Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]([O:12][C:13]1[CH:14]=[C:15]([N+:31]([O-])=O)[CH:16]=[CH:17][C:18]=1[O:19][C:20](=[O:30])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[H][H]>[Pd].C(OCC)(=O)C.C1COCC1>[O:1]=[C:2]([O:12][C:13]1[CH:14]=[C:15]([NH2:31])[CH:16]=[CH:17][C:18]=1[O:19][C:20](=[O:30])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCC(=O)Oc1ccc([N+](=O)[O-])cc1OC(=O)CCCCCCCCC
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCCCCCC(=O)Oc1ccc(N)cc1OC(=O)CCCCCCCCC
Yield: 92.2 %

Procedure:
A mixture of 2.9 g of 3,4-bis[(1-oxodecyl)oxy]nitrobenzene and 0.5 g of 10% palladium on carbon in 50 ml of ethyl acetate and 10 ml of THF was stirred in a hydrogen atmosphere at room temperature for 5 hours when uptake ceased. The catalyst was removed by filtration and the filtrate was concentrated to an oil which was crystallized from ethyl acetate-hexane to give 2.5 g (92% yield, mp 44°-46°) of 3,4-bis[(1-oxodecyl)oxy]benzenamine.
Reaction SMILES: [C:1]1([C:7]2[NH:11][CH:10]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>>[CH3:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([S:27]([N:11]2[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10]2)(=[O:29])=[O:28])=[CH:25][CH:26]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)c1c[nH]c(-c2ccccc2)c1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1cc(-c2ccccc2)n(S(=O)(=O)c2ccc(OC)cc2)c1
Yield: 96.7 %

Procedure:
Using ethyl 5-phenyl-1H-pyrrole-3-carboxylate (250 mg), sodium hydride (60% in oil, 60 mg) and 4-methoxybenzenesulfonyl chloride (264 mg), a procedure as in Reference Example 4 was performed to give the title compound as a colorless oil (yield 433 mg, 97%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C:3]=1[CH3:19].O.CC[O:23]C(C)=O>CN1C(=O)CCC1>[F:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([OH:23])=[C:3]([CH3:19])[C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:5]2)=[CH:10][CH:9]=1
Reactant: CCOC(C)=O
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Cl
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1O

Procedure:
4-Chloro-7-fluoro-3-methyl-2-(pyridin-2-yl)quinoline (200 mg, 0.73 mmol) in NMP (2 mL) and water (0.26 mL, 14.7 mmol) was heated in the microwave at 150° C. for 4 h. After this EtOAc (10 mL) was added. The resulting precipitate was filtered to give 7-fluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-ol. Mass Spectrum (ESI) m/e=255.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([NH:22][C:23]4[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[CH:24]=4)=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:9][N:8]([CH:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[CH:37](=O)[CH3:38].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C=O)C.C1COCC1>[NH2:1][C:2]1[C:3]2[C:10]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([NH:22][C:23]4[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[CH:24]=4)=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:9][N:8]([CH:31]3[CH2:32][CH2:33][N:34]([CH2:37][CH3:38])[CH2:35][CH2:36]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CC=O
Reactant: Nc1ncnc2c1c(C(=O)c1cccc(NC(=O)Nc3cc(Cl)cc(Cl)c3)c1)cn2C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCN1CCC(n2cc(C(=O)c3cccc(NC(=O)Nc4cc(Cl)cc(Cl)c4)c3)c3c(N)ncnc32)CC1
Reaction time: 3.5 h
Yield: 10.5 %

Procedure:
A solution of 1-[3-(4-Amino-7-piperidin-4-yl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-3-(3,5-dichloro-phenyl)-urea (100 mg, 0.19 mmol) and acetaldehyde (8.4 mg, 0.19 mmol) in DMF/THF (20%, 10 mL) was stirred for 30 minutes at room temperature. Sodium triacetoxyborohydride (61 mg, 0.29 mmol) was added to the reaction mixture, stirred for 3.5 hours, and concentrated in vacuo. Purification by reverse phase preparative HPLC (HPLC method 2) provided the title compound as a white solid (11 mg, 10%). MS: 553.5 (MH+); HPLC Rf: 1.7 min. (HPLC method 2); HPLC purity: 100%.
Reaction SMILES: CO[C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[CH:26]([NH2:29])([CH3:28])[CH3:27]>>[F:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:13]1[C:12]([CH2:11][O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([NH:29][CH:26]([CH3:28])[CH3:27])=[O:25])=[CH:5][N:6]=2)=[C:16]([CH3:17])[O:15][N:14]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccccc3F)noc2C)nc1
Reactant: CC(C)N
Product: Cc1onc(-c2ccccc2F)c1COc1ccc(C(=O)NC(C)C)cn1
Yield: 83 %

Procedure:
As described for example 84f, 6-[3-(2-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (200 mg, 0.58 mmol) was converted, using isopropylamine instead of 2,2,2-trifluoroethylamine, to the title compound (180 mg, 83%) which was obtained as a colourless oil. MS: m/e=370.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7](=[O:13])[CH2:8][C:9]([O:11][CH3:12])=[O:10].C(NC1C=CC(S([N:27]=[N+:28]=[N-])(=O)=O)=CC=1)(=O)C.C(N(CC)CC)C>C(#N)C>[N+:27](=[C:8]([C:7](=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])[C:9]([O:11][CH3:12])=[O:10])=[N-:28]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: COCCCCC(=O)CC(=O)OC
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COCCCCC(=O)C(=[N+]=[N-])C(=O)OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 121.8 %

Procedure:
To a solution (100 ml) of methyl 7-methoxy-3-oxoheptanoate (5.00 g) and 4-(acetylamino)benzenesulfonyl azide (7.02 g) in acetonitrile was added triethylamine (11.1 ml) and the mixture was stirred at room temperature for 2 days. Insoluble material was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was suspended in diethyl ether and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure to give the object product (6.93 g).
Reaction SMILES: Br[CH:2]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH:6]([OH:14])[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[CH:3]1Br.C([N-]C(C)C)(C)C.[Li+]>O1CCCC1>[CH:18]1[C:4]2[C:3]#[C:2][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[CH2:7][CH:6]([OH:14])[C:5]=2[CH:15]=[CH:16][CH:17]=1
Reactant: OC1Cc2ccccc2C(Br)C(Br)c2ccccc21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: OC1Cc2ccccc2C#Cc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.1 %

Procedure:
To a stirred solution of 44 (1.528 g, 4 mmol) in tetrahydrofuran (40 ml) was added dropwise lithium diisopropylamide in tetrahydrofuran (2.0 M) (8 ml, 16 mmol) under an atmosphere of Argon at room temperature. The reaction mixture was stirred for 0.5 hour at room temperature, after which it was quenched by addition of dropwise water (0.5 ml). The solvents were evaporated under reduced pressure, and the residue was purified by flash chromatography on silica gel (2:1-0:1 v/v hexanes/CH2Cl2) to give the product as white solid (0.503 g, 57%). 1H NMR (300 MHz, CDCl3): δ 7.67 (1H, aromatics), 7.37-7.18 (7H, aromatics), 4.5 (1H, dd, J=2.1, 14.7 Hz, CHOH), 3.0 (1H, dd, J=2.1, 14.7 Hz, CH), 2.8 (1H, dd, J=2.1, 14.7 Hz, CH2). 13C NMR (75 MHz, CDCl3): δ 154.5, 150.6, 128.6, 127.1, 1127.0, 126.0, 125.8, 125.1, 124.7, 123.0, 122.7, 121.7, 111.9, 109.6, 74.2, 47.7.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[CH:9]([C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1)=[O:10].C(=O)([O-])[O-].[K+].[K+]>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>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([C:14]2[CH:15]=[CH:16][C:11]([CH:9]=[O:10])=[CH:12][CH:13]=2)=[N:3][CH:4]=1
Reactant: Cc1ccc(Br)nc1
Reactant: O=Cc1ccc(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: [K+]
Product: Cc1ccc(-c2ccc(C=O)cc2)nc1
Temperature: 110 °C
Yield: 122.1 %

Procedure:
A mixture of 2-bromo-5-methylpyridine (2 g), (4-formylphenyl)boronic acid (3.5 g), tetrakistriphenylphosphinepalladium (0) (0.672 g) and potassium carbonate (4.8 g) was dried under high vacuum for 10 minutes and dry dimethylformamide (15 mL) was added at room temperature. The reaction mixture was heated at 110° C. for 6 hours, and then quenched with water and extracted with ethyl acetate. The organic layer was washed with water and brine solution and dried over anhydrous sodium sulphate. The solvent was evaporated under the reduced pressure to obtain a residue which was purified by column chromatography over silica gel using 20% ethylacetate in hexane as eluant to afford the title compound (2.8 g). Mass (m/z): 198.20
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([OH:11])=O)[CH:2]=1.C(Cl)(=O)C(Cl)=O.[O:18]=[C:19]1[N:23]([CH:24]2[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][CH2:32][CH2:33][NH2:34])[CH2:26][CH2:25]2)[C:22]2[CH:35]=[CH:36][CH:37]=[CH:38][C:21]=2[NH:20]1>>[O:18]=[C:19]1[N:23]([CH:24]2[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][CH2:32][CH2:33][NH:34][C:9](=[O:11])[CH:8]=[CH:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH2:26][CH2:25]2)[C:22]2[CH:35]=[CH:36][CH:37]=[CH:38][C:21]=2[NH:20]1
Reactant: O=C(O)C=Cc1cccnc1
Reactant: NCCCCN1CCC(n2c(=O)[nH]c3ccccc32)CC1
Agent: O=C(Cl)C(=O)Cl
Product: O=C(C=Cc1cccnc1)NCCCCN1CCC(n2c(=O)[nH]c3ccccc32)CC1

Procedure:
Batch size: 1.47 g (9.9 mmol) 3-(3-pyridyl)-acrylic acid, 1.15 ml (13.5 mmol) oxalyl chloride and 2.6 g (9.0 mmol) 4-[4-(2-oxo-2.3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-butylamine.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12])=[O:4].[S-:13][C:14]#[N:15].[K+].O>C(O)C>[Cl:12][C:6]1[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]=1[C:3](=[O:4])[CH2:2][S:13][C:14]#[N:15]
Reactant: O=C(CBr)c1ccc(Cl)cc1Cl
Reactant: N#C[S-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N#CSCC(=O)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Yield: 91.5 %

Procedure:
A solution of 2-bromo-1-(2,4-dichlorophenyl)ethanone (7.09 g, 26.5 mmol) and potassium thiocyanate (2.57 g, 26.5 mmol) in ethanol (70 ml) was stirred at 80° C. for 2 hours. After cooling to room temperature, water (70 ml) was poured to the reaction mixture, and crystals were collected by filtration and washed with water to give 5.97 g (91.7%) of the desired product as a solid.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[NH:9][N:8]=[C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[C:13]3([CH3:22])[S:20][CH3:21])[CH2:6][S:5]1.[C:23](Cl)(=[O:25])[CH3:24].C(OC(=O)C)C>CN(C=O)C>[C:23]([N:15]1[C:16]2[C:12](=[CH:11][C:10]([C:7]3[CH2:6][S:5][C:4](=[O:3])[NH:9][N:8]=3)=[CH:18][CH:17]=2)[C:13]([CH3:22])([S:20][CH3:21])[C:14]1=[O:19])(=[O:25])[CH3:24]
Reactant: CSC1(C)C(=O)Nc2ccc(C3=NNC(=O)SC3)cc21
Reactant: CC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSC1(C)C(=O)N(C(C)=O)c2ccc(C3=NNC(=O)SC3)cc21
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
0.131 g sodium hydride from a 55% dispersion in mineral oil was added during 0.5 hr to a solution of 0.921 g of 1,3-dihydro-5-(3,6-dihydro-2-oxo-2H-1,3,4-thiadiazin-5-yl)-3-methyl-3-methylthio-2H-indol-2-one (compound of Example 1) in 25 ml DMF at 5° C. The mixture was stirred for 0.5 hr at 5° C. then 0.5 hr at 20° C. and cooled at 5° C. 0.215 ml of acetyl chloride in 1 ml DMF was added dropwise under stirring. The mixture was stirred for 0.5 hr at 5° C. then 1.5 hrs at 20° C. 250 ml ethylacetate was added and the corresponding organic solution was washed with water, dried and evaporated to dryness. The residual oil was purified by chromatography on silica (methylene chloride-ethylacetate: 9/1) to yield 0.4 g of white crystalline compound.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[F:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[F:28])[CH:23]=[O:24].[F:29][C:30]([Si](C)(C)C)([F:32])[F:31].Cl>C1COCC1>[F:19][C:20]1[CH:21]=[C:22]([CH:23]([OH:24])[C:30]([F:32])([F:31])[F:29])[CH:25]=[CH:26][C:27]=1[F:28]
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: OC(c1ccc(F)c(F)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.6 %

Procedure:
Tetrabutylammonium fluoride (TBAF: 0.1 ml, 1M) in THF was added to a solution of 3,4-difluro-benzaldehyde (1.42 g, 10 mmol) and (trifluromethyl)trimethylsilane (1.70 g, 12 mmol) in 10 ml THF at 0° C. The mixture was warmed up to room temperature and stirred for 4 hours. The reaction mixture was treated with 12 ml of 1M HCl and stirred overnight. The product was extracted with dicloromethane (3×20 ml), the organic layer was combined and passed through a pad of silica gel. The organic solvent was evaporated to give 1.9 g of 1-(3,4-difluoro-phenyl)-2,2,2-trifluoro-ethanol, yield 90%.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([CH2:7][N:8]([CH3:12])[CH2:9][CH2:10][NH2:11])[CH:4]=[C:3]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH:2]=1.C(#N)C.[CH3:22][N:23]([CH3:78])[C@H:24]1[CH2:75][C@@H:74]([CH3:76])[O:73][CH:26]([O:27][C@@H:28]2[C@@H:44]([CH3:45])[C:43](=[O:46])[C@@H:42]([CH3:47])[C:41](=[O:48])[O:40][C@H:39]([CH2:49][CH3:50])[C@:38]3([CH2:51][CH3:52])[C@H:34](N(CCCCN4C5C(=NC=CC=5)N=C4)[C:36](=[O:53])[O:37]3)[C@@H:33]([CH3:67])[C:32](=[O:68])[C@H:31]([CH3:69])[CH2:30][C@@:29]2([O:71][CH3:72])[CH3:70])[C@@H:25]1[OH:77]>O>[CH3:78][N:23]([CH3:22])[C@H:24]1[CH2:75][C@@H:74]([CH3:76])[O:73][CH:26]([O:27][C@@H:28]2[C@@H:44]([CH3:45])[C:43](=[O:46])[C@@H:42]([CH3:47])[C:41](=[O:48])[O:40][C@H:39]([CH2:49][CH3:50])[C@:38]3([CH2:51][CH3:52])[C@H:34]([N:11]([CH2:10][CH2:9][N:8]([CH2:7][C:5]4[CH:4]=[C:3]([C:13]5[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=5)[CH:2]=[N:1][CH:6]=4)[CH3:12])[C:36](=[O:53])[O:37]3)[C@@H:33]([CH3:67])[C:32](=[O:68])[C@H:31]([CH3:69])[CH2:30][C@@:29]2([O:71][CH3:72])[CH3:70])[C@@H:25]1[OH:77]
Reactant: CN(CCN)Cc1cncc(-c2cccnc2)c1
Reactant: CC[C@H]1OC(=O)[C@H](C)C(=O)[C@H](C)[C@@H](OC2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@@](C)(OC)C[C@@H](C)C(=O)[C@H](C)[C@H]2N(CCCCn3cnc4ncccc43)C(=O)O[C@]12CC
Solvent: CC#N
Solvent: O
Product: CC[C@H]1OC(=O)[C@H](C)C(=O)[C@H](C)[C@@H](OC2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@@](C)(OC)C[C@@H](C)C(=O)[C@H](C)[C@H]2N(CCN(C)Cc3cncc(-c4cccnc4)c3)C(=O)O[C@]12CC
Yield: 27 %

Procedure:
C12 ethyl, C9, C10, C11 enone, 3 oxo, C12 OCOIm macrolide of Example 11 (1 eq) was added to N1-[3,3′]Bipyridinyl-5-ylmethyl-N1-methyl-ethane-1,2-diamine (3 eq), acetonitrile, and water (10%). The reaction conditions are the same as described previously for (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-3a,4-diethyl-1-[4-(1H-imidazo[4,5-b]pyridin-1-yl)butyl]-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxotetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl 3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside, yielding (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-1-{2-[(3,3′-bipyridin-5-ylmethyl)(methyl)amino]ethyl }-3a,4-diethyl-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxotetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl 3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside (27% yield) as a white solid. MH+(852.50).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[C:13]([O:18][CH2:19][CH3:20])(=[O:17])[CH:14]([CH3:16])[CH3:15].Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]([OH:32])=[O:31])=[CH:25][CH:24]=1.Cl>O1CCCC1>[CH2:19]([O:18][C:13](=[O:17])[C:14]([CH3:16])([CH3:15])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]([OH:32])=[O:31])=[CH:25][CH:24]=1)[CH3:20]
Reactant: O=C(O)Cc1ccc(CBr)cc1
Reactant: CCOC(=O)C(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)Cc1ccc(CC(=O)O)cc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 84 %

Procedure:
To a solution of diisopropylamine (13.11 mmol, 1.8 mL) in anhydrous tetrahydrofuran (40 mL) cooled to −78° C. under a nitrogen atmosphere was added 2.5M n-BuLi in hexanes (13.11 mmol, 5.24 mL). The resulting solution was allowed to stir at −78° C. for 20 minutes, warmed to room temperature for 10 minutes, then cooled back to −78° C. for 10 minutes. The mixture was added to a solution of ethyl isobutyrate (13.11 mmol, 1.76 mL) dissolved in anhydrous tetrahydrofuran (20 mL) cooled to −78° C. The resulting solution was allowed to stir at −78° C. for 1 h. (4-Bromomethyl-phenyl)-acetic acid (1 g, 4.37 mmol) in anhydrous tetrahydrofuran (10 mL) was added to the solution dropwise. The solution was warmed to room temperature and was allowed to stir for 20 minutes. The reaction mixture was poured over a dilute HCl solution (1 N). The aqueous layer was isolated and extracted with diethyl ether (1×). The organic layers were combined, washed with 2N HCl (2×), brine (1×), dried over anhydrous sodium sulfate, and concentrated to a crude oil. The oil was chromatographed on silica gel (Merck silica gel 60, art#9385-3) eluting with 10% methanol/methylene chloride to give 3-(4-carboxymethyl-phenyl)-2,2-dimethyl-propionic acid ethyl ester as a white solid (0.97 g, 84%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[Br:26][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]2[C:36]=1[C:35]([C:37](Cl)=[O:38])=[CH:34][CH:33]=[CH:32]2>>[Br:26][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]2[C:36]=1[C:35]([C:37]([N:20]1[CH2:21][CH2:22][CH:17]([N:15]3[C:14](=[O:23])[C:13]([CH3:25])([CH3:24])[C:12]([C:6]4[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH3:2])[CH:5]=4)=[N:16]3)[CH2:18][CH2:19]1)=[O:38])=[CH:34][CH:33]=[CH:32]2
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: O=C(Cl)c1cccc2cccc(Br)c12
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4cccc5cccc(Br)c45)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B1*HCl) and 8-bromonaphthalene-1-carbonyl chloride as starting compounds. The crude product is purified by crystallization from EA and diethyl ether to yield the title compound.
Reaction SMILES: C[O:2][C:3](=[O:37])[CH2:4][CH2:5][NH:6][C:7](=[O:36])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)[CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:10][CH:9]=1.CO.[OH-].[Na+]>CCOC(C)=O>[C:32]([C:29]1[CH:28]=[CH:27][C:26]([C:23]2[CH:24]=[CH:25][C:20]([NH:19][CH:14]([C:11]3[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:37])=[O:2])=[O:36])=[CH:9][CH:10]=3)[CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:21][CH:22]=2)=[CH:31][CH:30]=1)([CH3:34])([CH3:35])[CH3:33]
Reactant: COC(=O)CCNC(=O)c1ccc(C(CC(C)C)Nc2ccc(-c3ccc(C(C)(C)C)cc3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)CC(Nc1ccc(-c2ccc(C(C)(C)C)cc2)cc1)c1ccc(C(=O)NCCC(=O)O)cc1
Reaction time: 4 h
Yield: 54.9 %

Procedure:
3-{4-[1-(4′-tert-butyl-biphenyl-4-ylamino)-3-methyl-butyl]-benzoylamino}-propionic acid methyl ester (30 mg) is taken into MeOH (10 mL), followed by the addition of 5N NaOH (1 mL). The reaction is stirred for 4 h, diluted with EtOAc, washed with aqueous HCl, and brine. The organic portion is dried over MgSO4, and concentrated to afford 16 mg of the titled compound. MS (ES): 487.3 [M+H]+.
Reaction SMILES: [H-].[Na+].C(N(CC)[CH:6]=[C:7]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:8]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)=O)C.[C:25]([CH2:27][C:28]([NH2:30])=[O:29])#[N:26].Cl>CN(C=O)C.CO>[CH3:16][C:13]1[CH:12]=[CH:11][C:10]([C:8]2[NH:30][C:28](=[O:29])[C:27]([C:25]#[N:26])=[CH:6][C:7]=2[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:15][CH:14]=1
Reactant: N#CCC(N)=O
Reactant: CCN(C=C(C(=O)c1ccc(C)cc1)c1ccccc1)CC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1ccc(-c2[nH]c(=O)c(C#N)cc2-c2ccccc2)cc1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
To a slurry of NaH (1.38 g, 60% in mineral oil, 34.41 mmol) in DMF (20 mL) at 0° C. was added a solution of 3-dimethylamino)-1-(4-methylphenyl)-2-phenylprop-2-en-1-one (2-2; 4.15 g, 15.64 mmol) and 2-cyanoacetamide (1.45 g, 17.2 mmol) in MeOH (1.5 mL) and DMF (40 mL) dropwise over 40 min. The resulting mixture was stirred at 90° C. for 4 h and cooled to rt. The mixture was poured into dilute HCl aqueous solution (240 mL, 0.25 M) and filtered, washed with water (40 mL) and dried in vacuo to afford 6-(4-methylphenyl)-2-oxo-5-phenyl-1,2-dihydropyridine-3-carbonitrile (2-3). 1H-NMR (500 MHz, CDCl3) δ 7.96 (s, 1H), 7.15-7.28 (m, 7H), 7.05-7.07 (m, 2H), 2.36 (s, 3H). LRMS m/z (M+H) Calcd: 287.3, found: 287.1.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])=[C:6]([O:13][CH2:14][O:15][CH3:16])[CH:5]=[C:4]([O:17][CH2:18][O:19][CH3:20])[C:3]=1[C:21](=[O:23])[CH3:22].[H][H]>C(O)C>[OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])=[C:6]([O:13][CH2:14][O:15][CH3:16])[CH:5]=[C:4]([O:17][CH2:18][O:19][CH3:20])[C:3]=1[C:21](=[O:23])[CH3:22]
Reactant: COCOc1cc(OCOC)c(C(C)=O)c(O)c1CC=C(C)C
Reactant: [H][H]
Solvent: CCO
Product: COCOc1cc(OCOC)c(C(C)=O)c(O)c1CCC(C)C
Temperature: 25 °C
Yield: 82.7 %

Procedure:
A solution of 2.08 g of the 2'-hydroxy-4',6'-bis(methoxymethoxy)-3'-(3-methyl-2-butenyl)acetophenone obtained in Production Example 13 in ethanol (20 ml) was added to a sufficiently hydrogen gas-absorbed suspension of 1.0 g of 5% palladium-carbon in 30 ml of ethanol, and the mixture was stirred at room temperature under atmospheric pressure in a hydrogen atmosphere. After the reaction, the reaction mixture was filtered, and the solvent was removed from the filtrate by distillation. The obtained residue was subjected to the silica gel column chromatography (3.0 cm in diameter, 60 g of silica gel, 0.3 kg/cm2) using a mixed solvent of n-hexane and ethyl acetate (n-hexane/ethyl acetate-3/1). Fractions of 50 ml were recovered, and 1.73 g (yield=82.8%) of 2'-hydroxy-3'-isopentyl-4',6'-bis(methoxymethoxy)acetophenone in the form of a yellow oil was obtained from the third to fifth fractions.
Reaction SMILES: [OH-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12])([O-:5])=[O:4].Cl[CH2:14][CH:15]=[CH2:16].CS(C)=O>O>[CH2:16]([O:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[N+:3]([O-:5])=[O:4])[CH:15]=[CH2:14]
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: C=CCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: C=CCOc1ccccc1[N+](=O)[O-]
Reaction time: 18 h

Procedure:
A solution of 64 g of sodium hydroxide in 75 ml of water was added drop-by-drop (over 15 minutes) to a stirred mixture of 209.6 g of 2-nitrophenol, 115.5 g of 3-chloropropene and 500 ml of dimethyl sulfoxide (DMSO), at room temperature. The mixture was stirred at 85°-90° C. for 18 hours and then mixed with 3 liters of water. The resulting mixture was extracted with methylene chloride, the extract was washed with ice water, dried (MgSO4) and the solvent was evaporated, to give 1-(2-propen-1-yloxy)-2-nitrobenzene (1A), as an amber syrup.