:8]2([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:9][CH2:10][CH2:11][CH2:12]2)=[O:7])=[CH:26][CH:25]=1)=[O:33]
Reactant: COC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)C1(Cc2ccccc2)CCCC1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: Cc1cccc(C)n1
Product: O=C(Nc1ccc(C[C@H](NC(=O)C2(Cc3ccccc3)CCCC2)C(=O)O)cc1)c1c(Cl)cccc1Cl
Reaction time: 4 h
Yield: 48.5 %

Procedure:
4-Amino-N-[[1-(phenylmethyl)cyclopentyl]carbonyl]-L-phenylalanine methyl ester (67 mg, 0.176 mmol) and 2,6-dichlorobenzoyl chloride (50 mg, 0.23 mmol) were dissolved in 5 mL of dichloromethane and 2,6-lutidine (50 μL, 0.43 mmol) were added. After 4 hours, the mixture was diluted with ether and dichloromethane and washed with 1 N HCl, water, and saturated NAHCO3 and was dried (MgSO4). The crude product was dissolved in 4 mL of methanol and treated with 4 N NaOH (0.1 mL). After 2 hours, the excess base was quenched with 0.1 mL of acetic acid, the solution was filtered through a 0.2μ nylon filter and the filtrate was purified by RP-HPLC on a 4×30 cm Rainin C-18 column using a gradient of 5 to 95% acetonitrile:water containing 0.75% trifluoroacetic acid at a flow of 49 mL/min over 30 min. The peak eluting at 87% acetonitrile was concentrated and lyophilized to give 4-[[(2,6-dichlorophenyl)carbonyl]amino]-N-[[1-(phenylmethyl)cyclopentyl]carbonyl]-L-phenylalanine (46 mg), LR(+)LSIMS: m/z 539 (M+H) (2 Cl).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[NH2:6].C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:28][O:29][C:30]1[C:31](=[O:54])[C:32]([CH3:53])=[C:33]([CH2:39][C:40]2[CH:41]=[CH:42][C:43]([O:49][C:50](=[O:52])[CH3:51])=[C:44]([CH:48]=2)[C:45](O)=[O:46])[C:34](=[O:38])[C:35]=1[O:36][CH3:37]>C(Cl)Cl>[CH3:28][O:29][C:30]1[C:31](=[O:54])[C:32]([CH3:53])=[C:33]([CH2:39][C:40]2[CH:41]=[CH:42][C:43]([O:49][C:50](=[O:52])[CH3:51])=[C:44]([CH:48]=2)[C:45]([NH:6][C:5]2[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:3]([O:2][CH3:1])[CH:4]=2)=[O:46])[C:34](=[O:38])[C:35]=1[O:36][CH3:37]
Reactant: COc1ccc(N)cc1OC
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccc(OC)c(OC)c3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 40.4 %

Procedure:
3,4-Dimethoxyaniline (0.246 g, 1.604 mmol), triethylamine (0.162 g, 1.604 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.271 g, 1.604 mmol) were added to a methylene chloride solution (20 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.200 g, 0.535 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexand:ethyl acetate=1:2) to obtain the titled compound (0.110 g, 0.216 mmol, 40%).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].Cl[C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[C:12]([Cl:19])[N:11]=1>C(O)C>[Cl:19][C:12]1[N:11]=[C:10]([NH:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[Cl:1])[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: Nc1ccccc1Cl
Solvent: CCO
Product: O=[N+]([O-])c1ccc(Cl)nc1Nc1ccccc1Cl
Temperature: 180 °C
Yield: 58.8 %

Procedure:
2-Chloroaniline (1.32 mL, 10.4 mmol) was added to 2,6-dichloro-3-nitropyridine (1.00 g, 5.18 mmol) in ethanol (4 mL) and the solution was heated to 180° C. for 12 minutes under microwave irradiation in a heavy walled sealed tube. After cooling to room temperature, the resulting precipitate was collected by vacuum filtration, washed with cold ethanol and dried to give the title compound (0.8650 g). LCMS m/z=284.1 [M+H]+; 1H NMR (400 MHz, acetonitrile-d3) δ ppm 6.97 (d, J=8.6 Hz, 1H), 7.23 (td, J1=7.8 Hz, J2=1.6 Hz, 1H), 7.41 (td, J1=8.0 Hz, J2=1.5 Hz, 1H), 7.55 (dd, J1=8.0 Hz, J2=1.5 Hz, 1H), 8.20 (dd, J1=8.2 Hz, J2=1.50 Hz, 1H), 8.54 (d, J=8.6 Hz, 1H), 10.36 (broad s, 1H).