Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH2:14].[F:15][C:16]1[CH:26]=[CH:25][CH:24]=[CH:23][C:17]=1/[CH:18]=[CH:19]/[C:20]([Cl:22])=O.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1.Cl>CO>[ClH:22].[F:15][C:16]1[CH:26]=[CH:25][CH:24]=[CH:23][C:17]=1/[CH:18]=[CH:19]/[C:20]1[N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]=1
Reactant: Nc1ccccc1Nc1ccccn1
Reactant: O=C(Cl)/C=C/c1ccccc1F
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Agent: Cl
Solvent: CO
Product: Fc1ccccc1/C=C/c1nc2ccccc2n1-c1ccccn1

Procedure:
Free base of the titled compound was prepared from N-(2-pyridyl)-o-phenylenediamine and (E)-2-fluorocinnamoyl chloride (Amino, Y.; Kawada, K.; Toi, K.; Kumashiro, I.; Fukushima, K. Chem. Pharm. Bull., 1988, 36, 4426) according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). The free base was dissolved with a 10% methanol solution of hydrogen chloride (5 ml). Concentration and recrystallization from ethyl acetate/ethanol yielded the titled compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[F:17])[O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1.[CH3:18][CH:19]([CH3:35])[C:20]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:24]=1)=[O:21]>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[F:17])[O:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][N:32]2[CH2:33][CH2:34][CH:29]([C:25]3[CH:24]=[C:23]([NH:22][C:20](=[O:21])[CH:19]([CH3:18])[CH3:35])[CH:28]=[CH:27][CH:26]=3)[CH2:30][CH2:31]2)=[CH:8][CH:7]=1
Reactant: O=Cc1ccc(Oc2ccc(F)c(F)c2)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc(Oc4ccc(F)c(F)c4)cc3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 4-(3,4-difluorophenoxy)benzaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 465.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]2[C:30]([CH3:31])=[CH:29][C:28]([O:32][CH2:33][C:34](OC)=[O:35])=[CH:27][C:26]=2[CH3:38])=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:24]=[CH:23][C:15]3[C@H:16]([CH2:19][C:20]([OH:22])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.[CH3:39][NH:40][CH3:41]>O1CCCC1>[CH3:39][N:40]([CH3:41])[C:34](=[O:35])[CH2:33][O:32][C:28]1[CH:27]=[C:26]([CH3:38])[C:25]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[C:10]3[C:6]=2[CH2:7][CH2:8][C@H:9]3[O:11][C:12]2[CH:24]=[CH:23][C:15]3[C@H:16]([CH2:19][C:20]([OH:22])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=2)=[C:30]([CH3:31])[CH:29]=1
Reactant: COC(=O)COc1cc(C)c(-c2ccc(F)c3c2CC[C@H]3Oc2ccc3c(c2)OC[C@H]3CC(=O)O)c(C)c1
Reactant: CNC
Solvent: C1CCOC1
Product: Cc1cc(OCC(=O)N(C)C)cc(C)c1-c1ccc(F)c2c1CC[C@H]2Oc1ccc2c(c1)OC[C@H]2CC(=O)O

Procedure:
The title compound is prepared from 2-((S)-6-((R)-7-fluoro-4-(4-(2-methoxy-2-oxoethoxy)-2,6-dimethylphenyl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetic acid and 2 M solution of dimethylamin in tetrahydrofuran following a procedure analogous to that described in example 12. LC (method 9): tR=1.06 min; Mass spectrum (ESI+): m/z=534 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[C:5](=[O:18])[N:6]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[H][H]>[Pd].CO>[C:14]([O:13][C:11](=[O:12])[CH2:10][N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([NH2:1])[C:5]1=[O:18])([CH3:17])([CH3:15])[CH3:16]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)Cn1cccc([N+](=O)[O-])c1=O
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)Cn1cccc(N)c1=O
Yield: 98.6 %

Procedure:
The compound of Example 137 (54 g, 0.213 mole) and 880 ml of methanol and 5 g of 10% palladium on carbon were stirred under 1 Atm of hydrogen for 24 hours. The reaction mixture was filtered and the carbon was washed with 200 mL of dichloromethane. The organic layer was evaporated to yield 47.08 g (98.5 %) of the title compound as a brown solid.
Reaction SMILES: Br[C:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([O:11][CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[C:5]=2[N:4]([CH3:25])[CH:3]=1.[CH3:26][S:27]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)(=[O:29])=[O:28].C([O-])([O-])=O.[Na+].[Na+]>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.O1CCOCC1>[CH3:25][N:4]1[C:5]2[C:10]([O:11][CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)=[N:9][CH:8]=[N:7][C:6]=2[C:2]([C:33]2[CH:34]=[CH:35][C:30]([S:27]([CH3:26])(=[O:29])=[O:28])=[CH:31][CH:32]=2)=[CH:3]1
Reactant: Cn1cc(Br)c2ncnc(OC3CCN(C(=O)OC(C)(C)C)CC3)c21
Reactant: CS(=O)(=O)c1ccc(B(O)O)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: [Na+]
Solvent: C1COCCO1
Product: Cn1cc(-c2ccc(S(C)(=O)=O)cc2)c2ncnc(OC3CCN(C(=O)OC(C)(C)C)CC3)c21
Temperature: 100 °C
Reaction time: 12 h
Yield: 84.5 %

Procedure:
tert-butyl 4-(7-bromo-5-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-yloxy)piperidine-1-carboxylate (15 mg), 4-methanesulfonyl-phenylboronic acid (33 mg), Pd(PPh3)4 (7.5 mg) and 2N Na2CO3 (0.33 mL) were mixed with 1,4-dioxane (2 mL), and stirred at 100° C. for 12 hours in a hermetically sealed reactor. The reaction mixture was cooled to room temperature, extracted with ethyl acetate and distilled water, and the organic layer thus obtained was washed with water and a saline solution. Subsequently, the washed organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound (15 mg).
Reaction SMILES: [ClH:1].[Br:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9]N.O=[C:12]1[CH2:18][CH:17]2[N:19](C(OC(C)(C)C)=O)[CH:14]([CH2:15][CH2:16]2)[CH2:13]1>Cl.C(O)(=O)C>[ClH:1].[Br:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:4]=1[NH:9][C:12]1[CH2:13][CH:14]3[NH:19][CH:17]([C:18]2=1)[CH2:16][CH2:15]3
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(=O)C2
Reactant: NNc1ccccc1Br
Agent: Cl
Solvent: CC(=O)O
Product: Brc1cccc2c3c([nH]c12)CC1CCC3N1
Temperature: 22.5 °C
Reaction time: 20 h

Procedure:
A mixture of 2-bromophenylhydrazine hydrochloride (4.44 g, 19.81 mmol, Aldrich) and t-butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (4.48 g, 19.89 mmol, Chem-Impex) in 1 M HCl/acetic acid was stirred at 20-25° C. for 20 hours, and then heated at 65-70° C. for 48 hours. The mixture was cooled to room temperature and concentrated under vacuum. The residue was heated to boiling in absolute ethanol (25 mL) and the suspension was stirred at room temperature for 2 hours, then filtered. The solid was washed with cold ethanol and dried under vacuum to provide the title compound: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.74-1.86 (m, 1H), 2.07 (t, J=9.7 Hz, 1H), 2.15-2.32 (m, 2H), 2.88 (d, J=17.4 Hz, 1H), 3.35-3.49 (m, 1H), 4.41 (s, 1H), 5.16 (d, J=4.4 Hz, 1H), 6.98 (t, J=7.7 Hz, 1H), 7.25-7.37 (m, 1H), 7.58 (d, J=7.9 Hz, 1H), 8.63-9.49 (m, 1H), 11.37 (s, 1H); MS (DCI/NH3) m/z 277/279 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:7]1[N:8]([CH2:20][C:21]([CH3:24])([OH:23])[CH3:22])[C:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[CH:11][C:10]=2[N:19]=1)[CH2:4][CH2:5][CH3:6].[CH:25]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH2:26].O>O1CCCC1.[Cl-].[Na+].O>[CH2:3]([C:7]1[N:8]([CH2:20][C:21]([CH3:24])([O:23][CH2:26][CH2:25][S:27]([CH3:30])(=[O:29])=[O:28])[CH3:22])[C:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[CH:11][C:10]=2[N:19]=1)[CH2:4][CH2:5][CH3:6]
Reactant: C=CS(C)(=O)=O
Reactant: CCCCc1nc2cnc3ccccc3c2n1CC(C)(C)O
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCc1nc2cnc3ccccc3c2n1CC(C)(C)OCCS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 48.5 %

Procedure:
Sodium hydride (60% dispersion in oil, 55 mg, 1.38 mmol) was added to a stirred solution of 1-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol (4.10 g, 13.8 mmol) in tetrahydrofuran (55 mL). After 5 minutes, methyl vinyl sulfone (2.90 g, 27.6 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 1 hour. Water (50 mL) and a small amount of brine were added and the mixture was extracted with ethyl acetate (2×50 mL). The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford a solid that was purified by flash chromatography (silica gel, eluted with 5% methanol in dichloromethane) to provide 2.7 g of 2-butyl-1-{2-methyl-2-[2-(methylsulfonyl)ethoxy]propyl}-1H-imidazo[4,5-c]quinoline as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[O:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:28]=1[CH:27]([CH3:29])[NH:26][CH2:25][CH2:24]2>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:26]3[CH2:25][CH2:24][C:23]4[C:28](=[C:19]([C:15]5[O:14][CH:18]=[CH:17][CH:16]=5)[CH:20]=[CH:21][CH:22]=4)[CH:27]3[CH3:29])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2cccc(-c3ccco3)c21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC1c2c(cccc2-c2ccco2)CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 8-Furan-2-yl-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[C:4]2[C:9]([C:10](=[O:13])[C:11]=1Cl)=[CH:8][CH:7]=[CH:6][CH:5]=2.[S-2:15].[Na+].[Na+].[F:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH:21]=O.C(O)(=O)C>O>[O:14]=[C:3]1[C:2]2[N:1]=[C:21]([C:20]3[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=3[F:18])[S:15][C:11]=2[C:10](=[O:13])[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]1=2
Reactant: [S-2]
Reactant: O=Cc1ccccc1F
Reactant: NC1=C(Cl)C(=O)c2ccccc2C1=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(=O)c2sc(-c3ccccc3F)nc21
Yield: 26.9 %

Procedure:
To a suspension of 5.0 g (24 mmol) of 2-amino-3-chloro-1,4-dihydro-1,4-dioxonaphthalene in 80 mL of water, 8.4 g (35 mmol) of nonahydrated sodium sulfide are added. The reaction mixture is then heated to reflux for approximately 20 min, then 20 mL of an aqueous solution containing 2.0 g of sodium sulfide are added. When the color of the medium has completely changed to blue, 1.95 mL (24 mmol) of 2-fluorobenzaldehyde and 6.36 mL of glacial acetic acid are added successively. After 1 h of reflux, the black semisolid product obtained is filtered, dried, and purified on a flash column (support: silica; conditioning: heptane; eluant: dichloromethane/heptane, 50/50). The greenish crystals formed after evaporation of the solvent are washed several times with ethanol and ether, then they are uncolored and recrystallized in dichloromethane to produce 2.0 g of 4,9-dihydro-4,9-dioxo-2-(2-fluorophenyl)-naphtho[2,3-d]thiazole in the form of yellow crystals.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([Cl:12])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.O1CCOCC1.CCN(C(C)C)C(C)C.[CH2:28]([SH:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH2:28]([S:35][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([Cl:12])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: SCc1ccccc1
Reactant: Clc1ccnc2cc(Br)ccc12
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Clc1ccnc2cc(SCc3ccccc3)ccc12
Reaction time: 0.17 h
Yield: 88.9 %

Procedure:
A 250-mL 3-neck round-bottom flask was charged with 7-bromo-4-chloroquinoline (BioBlocks, Inc., San Diego, Calif.; 7.000 g, 28.9 mmol), Xantphos (0.835 g, 1.443 mmol), and Pd2(dba)3 (0.661 g, 0.722 mmol), and after flushing with argon, dioxane (57.7 ml) and n,n-diisopropylethylamine (10.08 ml, 57.7 mmol) were added in sequence. The flask was fitted with a reflux condenser, and was placed in a heating bath at 80° C. for 10 minutes, after which benzyl mercaptan (3.58 ml, 30.3 mmol) was added drop wise via syringe. The reaction was stirred for 20 minutes until completion. The material was diluted with water, and washed with DCM (×3), and the combined organics were dried via phase separator (Radley's Technology) and concentrated under a vacuum. Upon dissolving the material in DCM, solids remained out of solution, and they were filtered off and washed with DCM. The corresponding filtrate was concentrated under a vacuum and purified via silica gel chromatography (120-g column) eluting with 0 to 100% ethyl acetate in heptanes to yield 7-(benzylthio)-4-chloroquinoline (7.35 g, 25.7 mmol, 89% yield) as a light yellow solid. m/z (ESI) 286.0 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[C@@H:16]2[CH2:20][C@H:19]([NH:21][C:22](=[O:25])CC)[C@@H:18]([OH:26])[C@H:17]2[OH:27])=[C:9]([NH:28][CH2:29][CH:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:8]=1)=[O:6].COC(C1N=C2C(N=CN2[C@@H]2C[C@H](N(C([O:68][C:69]([CH3:72])([CH3:71])[CH3:70])=O)C(=O)CC)[C@@H](O)[C@H]2O)=C(NCC(C2C=CC=CC=2)C2C=CC=CC=2)N=1)=O>>[C:69]([O:68][C:22](=[O:25])[NH:21][C@H:19]1[CH2:20][C@@H:16]([N:13]2[CH:12]=[N:11][C:10]3[C:14]2=[N:15][C:7]([C:5](=[O:6])[NH:4][CH2:3][CH2:2][NH2:1])=[N:8][C:9]=3[NH:28][CH2:29][CH:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C@H:17]([OH:27])[C@@H:18]1[OH:26])([CH3:72])([CH3:71])[CH3:70]
Reactant: CCC(=O)N(C(=O)OC(C)(C)C)[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)OC)nc32)[C@H](O)[C@@H]1O
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCN)nc32)[C@H](O)[C@@H]1O
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCN)nc32)[C@H](O)[C@@H]1O

Procedure:
This compound is prepared analogously to 9-((1R,2S,3R,4S)-2,3-dihydroxy-4-propionylamino-cyclopentyl)-6-(2,2-diphenyl-ethylamino)-9H-purine-2-carboxylic acid (2-amino-ethyl)-amide by replacing 9-((1R,2S,3R,4S)-2,3-dihydroxy-4-propionylamino-cyclopentyl)-6-(2,2-diphenyl-ethylamino)-9H-purine-2-carboxylic acid methyl ester with 9-[(1R,2S,3R,4S)-4-(tert-butoxy-carbonyl-propionyl-amino)-2,3-dihydroxy-cyclopentyl]-6-(2,2-diphenyl-ethylamino)-9H-purine-2-carboxylic acid methyl ester.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:19][CH:20]=[CH2:21])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].C(=O)([O-])[O-].[Na+].[Na+].[N+:28]([O-])([N+]([O-])=O)=[O:29]>O1CCCC1.C(Cl)Cl>[Cl:1][CH2:2][CH2:3][N:4]([N:28]=[O:29])[C:5]([N:7]([CH2:19][CH:20]=[CH2:21])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: C=CCN(C(=O)NCCCl)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: C=CCN(C(=O)N(CCCl)N=O)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Yield: 71.7 %

Procedure:
3.2 g of 1-(2-chloroethyl)-3-(2-propenyl)-3-D-galactopyranosylurea are dissolved in a mixture of 60 ml of tetrahydrofuran and 60 ml of methylene chloride, and 15 g of sodium carbonate anhydrate are added thereto. 5 g of nitrogen tetroxide gas are introduced into the mixture for 10 minutes under ice-cooling and stirring. The mixture is treated in the same manner as described in Example 2. 2.5 g of 1-(2-chloroethyl)-1-nitroso-3-(2-propenyl)-3-D-galactopyranosylurea are thereby obtained as yellow caramel.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([C:6](=O)[CH2:7][CH:8]2[C:13](=O)[CH2:12][CH2:11][S:10][CH2:9]2)=[CH:4][CH:3]=1.[CH2:18]([NH:20][CH2:21][CH2:22][NH2:23])[CH3:19].C(O)C>Cl.O>[CH2:18]([NH:20][CH2:21][CH2:22][N:23]1[C:6]([C:5]2[CH:16]=[CH:17][C:2]([Br:1])=[CH:3][CH:4]=2)=[CH:7][C:8]2[CH2:9][S:10][CH2:11][CH2:12][C:13]1=2)[CH3:19]
Reactant: CCNCCN
Reactant: O=C(CC1CSCCC1=O)c1ccc(Br)cc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCNCCn1c(-c2ccc(Br)cc2)cc2c1CCSC2
Temperature: -5 °C

Procedure:
A solution of 4.0 g (0.012 mole) of 3-(4-bromophenacyl)-2,3,5,6-tetrahydrothiopyran-4-one [Example 2 (a)], 1.3 g of ethylaminoethylamine, 14 ml. of ethanol, and one drop of concentrated hydrochloric acid is heated under reflux for 2.5 hours, cooled to -5°C, and diluted with water. The oil which separates is collected and triturated with water to provide a solid. The resultant solid is recrystallized from ethanol to give off-white crystals of 1-(2-ethylaminoethyl)-2-(4-bromophenyl)-1,4,6,7-tetrahydrothiopyrano[4,3-b]pyrrole, m.p. 84° to 85°C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][CH2:15][C:16]2[CH:21]=[C:20]([CH:22]([C:24]#[N:25])[CH3:23])[CH:19]=[CH:18][C:17]=2[O:26][CH3:27])[C@@H:9]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=O)(C)(C)C.Cl>CCOC(C)=O>[C:24]([CH:22]([C:20]1[CH:19]=[CH:18][C:17]([O:26][CH3:27])=[C:16]([CH:21]=1)[CH2:15][NH:14][C@H:10]1[CH2:11][CH2:12][CH2:13][NH:8][C@H:9]1[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[CH3:23])#[N:25]
Reactant: COc1ccc(C(C)C#N)cc1CN[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1ccc(C(C)C#N)cc1CN[C@H]1CCCN[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of Compound 18 (280 mg) in AcOEt (6 ml) was added conc. HCl (1 ml). The mixture was stirred at room temperature for 45 minutes. The mixture was extracted with CH2Cl2. The combined extracts were dried (Na2SO4), and concentrated in vacuo to give Compound 19 as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]2[CH:21]=[C:20]([C:22]([O:24]CC)=[O:23])[S:19][C:11]=2[N:12]([CH:14]([CH:16]([OH:18])[CH3:17])[CH3:15])[N:13]=1.[OH-].[Na+:28].[ClH:29]>CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]2[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[S:19][C:11]=2[N:12]([CH:14]([CH:16]([OH:18])[CH3:17])[CH3:15])[N:13]=1.[Cl-:29].[Na+:28]
Reactant: Cl
Reactant: CCOC(=O)c1cc2c(-c3ccc(F)cc3F)nn(C(C)C(C)O)c2s1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(O)C(C)n1nc(-c2ccc(F)cc2F)c2cc(C(=O)O)sc21
Product: [Cl-]
Temperature: 50 °C
Reaction time: 18 h
Yield: 879.8 %

Procedure:
To a solution of ethyl 3-(2,4-difluorophenyl)-1-(3-hydroxybutan-2-yl)-1H-thieno[2,3-c]pyrazole-5-carboxylate (134 mg, 0.352 mmol) in methanol (3.5 mL) was added sodium hydroxide (1 M, 1.06 mL, 1.06 mmol). The mixture was stirred at 50° C. for 18 hr. Hydrochloric acid (6M, 0.176 mL, 1.06 mmol) was added. The mixture was concentrated to give the title compound with three equivalents of sodium chloride (181 mg): LC-MS [M+1]=353.3.
Reaction SMILES: C([O:5][C:6](=[O:33])[CH2:7][CH2:8][N:9]([C:18]1[S:19][CH:20]=[C:21]([C@H:23]2[CH2:28][CH2:27][C@H:26]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:25][CH2:24]2)[N:22]=1)[CH2:10][C:11]1[S:12][C:13]([CH2:16][CH3:17])=[CH:14][CH:15]=1)(C)(C)C.[OH-].[Na+].C1COCC1>CO>[C:29]([C@H:26]1[CH2:27][CH2:28][C@H:23]([C:21]2[N:22]=[C:18]([N:9]([CH2:10][C:11]3[S:12][C:13]([CH2:16][CH3:17])=[CH:14][CH:15]=3)[CH2:8][CH2:7][C:6]([OH:33])=[O:5])[S:19][CH:20]=2)[CH2:24][CH2:25]1)([CH3:31])([CH3:32])[CH3:30]
Reactant: CCc1ccc(CN(CCC(=O)OC(C)(C)C)c2nc([C@H]3CC[C@H](C(C)(C)C)CC3)cs2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1ccc(CN(CCC(=O)O)c2nc([C@H]3CC[C@H](C(C)(C)C)CC3)cs2)s1

Procedure:
2-Bromo-1-(trans-4-tert-butyl-cyclohexyl)-ethanone (72 mg, 0.277 mmol) was added to a methanol (about 4 mL) solution of 3-[1-(5-ethyl-thiophen-2-ylmethyl)-thioureido]-propionic acid tert-butyl ester (100 mg, 0.304 mmol) to obtain 3-[[4-(trans-4-tert-butyl-cyclohexyl)-thiazol-2-yl]-(5-ethyl-thiophen-2-ylmethyl)-amino]-propionic acid tert-butyl ester (108 mg, 0.220 mmol) following a method analogous to General Procedure C (and similar to the procedure found in Example 5). Hydrolysis of this ester following a method analogous to General Procedure G1 using 1 N NaOH (aq) solution (2 mL), THF (1 mL) and MeOH (1 mL) gave 3-[[4-(trans-4-tert-butyl-cyclohexyl)-thiazol-2-yl]-(5-ethyl-thiophen-2-ylmethyl)-amino]-propionic acid (37 mg, 0.085 mmol). LC-MS m/z: 435 (M+1)+.
Reaction SMILES: [C:1]([C:4]1[C:5]([C:15]2[C:20](F)=[CH:19][CH:18]=[CH:17][C:16]=2[F:22])=[N:6][O:7][C:8]=1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])([OH:3])=O.[NH2:23][C:24]1[CH:25]=[C:26]([CH2:30][C:31]([NH:33][C:34]2[CH:39]=[C:38]([O:40][CH3:41])[C:37]([O:42][CH3:43])=[C:36]([O:44][CH3:45])[CH:35]=2)=[O:32])[CH:27]=[CH:28][CH:29]=1.CCN=C=NCCCN(C)C.C(Cl)[Cl:58]>CN(C1C=CN=CC=1)C>[CH3:45][O:44][C:36]1[CH:35]=[C:34]([NH:33][C:31](=[O:32])[CH2:30][C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([NH:23][C:1]([C:4]3[C:5]([C:15]4[C:16]([F:22])=[CH:17][CH:18]=[CH:19][C:20]=4[Cl:58])=[N:6][O:7][C:8]=3[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:3])[CH:25]=2)[CH:39]=[C:38]([O:40][CH3:41])[C:37]=1[O:42][CH3:43]
Reactant: CCCCCCc1onc(-c2c(F)cccc2F)c1C(=O)O
Reactant: COc1cc(NC(=O)Cc2cccc(N)c2)cc(OC)c1OC
Reactant: ClCCl
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Product: CCCCCCc1onc(-c2c(F)cccc2Cl)c1C(=O)Nc1cccc(CC(=O)Nc2cc(OC)c(OC)c(OC)c2)c1
Yield: 65 %

Procedure:
4-Carboxy-5-hexyl-3-(2,6-difluorophenyl)isoxazole (150 mg, 0.46 mmol), 2-(3-aminophenyl)-N-(3,4,5-trimethoxyphenyl)acetamide (160 mg, 0.51 mmol), EDCI (150 mg, 0.78 mmol), DMAP (12 mg, 0.10 mmol) were reacted in CH2Cl2 (5 ml) for 19 h then applied to a silica gel column. Elution with hexanes/EtOAc (gradient) gave the title compound (185 mg, 65%).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[O:4][C@@H:3]([C:11]2[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=2)[CH2:2]1.[CH3:19][CH2:20][OH:21].[OH2:22]>>[O:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[O:4][C@@H:3]([C:11]2[CH:18]=[CH:17][C:14]([CH2:15][N:6]3[CH2:7][CH2:8][CH:19]([C:20]([OH:22])=[O:21])[CH2:10][CH2:5]3)=[CH:13][CH:12]=2)[CH2:2]1
Reactant: O
Reactant: O=Cc1ccc([C@H]2COc3cccnc3O2)cc1
Reactant: CCO
Product: O=C(O)C1CCN(Cc2ccc([C@H]3COc4cccnc4O3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-[(8)-4-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-piperidine-4-carboxylic acid ethyl ester (prepared from Intermediate C and piperidine-4-carboxylic acid ethyl ester according to General Method F) (3.00 g, 7.90 mmol) in 4:1 EtOH/water (80 mL) is added LiOH monohydrate (0.994 g, 23.7 mmol) and the reaction stirred overnight at about 25° C. The reaction is concentrated, diluted with water and washed with Et2O (2×). The aqueous layer is lypholized to dryness then purified by silica gel chromatography eluting with 20% (2M NH3 in MeOH)/DCM. The pooled fractions are concentrated and dried to provide the title compound (K) as a foamed solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:5]([N:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1)=[O:6].[CH3:22][O:23][C:24]([C:26]1[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=1)=[O:25].O>C(O)(=O)C>[CH2:16]([C:15]1[CH:14]=[CH:13][C:4]([C:5]([N:7]2[CH2:8][CH2:9][O:10][CH2:11][CH2:12]2)=[O:6])=[CH:3][C:2]=1[NH:1][CH2:30][C:29]1[CH:28]=[CH:27][C:26]([C:24]([O:23][CH3:22])=[O:25])=[CH:33][CH:32]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: CCCCCCc1ccc(C(=O)N2CCOCC2)cc1N
Solvent: CC(=O)O
Solvent: O
Product: CCCCCCc1ccc(C(=O)N2CCOCC2)cc1NCc1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The compound ([5]-(55)-75) (600 mg) prepared in Example 63 was dissolved in acetic acid (6.0 ml). Then, 4-methoxycarbonylbenzaldehyde (373 mg) was added. The mixture was stirred at room temperature for 4 hours. Then, borane-diethylamine complex (146 mg) was added to the solution. The mixture was stirred at room temperature for 30 minutes. After the reaction was completed, water was added to the solution. The solution was extracted with ethyl acetate, washed with distilled water, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (Kieselgel 60=30 g, hexane/ethyl acetate=1/1) to obtain the above-captioned compound ([5]-(57)-75') (841 mg) as a white solid.