Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH:7]=[O:8])[O:4][N:3]=1.[N+:9]([CH3:12])([O-])=[O:10].[O-]CC.[Na+].[Na]>C(O)C.CCOCC>[CH3:1][C:2]1[CH:6]=[C:5]([C:7]([CH:12]=[N:9][OH:10])=[O:8])[O:4][N:3]=1
Reactant: Cc1cc(C=O)on1
Reactant: C[N+](=O)[O-]
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCOCC
Solvent: CCO
Product: Cc1cc(C(=O)C=NO)on1
Temperature: 25 °C
Yield: 70.8 %

Procedure:
In 50 ml of ethanol were dissolved 5.5 g of 3-methylisoxazole-5-carbaldehyde and 3.3 g of nitromethane. To the solution was added dropwise a solution of sodium ethoxide in ethanol, which had been prepared from 1.5 g of sodium and 30 ml of ethanol, while stirring at room temperature. After completion of the dropwise addition, the resultant solution was stirred for a further 3 hrs. at room temperature and then ether was added thereto to separate the sodium salt. This was dissolved in water, which was followed by acidification with hydrochloric acid. The resulting precipitate was filtered off and recrystallized from chloroform to obtain 5.4 g of (3-methylisoxazole-5-yl)glyoxal-2-oxim having m.p. of 179° C.-180° C. Yield, 70%.
Reaction SMILES: [F:1][C:2]1([F:50])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]([NH:17][C:18]([C:20]2[CH:24]=[C:23]([CH3:25])[O:22][N:21]=2)=[O:19])[C:10](=[O:26])[N:9]2[CH2:27][C@H:28]([O:30][C:31]3[N:32]=[C:33]4[C:38](=[C:39]5[C:44]=3[CH:43]=[CH:42][CH:41]=[CH:40]5)[CH:37]=[CH:36][CH:35]=[CH:34]4)[CH2:29][C@H:8]2[C:7](=[O:45])[NH:6][C@:5]2([C:47](O)=[O:48])[CH2:46][C@H:4]2[CH2:3]1.[N:51]1(C(N2C=CN=C2)=O)C=CN=C1.C[S:64]([CH:67]1[CH2:69][CH2:68]1)(=[O:66])=[O:65].N1CCCN2CCCCCC=12>ClC(Cl)C.C(OCC)(=O)C>[CH:67]1([S:64]([NH:51][C:47]([C@@:5]23[CH2:46][C@H:4]2[CH2:3][C:2]([F:50])([F:1])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]([NH:17][C:18]([C:20]2[CH:24]=[C:23]([CH3:25])[O:22][N:21]=2)=[O:19])[C:10](=[O:26])[N:9]2[CH2:27][C@H:28]([O:30][C:31]4[N:32]=[C:33]5[C:38](=[C:39]6[C:44]=4[CH:43]=[CH:42][CH:41]=[CH:40]6)[CH:37]=[CH:36][CH:35]=[CH:34]5)[CH2:29][C@H:8]2[C:7](=[O:45])[NH:6]3)=[O:48])(=[O:66])=[O:65])[CH2:69][CH2:68]1
Reactant: Cc1cc(C(=O)N[C@H]2CCCCCC(F)(F)C[C@@H]3C[C@@]3(C(=O)O)NC(=O)[C@@H]3C[C@@H](Oc4nc5ccccc5c5ccccc45)CN3C2=O)no1
Reactant: CS(=O)(=O)C1CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)N[C@H]2CCCCCC(F)(F)C[C@@H]3C[C@@]3(C(=O)NS(=O)(=O)C3CC3)NC(=O)[C@@H]3C[C@@H](Oc4nc5ccccc5c5ccccc45)CN3C2=O)no1
Temperature: 42 °C
Reaction time: 2 h
Yield: 67.3 %

Procedure:
A solution of (2R,6S,13aS,14aR,16aS)-12,12-difluoro-6-(5-methylisoxazole-3-carboxamido)-5,16-dioxo-2-(phenanthridin-6-yloxy)octadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclo pentadecine-14a-carboxylic acid (Example 18i, 21 mg, 0.030 mmol) and di(1H-imidazol-1-yl)methanone (10.96 mg, 0.068 mmol) in dichloroethane (400 μl) was stirred for 2 hr at 42° C. To this mixture was added methylsulfonylcyclopropane (11.0 mg, 0.091 mmol) and 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (13.8 μl, 0.091 mmol) and the reaction mixture was stirred for 2 h at 42° C. The reaction mixture was diluted with ethyl acetate (7 mL) and washed with 10 mL of 1 N HCl followed by saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The resulting residue was purified by flash chromatography on silica gel (3% methanol/dichloromethane). The resulting material was further purified by reverse phase HPLC (40% acetonitrile/water with 0.1%TFA to 100% water) to provide the title compound N-((2R,6S ,13aS,14aR,16aS)-14a-(cyclopropylsulfonylcarbamoyl)-12,12-difluoro-5,16-dioxo-2-(phenanthridin-6-yloxy)octadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecin-6-yl)-5-methylisoxazole-3-carboxamide (16 mg, 66.3% yield). MS (ESI): m/z=793.1 [M+H], 791.0 [M−H].
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][N:20]([C:23]4[CH2:24][CH2:25][C:26]5[N:27]([C:29]([C:32]([F:35])([F:34])[F:33])=[N:30][N:31]=5)[N:28]=4)[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:36](O)(=[O:41])[CH2:37][CH2:38][CH2:39][CH3:40]>>[C:36]([N:4]1[CH2:3][CH2:2][N:1]([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([CH:17]3[CH2:18][CH2:19][N:20]([C:23]4[CH2:24][CH2:25][C:26]5[N:27]([C:29]([C:32]([F:35])([F:34])[F:33])=[N:30][N:31]=5)[N:28]=4)[CH2:21][CH2:22]3)=[CH:15][CH:16]=2)[CH2:6][CH2:5]1)(=[O:41])[CH2:37][CH2:38][CH2:39][CH3:40]
Reactant: FC(F)(F)c1nnc2n1N=C(N1CCC(c3ccc(OCCCN4CCNCC4)cc3)CC1)CC2
Reactant: CCCCC(=O)O
Product: CCCCC(=O)N1CCN(CCCOc2ccc(C3CCN(C4=Nn5c(nnc5C(F)(F)F)CC4)CC3)cc2)CC1
Yield: 66 %

Procedure:
Obtained in 66% yield by an analogous method to Example 4.1, starting from 6-[4-[4-[3-(piperazin-1-yl)propoxy]phenyl]piperidin-1-yl]-3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazine and pentanoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[N:13][N:14]=[C:10]3[CH2:9][NH:8][C:7](=S)[C:6]=2[CH:17]=1.[NH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[C:6]=2[CH:17]=1
Reactant: Cc1nnc2n1-c1ccc(Cl)cc1C(=S)NC2
Reactant: C1CCNC1
Solvent: O
Product: Cc1nnc2n1-c1ccc(Cl)cc1C(N1CCCC1)=NC2
Yield: 51 %

Procedure:
A stirred mixture of 8-chloro-4,5-dihydro-1-methyl-6H-s-triazolo[4,3-a][1,4]benzodiazepine-6-thione (VIIIa)(2.65 g., 0.01 mole) and pyrrolidine (25 ml.) was refluxed under nitrogen for 10 hours, cooled, mixed with water and extracted with methylene chloride. The extract was washed with water, dried (Na2SO4) and concentrated in vacuo. The residue was dissolved in methylene chloride/ethyl acetate, decolorized with charcoal (Darco) and concentrated until the product crystallized. The product was recrystallized from methylene chloride/acetate to give 1.43 g., melting point 223°-225° and 0.10 g., melting point 222°-225° of the titled compound (Ic)(51% yield). The analytical sample had: melting point 223°-225°; uv (EtOH) λ max 210.5 mμ (ε 41,050), 233 (sh 17,700), 287 (sh, 3450), 292 (3550). The ir and nmr spectra support the proposed structure.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([Cl:15])[CH:9]=2)=[O:5])C.Br[CH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1>>[Cl:15][C:10]1[CH:9]=[C:8]2[C:13]([CH:14]=[C:6]([C:4]([OH:3])=[O:5])[N:7]2[CH2:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=2)=[CH:12][CH:11]=1
Reactant: BrCc1cccc2ccccc12
Reactant: CCOC(=O)c1cc2ccc(Cl)cc2[nH]1
Product: O=C(O)c1cc2ccc(Cl)cc2n1Cc1cccc2ccccc12

Procedure:
Using general procedure B, 6-chloro-1H-indole-2-carboxylic acid ethyl ester was coupled with 1-bromomethyl-naphthalene and the product obtained was hydrolyzed to give the title compound as a pale yellow solid. MS: 334.0 ([M−H]−).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH2:6][N:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13](I)[CH:14]=2)[N:9]([CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:8]1=[O:25].[CH2:31](C([Sn])=C(CCCC)CCCC)[CH2:32]CC>C1(C)C=CC=CC=1.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>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH2:6][N:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH:31]=[CH2:32])[CH:14]=2)[N:9]([CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:8]1=[O:25]
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: COc1ccc(Cn2c(=O)c3cc(I)ccc3n(C3CCOCC3)c2=O)cc1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1ccc2c(c1)c(=O)n(Cc1ccc(OC)c(OC)c1)c(=O)n2C1CCOCC1
Yield: 57.7 %

Procedure:
A mixture of 3.0 g of 3-(3,4-dimethoxybenzyl)-6-iodo-1-(tetrahydro-2H-pyran-4-yl)-quinazoline-2,4(1H,3H)-dione, 3.64 g of tributylvinyltin and Pd(PPh3)4 in 2 ml of toluene is irradiated in a microwave field for 30 minutes at 130° C. The reaction mixture is filtered and evaporated under reduced pressure. The residue is chromatographed on silica gel, eluting with a DCM/EtOAc mixture from (100/0, v/v) to (80/20, v/v) to give 1.4 g of the expected product.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]([NH:7][NH:8][C:9]([N:11]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[O:14][C:13]2[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:12]1=2)=[O:10])=[O:6].[CH3:27][N:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[C:33](Cl)=[O:34]>>[CH3:27][N:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[C:33]([NH:2][CH2:3][CH2:4][C:5]([NH:7][NH:8][C:9]([N:11]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[O:14][C:13]2[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:12]1=2)=[O:10])=[O:6])=[O:34]
Reactant: Cn1cccc1C(=O)Cl
Reactant: NCCC(=O)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Agent: Cl
Product: Cn1cccc1C(=O)NCCC(=O)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21

Procedure:
8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[3-[[(1-methyl-2-pyrrolyl)carbonyl]amino]-1-oxopropyl]hydrazide (29) was prepared from 8-chlorodibenz[b,f][1,4]-oxazepine-10(11H)-carboxylic acid, 2-(3-amino-1-oxopropyl) hydrazide, monohydrochloride (9), prepared as described above in Example 9, and 1-methylpyrrole-2-carbonyl chloride in the same manner as described in Example 10 on a 1.9 mmol scale to yield 0.58 g (66%) of product.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH:25]4[CH2:27][CH2:26]4)=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[C:28]([N:31]1[CH2:35][CH2:34][NH:33][C:32]1=[O:36])(=[O:30])[CH3:29]>>[C:28]([N:31]1[CH2:35][CH2:34][N:33]([C:2]2[CH:3]=[CH:4][C:5]([C:10]([N:12]3[CH2:17][CH2:16][N:15]([C:18]4[C:23]([CH3:24])=[CH:22][C:21]([CH:25]5[CH2:27][CH2:26]5)=[CH:20][N:19]=4)[CH2:14][CH2:13]3)=[O:11])=[C:6]([CH:9]=2)[C:7]#[N:8])[C:32]1=[O:36])(=[O:30])[CH3:29]
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2C#N)CC1
Reactant: CC(=O)N1CCNC1=O
Product: CC(=O)N1CCN(c2ccc(C(=O)N3CCN(c4ncc(C5CC5)cc4C)CC3)c(C#N)c2)C1=O
Yield: 41.9 %

Procedure:
Using 5-bromo-2-[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]benzonitrile (1.06 g) described in Preparation Example 189 and 1-acetylimidazolidin-2-one (384 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (494 mg) was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[O:19][CH:18]=[N:17][CH:16]=2)[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.CC(O)C>CCCCCC>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:15]2[O:19][CH:18]=[N:17][CH:16]=2)[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(c1ccc(O)cc1)c1cnco1
Solvent: CCCCCC
Solvent: CC(C)O
Product: CCOC(=O)C[C@@H](c1ccc(O)cc1)c1cnco1
Yield: 47.6 %

Procedure:
Racemic compound 75.4 (1.3 g, 5 mmol) was separated on a semi-preparatory chiral CHIRALCEL OJ-H column (30×250 mm), using 20% i-PrOH in hexane as eluant. Eluant containing the peak with greater retention time was concentrated and compound 75.5 (620 mg, 2.38 mmol) was obtained as off-white solid. The absolute configuration was assigned by analogy to other GPR40 agonist compounds. MS ESI (pos.) m/e 262.1 (M+H).
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]#[N:10])=[CH:7][N:6]=[C:5]([NH:11][C:12]([N:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([CH:24](OC)[O:25]C)[N:22]=3)[CH2:17][CH2:16][CH2:15]2)=[O:13])[CH:4]=1)#[N:2].O.Cl>C1COCC1.CCOC(C)=O>[C:1]([C:3]1[C:8]([C:9]#[N:10])=[CH:7][N:6]=[C:5]([NH:11][C:12]([N:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([CH:24]=[O:25])[N:22]=3)[CH2:17][CH2:16][CH2:15]2)=[O:13])[CH:4]=1)#[N:2]
Reactant: COC(OC)c1ccc2c(n1)N(C(=O)Nc1cc(C#N)c(C#N)cn1)CCC2
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cnc(NC(=O)N2CCCc3ccc(C=O)nc32)cc1C#N
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
N-(4,5-dicyanopyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 2F, 15 mg, 0.040 mmol) was dissolved in THF (0.6 ml) and water (0.6 ml) and treated at room temperature with conc. HCl (0.10 ml). The reaction mixture was stirred at room temperature for 1.5 h, diluted in EtOAc and washed with sat. aq. NaHCO3 (2×) and brine. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was triturated with MeOH, the solid was filtered and dried overnight at 40° C. under vacuum to obtain the title compound as a white solid.
Reaction SMILES: [C:1]([Si:3]([CH3:6])([CH3:5])[CH3:4])#[CH:2].C([Li])CCC.[F:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]=[C:20]=[S:21])=[CH:15][CH:14]=1.[CH:22]1([CH2:28]Br)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>C1COCC1.CCCCCC>[F:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]=[C:20]([S:21][CH2:28][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:2][CH2:1][Si:3]([CH3:6])([CH3:5])[CH3:4])=[CH:15][CH:14]=1
Reactant: Fc1ccc(N=C=S)cc1
Reactant: BrCC1CCCCC1
Reactant: C#C[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C[Si](C)(C)CCC(=Nc1ccc(F)cc1)SCC1CCCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 12.7 %

Procedure:
To a solution of ethynyltrimethylsilane (0.89 g) in THF (15 mL) was added a 1.57M solution (5.0 mL) of n-butyllithium in hexane at −78° C. under a nitrogen atmosphere, and the mixture was stirred at the same temperature for 0.5 hours. After the reaction mixture was warmed to 0° C., a 4-fluorophenyl isothiocyanate (1.30 g) in THF (5 mL) was added dropwise thereto at −78° C. Then, the reaction mixture was slowly warmed to 0° C. At the same temperature, a solution of cyclohexylmethyl bromide (1.52 g) in THF (5 mL) was added dropwise thereto, and the mixture was stirred at 50° C. for 7 hours. The solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:ethyl acetate=20:1) to obtain cyclohexylmethyl N-(4-fluorophenyl)-3-(trimethylsilyl)thiopropionimidate (0.38 g) as a brown oil.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:11])=[CH:8][CH:9]=2)[NH:4][N:3]=1.[N:12]12[CH2:19][CH:16]([CH2:17][CH2:18]1)[NH:15][CH2:14][CH2:13]2.C(N(CC)CC)C.CN(C)[CH:29]=[O:30]>C1(P([Pd](P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(Cl)Cl)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[BrH:1].[N:12]12[CH2:19][CH:16]([CH2:17][CH2:18]1)[N:15]([C:29]([C:2]1[C:10]3[C:5](=[N:6][C:7]([CH3:11])=[CH:8][CH:9]=3)[NH:4][N:3]=1)=[O:30])[CH2:14][CH2:13]2
Reactant: C1CN2CCC(C2)N1
Reactant: Cc1ccc2c(Br)n[nH]c2n1
Reactant: CN(C)C=O
Agent: Cl[Pd](Cl)([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: Br
Product: Cc1ccc2c(C(=O)N3CCN4CCC3C4)n[nH]c2n1

Procedure:
By analogy with Example 2, 0.7 g (3.3 mmol) of 3-bromo-6-methyl-1H-pyrazolo[3,4-b]pyridine is reacted with 1.1 g (9.9 mmol) of 1,4-diazabicyclo[3.2.1]octane in the presence of 0.35 g (0.5 mmol) of bis(triphenylphosphino)dichloropalladium and 2.3 ml of triethylamine in 10 ml of dimethylformamide under the conditions described for Example 1, giving 0.21 g of product, which is dissolved in 20 ml of acetone before addition of 0.27 ml of a 5.7 N solution of hydrobromic acid in acetic acid. The dihydrobromide crystals are collected by filtration and dried under vacuum.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[C:18]([CH2:20]O)[CH:17]=[C:16]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][Cl:29])[CH:15]=2)=[C:8]([O:30][CH3:31])[CH:7]=1.[CH3:33][O:34][C:35](=[O:49])/[C:36](/[C:47]#[N:48])=[CH:37]/[C:38]1[CH:43]=[CH:42][C:41]([OH:44])=[C:40]([O:45][CH3:46])[CH:39]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OCC)=O)=O)C.Cl>O1CCCC1.C1(C)C=CC=CC=1>[CH3:33][O:34][C:35](=[O:49])/[C:36](/[C:47]#[N:48])=[CH:37]/[C:38]1[CH:43]=[CH:42][C:41]([O:44][CH2:20][C:18]2[CH:19]=[C:14]([CH2:13][O:12][C:9]3[CH:10]=[CH:11][C:6](/[CH:5]=[CH:4]/[C:3]([O:2][CH3:1])=[O:32])=[CH:7][C:8]=3[O:30][CH3:31])[CH:15]=[C:16]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][Cl:29])[CH:17]=2)=[C:40]([O:45][CH3:46])[CH:39]=1
Reactant: COC(=O)/C(C#N)=C/c1ccc(O)c(OC)c1
Reactant: COC(=O)/C=C/c1ccc(OCc2cc(CO)cc(OCCCCCCCl)c2)c(OC)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)/C=C/c1ccc(OCc2cc(COc3ccc(/C=C(\C#N)C(=O)OC)cc3OC)cc(OCCCCCCCl)c2)c(OC)c1
Temperature: 0 °C
Yield: 73.7 %

Procedure:
1 g (2.2 mmol) (E)-3-[4-[3-[(6-chlorohexyl)oxy]-5-[hydroxymethyl]benzyloxy]-3-methoxyphenyl]acrylic acid methyl ester was added to a solution of 0.62 g (2.7 mmol) 2-cyano-(E)-3-(4-hydroxy-3-methoxyphenyl)acrylic acid methyl ester and 0.73 g (2.7 mmol) triphenylphosphine in 10 ml tetrahydrofuran. The solution was cooled to 0°C. and then 1.1 ml (2.7 mmol) of a solution of azodicarboxlic acid diethyl ester in toluene were added dropwise. The mixture was allowed to react for 1 hour at 0° C. and then it was poured into an ice cold 1 M solution of HCl. The mixture was extracted three times with tert.-butyl-methylether/ethyl acetate. The organic phase was washed with a saturated sodium bicarbonate solution and repeatedly with water, dried over magnesium sulfates filtered and concentrated in vacuum. The solid residue was first treated with diethylether, filtered and then it was recrystallized twice from tert.-butyl-methylether to give 1.1 g (79%) of (E)-3-[4-[[3-[(6-Chlorohexyl)oxy]-5-[[2-methoxy-4-[(E)-2-(methoxycarbonyl)vinyl]phenoxy]methyl]benzyl]oxy)-3-methoxyphenyl]-2-cyanoacrylic acid methyl ester in form of slightly yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH2:8].[C:9](Cl)(Cl)=[O:10].[C:13]1([C@H:19]([OH:21])[CH3:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([C@H:19]([O:21][C:9](=[O:10])[NH:8][C:3]2[CH:4]=[N:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH3:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)Cl
Reactant: C[C@@H](O)c1ccccc1
Reactant: Nc1cnccc1Cl
Product: C[C@@H](OC(=O)Nc1cnccc1Cl)c1ccccc1

Procedure:
Prepared according to the procedure described in Example 1, Step 1, using the following starting materials: 4-chloro-pyridin-3-ylamine, phosgene, and (R)-1-phenyl-ethanol.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.[N:21]1[C:30]2[C:25](=[CH:26][C:27]([OH:31])=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1.CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[CH3:19][O:18][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:31][C:27]2[CH:26]=[C:25]3[C:30](=[CH:29][CH:28]=2)[N:21]=[CH:22][CH:23]=[CH:24]3)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:20]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Reactant: Oc1ccc2ncccc2c1
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc3ncccc3c2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 284, Step 2) and quinolin-6-ol via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1), to produce a colorless oil. MS (ES) for C22H23NO5 [M+H]+: 382.4.
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1[S:8][C:7]([C:9](=[O:13])[C:10]([OH:12])=[O:11])=[CH:6][CH:5]=1.C([O-])(=O)C.[Na+].O>C(O)(=O)C>[Br:1][C:5]1[CH:6]=[C:7]([C:9](=[O:13])[C:10]([OH:12])=[O:11])[S:8][C:4]=1[CH3:3]
Reactant: BrBr
Reactant: Cc1ccc(C(=O)C(=O)O)s1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1sc(C(=O)C(=O)O)cc1Br
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 91.4 %

Procedure:
Br2 (0.665 mL, 12.9 mmol) was added dropwise to a solution of (5-methylthiophen-2-yl)-oxo-acetic acid (1.05 g, 6.15 mmol) and sodium acetate (757 mg, 9.23 mmol) in 10 ml of glacial acetic acid and stirred at room temperature for 6.5 hours. The reaction mixture was poured into 150 ml water and extracted with diethyl ether (2×75 ml). The combined diethyl ether layers were extracted with aqueous Na2S2O3, the organic layer was then dried over sodium sulfate, and concentrated under vacuum to provide crude (4-bromo-5-methylthiophen-2-yl)-oxo-acetic acid (1.40 g, 91%). 1H NMR (300 MHz, CDCl3) δ8.35 (1H, s), 2.54 (3H, s).
Reaction SMILES: [N+:1]([C:4]1[C:5]([C:9]([OH:11])=O)=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].[F:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[F:12][C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:9]([C:5]2[C:4]([N+:1]([O-:3])=[O:2])=[CH:8][NH:7][N:6]=2)=[O:11])=[CH:15][CH:14]=1
Reactant: O=C(O)c1n[nH]cc1[N+](=O)[O-]
Reactant: Nc1ccc(F)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(F)cc1)c1n[nH]cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.3 %

Procedure:
4-Nitropyrazole-3-carboxylic acid (10 g; 63.66 mmol) was added to a stirred solution of 4-fluoroaniline (6.7 ml; 70 mmol), EDC (14.6 g; 76.4 mmol), and HOBt (10.3 g; 76.4 mmol) in DMF (25 ml), then stirred at room temperature overnight. The solvent was removed by evaporation under reduced pressure and the residue triturated with ethyl acetate/saturated brine solution. The resultant yellow solid was collected by filtration, washed with 2M hydrochloric acid, then dried under vacuum to give 15.5 g of the title compound. (LC/MS: Rt 2.92 [M+H]+ 250.89).
Reaction SMILES: [CH3:1][C@@:2]12[C:10](=O)[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH2:13][C:14]3[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=3[C@H:5]1[CH2:4][CH2:3]2.NCCC1C=CC=[CH:27][N:26]=1.C(O)=[O:32]>>[CH:27]([NH:26][C@H:10]1[CH2:9][CH2:8][C@H:7]2[C@H:6]3[C@H:12]([CH2:4][CH2:3][C@:2]12[CH3:1])[C:13]1[CH:14]=[CH:19][C:18]([O:20][CH3:21])=[CH:17][C:16]=1[CH2:15][CH2:5]3)=[O:32]
Reactant: O=CO
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: NCCc1ccccn1
Product: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](NC=O)CC[C@@H]12

Procedure:
A mixture of estrone methyl ether (14.2 g) and 2-(2-aminoethyl)-pyridine (24 ml, 24.4 g) is stirred and cooled in an ice bath. To this mixture, formic acid (97-98%, 11.5 ml) is added in portions. The mixture is then heated in an oil bath (180°-190° C. bath temp.) for 24 hours. The mixture is poured onto ice, treated with NAOH, and extracted with methylene chloride (3×). The extracts are dried (Na2SO4), filtered, and concentrated to give a solid. The solid is crystallized from methylene chloride-hexane to give crystals. Recrystallization from methylene chloride-acetone gives the title compound, mp 252°-253° C. preceded by yellowing. (PLA2-, diabetes)
Reaction SMILES: Cl.[NH2:2][C:3]1[C:11]([OH:12])=[C:10]2[C:6]([CH2:7][CH2:8][CH:9]2[CH2:13][CH2:14][NH:15][C:16](=[O:18])[CH3:17])=[CH:5][CH:4]=1.[CH3:19][O:20][C:21](OC)(OC)OC>O1CCCC1.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>[CH3:19][O:20][C:21]1[O:12][C:11]2[C:10]3[CH:9]([CH2:13][CH2:14][NH:15][C:16](=[O:18])[CH3:17])[CH2:8][CH2:7][C:6]=3[CH:5]=[CH:4][C:3]=2[N:2]=1
Reactant: CC(=O)NCCC1CCc2ccc(N)c(O)c21
Reactant: COC(OC)(OC)OC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1nc2ccc3c(c2o1)C(CCNC(C)=O)CC3
Yield: 57.7 %

Procedure:
N-[2-(6-Amino-7-hydroxy-2,3-dihydro-1H-inden-1-yl)ethyl]acetamide hydrochloride (100 mg, 0.369 mmol) and tetramethoxymethane (151 mg, 1.11 mmol) were heated under reflux in tetrahydrofuran (3.7 mL) for 2 hr. The reaction solution was diluted with ethyl acetate and saturated aqueous sodium hydrogencarbonate solution, washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol=100/0→95/5) to give the title compound (58.4 mg, yield 58%).