Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.Br[CH2:21][C:22]1[C:30]2[O:29][C:28]([C:31]#[N:32])=[N:27][C:26]=2[CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OC(=O)C)C>[C:31]([C:28]1[O:29][C:30]2[C:22]([CH2:21][O:19][C:16]3[CH:15]=[CH:14][C:13]([O:12][CH2:11][C:2]4[CH:3]=[CH:4][C:5]5[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=5)[N:1]=4)=[CH:18][CH:17]=3)=[CH:23][CH:24]=[CH:25][C:26]=2[N:27]=1)#[N:32]
Reactant: N#Cc1nc2cccc(CBr)c2o1
Reactant: Oc1ccc(OCc2ccc3ccccc3n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1nc2cccc(COc3ccc(OCc4ccc5ccccc5n4)cc3)c2o1

Procedure:
1.0 g of 4-(2-quinolinylmethyloxy)phenol, .9 g of 7-bromomethyl-2-cyanobenzoxazole and 0.5 g of potassium carbonate are stirred at room temperature in 5 ml of dimethylformamide for 2 days. The reaction mixture is diluted with ethylacetate, filtered and concentrated. The residue is chromatographed on silica gel to give 2-cyano-7-(4-(quinolin-2-ylmethyloxy)phenoxymethyl)benzoxazole.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][N:10]2[CH2:15][CH2:14][S:13][CH2:12][CH2:11]2)[CH:6]=[C:5]([O:16][CH3:17])[C:4]=1B(O)O.[CH2:21]([O:23][C:24](=[O:45])[C@H:25]([CH2:37][C:38]1[CH:43]=[CH:42][C:41](Br)=[CH:40][CH:39]=1)[NH:26][C:27](=[O:36])[C:28]1[C:33]([Cl:34])=[CH:32][CH:31]=[CH:30][C:29]=1[Cl:35])[CH3:22].C([O-])([O-])=O.[K+].[K+]>COCCOC.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>[CH2:21]([O:23][C:24](=[O:45])[C@H:25]([CH2:37][C:38]1[CH:43]=[CH:42][C:41]([C:4]2[C:3]([O:2][CH3:1])=[CH:8][C:7]([CH2:9][N:10]3[CH2:15][CH2:14][S:13][CH2:12][CH2:11]3)=[CH:6][C:5]=2[O:16][CH3:17])=[CH:40][CH:39]=1)[NH:26][C:27](=[O:36])[C:28]1[C:29]([Cl:35])=[CH:30][CH:31]=[CH:32][C:33]=1[Cl:34])[CH3:22]
Reactant: COc1cc(CN2CCSCC2)cc(OC)c1B(O)O
Reactant: CCOC(=O)[C@H](Cc1ccc(Br)cc1)NC(=O)c1c(Cl)cccc1Cl
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: COCCOC
Solvent: O
Product: CCOC(=O)[C@H](Cc1ccc(-c2c(OC)cc(CN3CCSCC3)cc2OC)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 80 °C
Yield: 15.2 %

Procedure:
A mixture of 2,6-dimethoxy-4-(thiomorpholinomethyl)benzeneboronic acid (1.1 g), N-(2,6-dichlorobenzoyl)-4bromo-L-phenylalanine ethyl ester (0.71 g), Pd(PPh3)4 (1.0 g) and K2CO3 (1.00 g) in DME/H2O (10 mL/0.5 mL) was heated at 80° C. for 6 h under N2. The mixture was worked up and purified according to the procedure described in Example 8-3) to yield 0.15 g of N-(2,6-dichlorobenzoyl)-4-[2,6-dimethoxy-4-(thiomorpholinomethyl)phenyl]-L-phenylalanine ethyl ester. mp. 86-89° C. ESMS: m/z 616 (MH+). HCl salt: mp. 204-205° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[CH:13][C:12](=O)[NH:11][N:10]=1.O=P(Cl)(Cl)[Cl:18].C(N(CC)CC)C>O1CCOCC1>[Cl:18][C:12]1[N:11]=[N:10][C:9]([C:3]2[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=2[F:8])=[N:14][CH:13]=1
Reactant: O=c1cnc(-c2c(F)cccc2F)n[nH]1
Reactant: O=P(Cl)(Cl)Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Fc1cccc(F)c1-c1ncc(Cl)nn1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
1 g of 3-(2,6-difluorophenyl)-[1,2,4]triazin-6(1H)-one is placed in 20 ml of dioxane and at room temperature 0.73 g of POCl3 is added. Then, within a period of 5 min, 0.48 g of triethylamine in 3 ml of dioxane is added dropwise and stirring is carried out at room temperature for 30 min. The reaction mixture is then poured into ice-water and extracted with ethyl acetate, and the organic phase is separated off and concentrated. In this way 6-chloro-3-(2,6-difluorophenyl)-[1,2,4]triazine is obtained in the form of a yellow oil. The crude product is reacted further without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([OH:18])=[C:13]([O:16][CH3:17])[CH:14]=2)[N:9]=[CH:8][N:7]=1.[C:22]([C:26]1[O:30][N:29]=[C:28]([NH:31][C:32](=O)[O:33]C2C=CC=CC=2)[CH:27]=1)([CH3:25])([CH3:24])[CH3:23]>CN(C)C=O>[C:22]([C:26]1[O:30][N:29]=[C:28]([NH:31][C:32]([NH:1][C:2]2[CH:21]=[CH:20][CH:19]=[C:4]([O:5][C:6]3[C:15]4[C:10](=[CH:11][C:12]([OH:18])=[C:13]([O:16][CH3:17])[CH:14]=4)[N:9]=[CH:8][N:7]=3)[CH:3]=2)=[O:33])[CH:27]=1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)no1
Reactant: COc1cc2c(Oc3cccc(N)c3)ncnc2cc1O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1O
Temperature: 60 °C
Yield: 82 %

Procedure:
A stirred mixture of 4-(3-aminophenoxy)-6-methoxyquinazolin-7-ol from the previous step (500 mg, 1.77 mmol) and phenyl 5-tert-butylisoxazol-3-ylcarbamate (460 mg, 1.77 mmol) in dry N,N-dimethylformamide (10 mL) was heated at 60° C. for 5 h. After cooling to room temperature the mixture was concentrated under reduced pressure. The residue was triturated with diethyl ether and filtered and dried under reduced pressure to afford 1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-hydroxy-6-methoxyquinazolin-4-yloxy)phenyl)urea as a cream solid (650 mg, 82%) which did not require further purification. 1H NMR (300 MHz, DMSO-d6) δ 10.78 (brs, 1H), 9.58 (brs, 1H), 9.00 (brs, 1H), 8.48 (s, 1H), 7.55-7.57 (m, 2H), 7.40 (m, 1H), 7.24-7.26 (m, 2H), 6.97 (m, 1H), 6.48 (s, 1H), 3.99 (s, 3H), 1.28 (s, 9H); LC-MS (ESI) m/z 450 (M+H)+.
Reaction SMILES: [OH:1][C@H:2]1[CH2:16][CH:15]=[C:14]2[C@:4]([CH3:17])([CH2:5][C:6]3[C:7](=[CH:13]2)[O:8][C:9](=[O:12])[C:10]=3[CH3:11])[C@H:3]1[CH3:18].[C:19](Cl)(=[O:24])[CH2:20][CH:21]([CH3:23])[CH3:22]>>[CH3:22][CH:21]([CH3:23])[CH2:20][C:19]([O:1][C@H:2]1[CH2:16][CH:15]=[C:14]2[C@:4]([CH3:17])([CH2:5][C:6]3[C:7](=[CH:13]2)[O:8][C:9](=[O:12])[C:10]=3[CH3:11])[C@H:3]1[CH3:18])=[O:24]
Reactant: CC1=C2C[C@@]3(C)C(=CC[C@H](O)[C@@H]3C)C=C2OC1=O
Reactant: CC(C)CC(=O)Cl
Product: CC1=C2C[C@@]3(C)C(=CC[C@H](OC(=O)CC(C)C)[C@@H]3C)C=C2OC1=O

Procedure:
The title compound was prepared in the same manner as in Example B2, except that the compound prepared in Example B1 was reacted with isovaleryl chloride.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]=[C:8]=[O:9])[CH:2]=1.[Cl:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][C:19]=1[Cl:20])[NH:16][CH2:15][CH2:14]2>>[Cl:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][C:19]=1[Cl:20])[N:16]([C:8](=[O:9])[NH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH2:15][CH2:14]2
Reactant: O=C=Nc1cccnc1
Reactant: Clc1cc2c(cc1Cl)NCC2
Product: O=C(Nc1cccnc1)N1CCc2cc(Cl)c(Cl)cc21

Procedure:
The title compound was prepared as in the method of (Example 2) from 3-pyridylisocyanate and 5,6-dichloroindoline (D39) to give (E20) (1.27 g, 65%) m.p. 236°-238° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[N:7]([CH:9]([C:11](=[O:29])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[N:14]=1)[CH3:10])[CH3:8])([CH3:4])([CH3:3])[CH3:2].C1C[O:34][CH2:33]C1>>[C:1]([O:5][C:6](=[O:30])[N:7]([CH:9]([C:11](=[O:29])[NH:12][C:13]1[N:14]=[C:15]2[N:20]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=3)[C:33](=[O:34])[NH:19][C:16]2=[CH:17][CH:18]=1)[CH3:10])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C(=O)Nc1ccc(N)c(NCc2ccc(Cl)cc2)n1)N(C)C(=O)OC(C)(C)C
Reactant: C1CCOC1
Product: CC(C(=O)Nc1ccc2[nH]c(=O)n(Cc3ccc(Cl)cc3)c2n1)N(C)C(=O)OC(C)(C)C
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A solution of the product from Step 3, in THF (3 mL), was added to a solution of N,N′-carbonyldiimidazole (110 mg, 0.68 mmol) in THF (3 mL). The mixture was then heated at 70° C. for 3 hours. After allowing to cool, the mixture was concentrated in vacuo, treated with water and then left overnight. The product was extracted with EtOAc. The EtOAc layer was washed successively with aqueous potassium hydrogensulfate solution, brine and then dried (MgSO4). The solution was concentrated to ˜1 mL and then Et2O (3 mL) was added. The resulting precipitate was collected by filtration to give {1-[3-(4-chloro-benzyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-ylcarbamoyl]ethyl}-methyl-carbamic acid tert-butyl ester (90 mg) as a white crystalline solid. MS: [M+H]+=460.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.Cl[Si:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:24]1([Si:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:2]2[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([CH3:8])[CH:7]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Cc1cc(C)cc(Br)c1
Reactant: Cl[Si](c1ccccc1)(c1ccccc1)c1ccccc1
Product: Cc1cc(C)cc([Si](c2ccccc2)(c2ccccc2)c2ccccc2)c1

Procedure:
In the same manner as described in preparation 1, 5-bromo-m-xylene was allowed to react with chlorotriphenylsilane, and afforded TPSIX. The yield and properties are summarized in Table 1.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][CH2:15][CH:14]([NH:18][C@@H:19]3[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]3[NH2:25])[CH2:13]2)=[CH:8][CH:7]=1.[C:26](=O)([O:35]N1C(=O)CCC1=O)[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][CH2:15][C@H:14]([NH:18][C@@H:19]3[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]3[NH:25][C:26](=[O:35])[O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:13]2)=[CH:8][CH:7]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: N[C@@H]1CCCC[C@H]1NC1CCCN(c2ccc(-c3ncco3)cc2)C1
Product: O=C(N[C@@H]1CCCC[C@H]1N[C@H]1CCCN(c2ccc(-c3ncco3)cc2)C1)OCc1ccccc1
Yield: 31 %

Procedure:
Benzyl (1R,2R)-2-((S)-1-(4-(oxazol-2-yl)phenyl)piperidin-3-ylamino)cyclohexylcarbamate was synthesized using (1R,2R)—N1-(1-(4-(oxazol-2-yl)phenyl)piperidin-3-yl)cyclohexane-1,2-diamine (from Example 15, step D) (11.58 mg, 0.034 mmol) and benzyl 2,5-dioxopyrrolidin-1-yl carbonate (8.5 mg, 0.034 mmol) according to General Procedure H to give 5 mg (20% yield) of the title compound as a pink solid. Anal. Calcd. for C28H34N4O3 m/z 474.5, found: 475.3 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.90 (d, J=8.8 Hz, 2H), 7.71 (s, 1H), 7.39 (s, 1H), 7.24-7.08 (m, 5H), 6.98 (d, J=8.7 Hz, 2H), 4.79 (s, 2H), 3.67-3.53 (m, 1H), 3.53-3.42 (m, 2H), 3.42-3.30 (m, 2H), 3.29-3.19 (m, 2H), 2.22 (d, J=10.4 Hz, 1H), 2.14-1.85 (m, 5H), 1.84-1.54 (m, 4H), 1.44-1.19 (m, 2H).
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O.C(=O)(O)O.[NH2:18][C:19]([NH2:21])=[NH:20].C[O-].[Na+]>CO>[NH2:20][C:19]1[N:21]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:4]=[CH:3][N:18]=1
Reactant: CN(C)C=CC(=O)c1ccccc1
Reactant: N=C(N)N
Agent: C[O-]
Agent: O=C(O)O
Agent: [Na+]
Solvent: CO
Product: Nc1nccc(-c2ccccc2)n1
Yield: 82 %

Procedure:
To a stirred solution of 3.0 g (17.1 mmol) 3-(dimethylamino)acrylophenone and 10.2 g (56.5 mmol) guanidine carbonate in 50 ml methanol was added 21.2 ml (114 mmol) sodium methylate (5.4M in methanol) and the mixture heated at reflux for 3 hours. The reaction mixture was then concentrated in vacuo. On addition of 50 ml water, a precipitate appeared which was collected by filtration and washed sequentially with water and ether to afford 2.4 g (82%) 2-amino-4-phenylpyrimidine as a crystalline solid. EI-MS m/e (%): 171 (M+, 100), 170 ([M—H]+, 94).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][CH:18]=1)[CH2:7]P(=O)(OCC)OCC.O=[C:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH2:22][CH2:21]1>C1COCC1>[F:3][C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][CH:18]=1)[CH:7]=[C:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[O:27])[CH2:22][CH2:21]1
Reactant: CCOP(=O)(Cc1cccc(F)c1)OCC
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC(=Cc2cccc(F)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.5 %

Procedure:
Sodium hydride (0.245 g) was added portionwise to a solution of diethyl (3-fluorobenzyl)phosphonate (Intermediate 182, 1 g) in THF (40 mL) at 0° C. The mixture was stirred for 30 minutes then benzyl 4-oxopiperidine-1-carboxylate (0.947 g) was added at 0° C. The mixture was allowed to warm to room temperature and stirred for 21.5 hours. The mixture was partitioned between water and ethyl acetate and the organic layer was washed with brine, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-25% to give benzyl 4-(3-fluorobenzylidene)piperidine-1-carboxylate (1.05 g)
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]2[O:8][C:9]([CH:15]([Cl:20])[C:16]([F:19])([F:18])[F:17])([C:11]([F:14])([F:13])[F:12])[O:10][C:6]=2[CH:5]=1)([O-])=O>O1CCCC1.[H][H]>[NH2:1][C:4]1[CH:22]=[CH:21][C:7]2[O:8][C:9]([CH:15]([Cl:20])[C:16]([F:19])([F:17])[F:18])([C:11]([F:12])([F:13])[F:14])[O:10][C:6]=2[CH:5]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc2c(c1)OC(C(Cl)C(F)(F)F)(C(F)(F)F)O2
Solvent: C1CCOC1
Product: Nc1ccc2c(c1)OC(C(Cl)C(F)(F)F)(C(F)(F)F)O2

Procedure:
72 g of 5-nitro-2-(1-chloro-2,2,2-trifluoroethyl)-2-trifluoromethyl-1,3-benzodioxole from Example 28 were dissolved in 500 ml of tetrahydrofuran and hydrogenated with 15-20 bar of hydrogen over 5 g of palladium-oncharcoal (5% strength) at room temperature for 5 hours. The mixture was then filtered and the solvent was stripped off in vacuo. The yield was 60 g (93% of theory), and the boiling point was 80°-82° C. under 0.1 mbar. The NMR spectra showed the following characteristic absorptions: 19F-NMR: -66.5 and -79.4 ppm. 1H-NMR: 4.68 ppm.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8]O)=[N:6][CH:7]=1.[C:10]([CH:15]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:12][CH2:13][CH3:14])=[O:11]>O1CCOCC1.[O-2].[Mn+4].[O-2]>[Cl:1][C:2]1[N:3]=[CH:4][C:5](/[CH:8]=[CH:15]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:6][CH:7]=1
Reactant: OCc1cnc(Cl)cn1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1COCCO1
Product: CCOC(=O)/C=C/c1cnc(Cl)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
To a solution of (5-chloro-2-pyrazinyl)methanol (11.0 g) in dioxane (110 mL) was added manganese(IV) oxide (26.5 g) and (carbethoxymethylene)triphenylphosphorane (29.2 g). After stirring for 2 hours at room temperature, a resulting precipitate was filtered and the filtrate was evaporated in vacuo. The residue was purified by column chromatography on silica gel to give ethyl (2E)-3-(5-chloro-2-pyrazinyl)acrylate (11.0 g).
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[OH:26][C@H:27]([CH3:31])[C:28](O)=[O:29]>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:28](=[O:29])[C@H:27]([OH:26])[CH3:31])[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Reactant: C[C@@H](O)C(=O)O
Agent: Cl
Product: C[C@@H](O)C(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, white solid (17.7 mg, 53.8%), MS (ISP) m/z=403.3 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (30 mg, 0.0818 mmol) and (R)-2-hydroxypropanoic acid.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:26])[C:10]([CH3:25])([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]2[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]2)[CH:14]=1)[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:27]([C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37](O)=[O:38])=[CH:32][CH:31]=1)([CH3:29])[CH3:28].Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:26])[C:10]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]2[CH2:24][CH2:23][CH2:22][N:21]([C:37](=[O:38])[CH2:36][C:33]3[CH:34]=[CH:35][C:30]([CH:27]([CH3:28])[CH3:29])=[CH:31][CH:32]=3)[CH2:20]2)[CH:14]=1)([CH3:11])[CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1ccc(CC(=O)O)cc1
Reactant: CC(C)(Oc1cccc(C2CCCNC2)c1)C(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)c1ccc(CC(=O)N2CCCC(c3cccc(OC(C)(C)C(=O)OCc4ccccc4)c3)C2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.1 %

Procedure:
To a solution of 2-methyl-2-(3-piperidin-3-yl-phenoxy)-propionic acid benzyl ester (Preparation 2, Method C; 0.54 g, 1.52 mmol) in 5 mL methylene chloride was added 4-isopropylphenyl acetic acid (0.33 g, 1.83 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.58 g, 3.04 mmol) and allowed to stir 18 h at ambient temperature. The reaction was concentrated under reduced pressure and the resultant oil flash chromatographed with 30% ethyl acetate/hexanes to yield 0.696 g (89%) of 2-(3-{1-[(4-Isopropyl-phenyl)-acetyl]-piperidin-3-yl}-phenoxy)-2-methyl-propionic acid benzyl ester as a clear oil.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]([NH2:10])=[N:8][CH:9]=1.[CH3:11]I>CN(C)C=O>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][CH3:11])=[N:8][CH:9]=1
Reactant: CI
Reactant: Nc1ccc(Br)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23.6 %

Procedure:
NaH (47.3 mg, 1.971 mmol) and 5-bromo-2-pyridinamine (310 mg, 1.792 mmol, available from Aldrich) were added to N,N-Dimethylformamide (DMF) (7 mL) and stirred in an ice bath for 30 mins. The reaction mixture was then allowed to warm to room temperature and methyl iodide (0.123 mL, 1.971 mmol) was added and the reaction mixture stirred for 24 hr. The reaction mixture was partitioned between DCM (20 mL) and water (20 mL) and the organic layer washed with more water (20 mL) before being dried through an hydrophobic frit and concentrated. The residue was dissolved in DCM and purified by SP4 on a 25+S silica cartridge using a gradient of 10%-40% EtOAc in cyclohexane. Appropriate fractions were collected and concentrated to yield the desired product as a white solid (79.1 mg). LCMS (Method C): Rt 0.39, MH+=187
Reaction SMILES: [CH:1]1([CH:7]([NH:19][C:20]2[N:25]=[CH:24][C:23]([C:26]([O:28]C)=[O:27])=[CH:22][CH:21]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)C.[OH-].[Na+]>O1CCCC1>[CH:1]1([CH:7]([NH:19][C:20]2[N:25]=[CH:24][C:23]([C:26]([OH:28])=[O:27])=[CH:22][CH:21]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(NC(c2oc3ccc(F)cc3c2C)C2CCCCC2)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(C(Nc2ccc(C(=O)O)cn2)C2CCCCC2)oc2ccc(F)cc12
Reaction time: 8 h
Yield: 90.6 %

Procedure:
To a mixture of methyl 6-{[cyclohexyl(5-fluoro-3-methyl-1-benzofuran-2-yl)methyl]amino}pyridine-3-carboxylate (547 mg) synthesized above, ethanol (10 mL) and tetrahydrofuran (10 mL) was added 1N aqueous sodium hydroxide solution (10 mL), and the mixture was stirred overnight with heating under reflux. In addition, 1N aqueous sodium hydroxide solution (5.00 mL) was added, and the mixture was stirred with heating under reflux for 5 hr, and concentrated under reduced pressure. The residue was dissolved in water (20 mL), and 1N hydrochloric acid (15 mL) was added at 0° C. The resulting precipitate was collected by filtration, and the obtained pale-brown solid was dissolved in ethyl acetate. The solution was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give the title object compound (478 mg, 90%) as a pale-brown solid.
Reaction SMILES: [CH3:1][C:2]1([CH2:19][C:20]([F:23])([F:22])[F:21])[C@@:7]2([C:8]3[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=3)[CH:5]([O:6]2)[C:4](=[O:18])[O:3]1.[K].[Br:25][C:26]1[CH:27]=[CH:28][C:29](O)=[N:30][CH:31]=1.[OH-].[K+]>CN(C)C=O.C(O)(C)C>[Br:25][C:26]1[CH:27]=[CH:28][C:29]([O:6][C:5]2[C:4](=[O:18])[O:3][C@:2]([CH3:1])([CH2:19][C:20]([F:23])([F:22])[F:21])[C:7]=2[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[N:30][CH:31]=1
Reactant: CC1(CC(F)(F)F)OC(=O)C2O[C@]21c1ccc(S(C)(=O)=O)cc1
Reactant: Oc1ccc(Br)cn1
Agent: [K+]
Agent: [K]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CN(C)C=O
Product: C[C@]1(CC(F)(F)F)OC(=O)C(Oc2ccc(Br)cn2)=C1c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C

Procedure:
To a 0° C. mixture of the epoxide (0.930 g) from step 1 in dimethylformamide (3 mL) and isopropanol (12 mL) was added the potassium salt of 5-bromo-2-hydroxypyridine, prepared from 5-bromo-2-hydroxypyridine and one equivalent of 8N KOH followed by evaporation to dryness with toluene and high vacuum drying, (0.742 g, 3.5 mmol) and the mixture was warmed up slowly to reflux for 16 hrs. It was then cooled to room temperature and poured on icy dilute ammonium chloride and ethyl acetate; the organic layer was separated and the aquous further extracted ounce with ethyl acetate. The combined organic layers were washed with brine, dried with MgSO4 and the solvents were removed in vacuo to yield after purification on silica gel (10% acetone/toluene) the title compound (0.380 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[C:5](=[CH:7][CH:8]=1)[OH:6].[CH2:10]([CH:12]1[O:14][CH2:13]1)Cl.[OH-].[Na+]>O>[OH:14][CH2:13][CH:12]1[O:6][C:5]2[CH:7]=[CH:8][C:2]([CH3:1])=[CH:3][C:4]=2[O:9][CH2:10]1
Reactant: ClCC1CO1
Reactant: Cc1ccc(O)c(O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc2c(c1)OCC(CO)O2

Procedure:
In a vessel fitted with a mechanical stirring device and a thermostatic device, 298 g 4-methyl pyrocatechol and 288 g epichlorhydrin are mixed then heated to 70°. A solution of 106 g sodium hydroxide in 800 ml water is then poured. The reaction is exothermic and the inner temperature increases up to about 80°-90°. The whole mixture is thereafter heated at 70° for 2,5 hours then poured into water. The resulting mixture is extracted with ethyl acetate. The organic phase is separated, washed with dilute sodium hydroxide then with saline water until the washings are neutral.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][CH2:12][CH2:13][OH:14])(=[O:10])=[O:9].[NH2:15][C:16]1[C:17]([C:38]#[N:39])=[N:18][C:19]([C:22]2[CH:27]=[CH:26][C:25](B3OC(C)(C)C(C)(C)O3)=[CH:24][C:23]=2[F:37])=[CH:20][N:21]=1>>[NH2:15][C:16]1[N:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([C:2]3[C:3]([S:8]([NH:11][CH2:12][CH2:13][OH:14])(=[O:10])=[O:9])=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:24][C:23]=2[F:37])=[N:18][C:17]=1[C:38]#[N:39]
Reactant: O=S(=O)(NCCO)c1ccccc1Br
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)c(C#N)n3)c(F)c2)OC1(C)C
Product: N#Cc1nc(-c2ccc(-c3ccccc3S(=O)(=O)NCCO)cc2F)cnc1N

Procedure:
The title compound was prepared in manner similar to that described in Example 88 using 2-bromo-N-(2-hydroxyethyl)benzenesulfonamide and 3-amino-6-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazine-2-carbonitrile. MS (ESI): mass calcd. for C19H16FN5O3S, 413.10; m/z found, 414.0 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.81 (d, J=1.8, 1H), 8.17 (dd, J=8.0, 1.4, 1H), 8.02 (m, 1H), 7.64 (m, 1H), 7.56 (m, 1H), 7.40-7.31 (m, 3H), 5.38 (s, 2H), 4.35 (s, 1H), 3.64-3.58 (m, 2H), 2.95-2.87 (m, 2H), 1.64 (t, J=5.2, 1H).