Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][N:15]([CH:18]3[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O>CCOC(C)=O.CCO.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:13][CH2:14][N:15]([CH:18]3[CH2:19][CH2:20][N:21]([CH2:24][CH2:25][S:26]([CH3:29])(=[O:27])=[O:28])[CH2:22][CH2:23]3)[CH2:16][CH2:17]2)[CH:6]=[CH:7][C:8]=1[NH2:9]
Reactant: COc1cc(N2CCN(C3CCN(CCS(C)(=O)=O)CC3)CC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1cc(N2CCN(C3CCN(CCS(C)(=O)=O)CC3)CC2)ccc1N
Temperature: 25 °C
Yield: 63.4 %

Procedure:
To 1-[3-(methyloxy)-4-nitrophenyl]-4-{1-[2-(methylsulfonyl)ethyl]-4-piperidinyl}piperazine (1.18 g, 2.76 mmol) in EtOAc (100 mL) and EtOH (25 mL) was added Pd on carbon in one portion. The mixture was stirred at rt under H2 (1 atm.) until complete by TLC. The reaction was filtered through Celite® and concentrated. Purification by flash chromatography provided the title compound of step F (0.690 g, 1.75 mmol, 63%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.31-1.42 (m, 2H), 1.75 (d, J=11.4 Hz, 2H), 1.86-1.97 (m, 2H), 2.15 (tt, J=11.3, 3.9 Hz, 1H), 2.54-2.59 (m, 4H), 2.65 (t, J=6.8 Hz, 2H), 2.88-2.94 (m, 6H), 3.00 (s, 3H), 3.25 (t, J=6.8 Hz, 2H), 3.71 (s, 3H), 4.18 (br. s., 2H), 6.25 (dd, J=8.4, 2.6 Hz, 1H), 6.46 (d, J=2.6 Hz, 1H), 6.49 (d, J=8.4 Hz, 1H).
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH2:16].[Cl:17][CH2:18][C:19](Cl)=[O:20].N1C=CC=CC=1>ClC(Cl)C>[Cl:17][CH2:18][C:19]([NH:16][C:2]1[CH:3]=[CH:4][C:5]2[O:6][C:7]3[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:8]=3[C:9]=2[CH:1]=1)=[O:20]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc2oc3c(c2c1)CCCCCC3
Solvent: CC(Cl)Cl
Solvent: c1ccncc1
Product: O=C(CCl)Nc1ccc2oc3c(c2c1)CCCCCC3
Yield: 101.9 %

Procedure:
Following the procedure of Example 1, 6,7,8,9,10,11-Hexahydro-benzo[b]-cycloocta[d]furan-2-ylamine (0.80 g, 3.7 mmol), chloroacetyl chloride (0.31 mL, 3.9 mmol), and pyridine (0.60 mL, 7.4 mmol) in dichloroethane (25 mL) provided 2-chloro-N-6,7,8,9,10,11-hexahydrobenzo[b]cycloocta[d]furan-2-ylacetamide (1.1 g). MS (ESI) m/z 292 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:17][O:16][C@H:15]([CH2:18][O:19]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C@H:14]1[CH2:13][S:12][C:11]([NH:39][C:40](=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[N:10]2.O.Cl>CO>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:17][O:16][C@H:15]([CH2:18][OH:19])[C@H:14]1[CH2:13][S:12][C:11]([NH:39][C:40](=[O:47])[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)=[N:10]2
Reactant: O=C(NC1=N[C@@]2(c3cccc(F)c3F)CO[C@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)[C@H]2CS1)c1ccccc1
Agent: Cl
Solvent: O
Solvent: CO
Product: O=C(NC1=N[C@@]2(c3cccc(F)c3F)CO[C@H](CO)[C@H]2CS1)c1ccccc1
Reaction time: 8 h

Procedure:
N-((4aS,5S,7aS)-7a-(2,3-difluorophenyl)-5-((trityloxy)methyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)benzamide, obtained in preparation example 1-(5), (8.42 g) was suspended in methanol (100 mL) and water (3 mL) and conc. hydrochloric acid (5 mL) were added. The reaction mixture was stirred vigorously overnight, and then concentrated under reduced pressure to a volume of about 30 mL. The mixture was then carefully neutralised with NaHCO3 (sat., aq., 100 mL) and extracted with EtOAc (3×100 mL). The combined organic portions were dried over MgSO4, evaporated, and the residue purified by silica gel column chromatography (0% to 50% EtOAc in hexanes) to afford the title compound (4.20 g). 1H NMR (400 MHz, CDCl3) δ ppm 1.94 (br. s., 1H), 2.83 (d, J=10.6 Hz, 1H), 3.14-3.49 (m, 2H), 3.77 (d, J=8.8 Hz, 1H), 3.97 (dd, J=11.7, 2.7 Hz, 1H), 4.08 (d, J=6.3 Hz, 1H), 4.46-4.63 (m, 2H), 7.07-7.25 (m, 3H), 7.37-7.60 (m, 3H), 8.00-8.26 (m, 2H)
Reaction SMILES: N(C(C)(C)C#N)=NC(C)(C)C#N.[CH3:13][C:14]1[CH:23]=[C:22]2[C:17]([CH:18]=[CH:19][C:20]([C:24]#[N:25])=[CH:21]2)=[CH:16][CH:15]=1.[Br:26]N1C(=O)CCC1=O>C(#N)C(C)C>[Br:26][CH2:13][C:14]1[CH:23]=[C:22]2[C:17]([CH:18]=[CH:19][C:20]([C:24]#[N:25])=[CH:21]2)=[CH:16][CH:15]=1
Reactant: Cc1ccc2ccc(C#N)cc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CC(C)C#N
Product: N#Cc1ccc2ccc(CBr)cc2c1
Temperature: 80 °C
Yield: 58.2 %

Procedure:
2,2′-azobisisobutyronitrile (491 mg, 3 mmol) and isobutyronitrile (50 ml) were added to 7-methyl-2-naphthalene carbonitrile (5.0 g, 30 mmol) at room temperature. N-bromosuccinimide (5.3 g, 30 mmol) was added thereto, and the mixture was heated at an internal temperature of 80° C. for 2 hours. After that, the experiment was conducted in the same way as Example 12. Analysis by reversed-phase chromatography, by use of the obtained product from Example 11 as a standard sample revealed that 4.3 g of the title compound was obtained (58% yield).
Reaction SMILES: [C:1]([C:3]1[CH:27]=[CH:26][C:6]([O:7][C:8]2[C:13]([N+:14]([O-])=O)=[CH:12][CH:11]=[C:10]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=3)[N:9]=2)=[CH:5][CH:4]=1)#[N:2]>CO.C(OCC)(=O)C.[Pd].[C]>[NH2:14][C:13]1[C:8]([O:7][C:6]2[CH:26]=[CH:27][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)=[N:9][C:10]([O:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]#[N:25])=[CH:22][CH:23]=2)=[CH:11][CH:12]=1
Reactant: N#Cc1ccc(Oc2ccc([N+](=O)[O-])c(Oc3ccc(C#N)cc3)n2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: N#Cc1ccc(Oc2ccc(N)c(Oc3ccc(C#N)cc3)n2)cc1
Reaction time: 1 h
Yield: 86.4 %

Procedure:
10% Pd/carbon (0.24 g) was added under hydrogen atmosphere (balloon pressure) to a stirred solution of 2,6-Bis(4-Cyano phenoxy)-3-nitro pyridine (1.20 g, 3.35 mmol) in 20 ml of methanol:ethyl acetate (1:1) at ambient temperature and the reaction mixture was stirred for 1 h. The reaction mixture was filtered through celite, washed with 20 ml of ethyl acetate and concentrated under reduced pressure. Water was added to the residual mixture and it was extracted with ethyl acetate. Ethyl acetate layer was washed with water followed by brine. The organic layer was dried over sodium sulphate to afford 0.95 g of the title product which was used for the next step without further purification. 1H NMR (DMSO-d6): δ 5.32 (2H, brs), 6.82 (1H, d), 7.15 (1H, d), 7.22 (2H, d), 7.34 (2H, d), 7.80 (4H, m).
Reaction SMILES: [CH:1]1([C:4]2[CH:8]=[CH:7][NH:6][N:5]=2)[CH2:3][CH2:2]1.[N+:9]([O-])([OH:11])=[O:10]>OS(O)(=O)=O>[CH:1]1([C:4]2[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][NH:6][N:5]=2)[CH2:3][CH2:2]1
Reactant: c1cc(C2CC2)n[nH]1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1c[nH]nc1C1CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
To a cooling (0° C.) solution of 3-cyclopropyl-1H-pyrazole (1.5 g, 13.89 mmol) in concentrated H2SO4 (20 mL, 98%) was added concentrated HNO3 (20 mL, 65%) over 2 min. The reaction mixture was stirred over 1 hr at this temperature. It was then diluted with ice-water and extracted with EA (30 mL×4). The organic phase was combined and washed with saturated sodium bicarbonate (50 mL). It was dried over Na2SO4 and concentrated in vacuo to give a crude product (1.5 g, 70%). This crude product was pure enough to be delivered or used to the next step reaction. MS: [M+H]+154. 1H NMR (500 MHz, CDCl3) δ 0.97 (m, 2H), 1.22 (m, 2H), 2.66 (m, 1H), 8.20 (s, 1H), 8.38 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[Cl:15])[N:6]=[CH:5][C:4]=1[C:16]([O:18]CC)=O)#[N:2].[CH3:21][NH2:22]>CN(C=O)C>[C:1]([C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[Cl:15])[N:6]=[CH:5][C:4]=1[C:16]([NH:22][CH3:21])=[O:18])#[N:2]
Reactant: CCOC(=O)c1cnn(-c2ccc(Cl)cc2Cl)c1C#N
Reactant: CN
Solvent: CN(C)C=O
Product: CNC(=O)c1cnn(-c2ccc(Cl)cc2Cl)c1C#N
Temperature: 25 °C

Procedure:
To a solution of 2.5 g of 5-cyano-1-(2,4-dichlorophenyl)-1H-pyrazole-4-carboxylic acid, ethyl ester in 20 ml of DMF was added 20 ml of 40% aqueous monomethylamine. The reaction mixture was stirred at room temperature for approximately two and one-half hours whereupon the solution was poured into ice water. The precipitate was collected by filtration and recrystallized from methanol/water to afford 1.3 g of 5-cyano-1-(2,4-dichlorophenyl)-N-methyl-1H-pyrazole-4-carboxamide. mp=182°-183° C.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]=1[O:20][CH3:21])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[N:22]1[CH:27]=[CH:26][CH:25]=[N:24][C:23]=1[C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH:31]=O>>[CH3:21][O:20][C:11]1[CH:12]=[CH:13][C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]=1[CH:2]1[N:1]([CH2:31][C:30]2[CH:33]=[CH:34][CH:35]=[C:28]([C:23]3[N:22]=[CH:27][CH:26]=[CH:25][N:24]=3)[CH:29]=2)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]1
Reactant: O=Cc1cccc(-c2ncccn2)c1
Reactant: COC(=O)CCCC(N)c1c(OC)ccc2ccccc12
Product: COc1ccc2ccccc2c1C1CCCC(=O)N1Cc1cccc(-c2ncccn2)c1

Procedure:
Prepared according to general procedure 1 (GP1) using methyl 5-amino-5-(2-methoxynaphthalen-1-yl)pentanoate and commercially available 3-(pyrimidin-2-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.84 min.; [M+H]+: 424.10 g/mol.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]([N:18]3[CH2:22][CH2:21][N:20]([CH:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[C:19]3=[O:29])=[O:17])=[N:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH2:30]([N:32]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[N:33]1)[CH3:31].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.O1CCOCC1.O>[CH2:30]([N:32]1[CH:36]=[C:35]([C:2]2[CH:7]=[C:6]([O:8][C:9]3[CH:10]=[CH:11][C:12]([NH:15][C:16]([N:18]4[CH2:22][CH2:21][N:20]([CH:23]5[CH2:28][CH2:27][O:26][CH2:25][CH2:24]5)[C:19]4=[O:29])=[O:17])=[N:13][CH:14]=3)[CH:5]=[CH:4][N:3]=2)[CH:34]=[N:33]1)[CH3:31]
Reactant: O=C(Nc1ccc(Oc2ccnc(Cl)c2)cn1)N1CCN(C2CCOCC2)C1=O
Reactant: CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
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: O
Solvent: C1COCCO1
Product: CCn1cc(-c2cc(Oc3ccc(NC(=O)N4CCN(C5CCOCC5)C4=O)nc3)ccn2)cn1
Temperature: 80 °C
Yield: 71.7 %

Procedure:
A mixture of Example C1 (0.15 g, 0.40 mmol), 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.088 g, 0.40 mmol), and K2CO3 (0.2 g, 1.44 mmol) in 4:1 dioxane/water (5 mL) was sparged with Ar, treated with Pd(PPh3)4 (0.040 g, 0.036 mmol), sparged again with Ar and heated at 80° C. overnight. The mixture was cooled to RT, treated with brine, extracted with EtOAc (2×) and the combined organics were dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM). The material was treated with Et2O, allowed to stand at RT and the resulting solid collected via filtration to afford N-(5-((2-(1-ethyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide (137 mg, 80%). 1H NMR (400 MHz, DMSO-d6): δ 10.96 (s, 1 H), 8.37 (d, J=5.7 Hz, 1 H), 8.30 (s, 1 H), 8.23 (d, J=2.9 Hz, 1 H), 8.07 (d, J=9.0 Hz, 1 H), 7.97 (s, 1 H), 7.71 (dd, J=9.0, 2.9 Hz, 1 H), 7.24 (d, J=2.4 Hz, 1 H), 6.69 (dd, J=5.7, 2.4 Hz, 1 H), 4.13 (q, J=7.3 Hz, 2 H), 3.86 (m, 5 H), 3.40 (m, 4 H), 1.71 (m, 2 H), 1.59 (m, 2 H), 1.37 (t, J=7.3 Hz, 3 H); MS (ESI) m/z: 478.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](OS(C(F)(F)F)(=O)=O)[CH:5]=[C:6]([Cl:23])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:19][CH2:18][C:17]([F:21])([F:20])[CH2:16][CH2:15]2)[C:10]1=[O:22].[CH3:32][O:33][C:34]([C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1)=[O:35].C([O-])([O-])=O.[K+].[K+]>COCCOC.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>[CH3:32][O:33][C:34]([C:36]1[CH:41]=[CH:40][C:39]([C:4]2[CH:3]=[C:2]([Cl:1])[C:7]([CH2:8][C@@H:9]3[CH2:13][CH2:12][N:11]([CH:14]4[CH2:15][CH2:16][C:17]([F:20])([F:21])[CH2:18][CH2:19]4)[C:10]3=[O:22])=[C:6]([Cl:23])[CH:5]=2)=[CH:38][CH:37]=1)=[O:35]
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: O=C1[C@H](Cc2c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc2Cl)CCN1C1CCC(F)(F)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+]
Solvent: COCCOC
Product: COC(=O)c1ccc(-c2cc(Cl)c(C[C@@H]3CCN(C4CCC(F)(F)CC4)C3=O)c(Cl)c2)cc1
Reaction time: 8 h
Yield: 57.6 %

Procedure:
Treat a solution of Trifluoro-methanesulfonic acid 3,5-dichloro-4-[(R)-1-(4,4-difluoro-cyclohexyl)-2-oxo-pyrrolidin-3-ylmethyl]-phenyl ester (Preparation 12) (1.8 g, 3.5 mmol), 4-Methoxycarbonylphenylboronic acid (1.3 g, 7.0 mmol), and Tetrakis(triphenylphosphine)palladium(0) (0.4 g, 0.4 mmol) in DME (20 mL) with 2M aqueous K2CO3 (5.2 mL). Heat the reaction to 80° C. and stir overnight. Cool the reaction and quench with 1N HCl. Extract the aqueous with EtOAc. Wash the organic with brine, dried over MgSO4, and filter. Purify the crude by silica gel column chromatography using Hexanes:EtOAc to elute the pure product. Remove the solvent to afford 1.0 g (57%) of desired product. MS (m/e): 498 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].Br[CH2:13][C:14]([O:16]CC)=[O:15]>C(#N)C>[CH:4]([C:3]1[CH:6]=[CH:7][CH:8]=[C:9]([O:10][CH3:11])[C:2]=1[O:1][CH2:13][C:14]([OH:16])=[O:15])=[O:5]
Reactant: COc1cccc(C=O)c1O
Reactant: CCOC(=O)CBr
Solvent: CC#N
Product: COc1cccc(C=O)c1OCC(=O)O

Procedure:
The starting product is 2-hydroxy-3-methoxy benzaldehyde, known commonly as o-vanillin. Alkylation is conducted by the already described method, using ethyl bromoacetate under reflux in acetonitrile. In this manner 2-formyl-6-methoxy-phenoxyacetic acid is obtained in the form of the ethyl ester. The oily crude product is saponified to give the corresponding acid in the form of a white crystalline solid. Melting point 118/119° C. NMR (DMSO-d6): 13 (b, 1H), 10.5 (s, 1H), 7.4/7.1 (m, 3H), 4.8 (s, 2H), 3.85 (s, 3H). IR (KBr, cm-1): 3100/2600, 1735, 1700. This is transformed into the corresponding oxime using hydroxylamine hydrochloride.
Reaction SMILES: C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[CH3:19][O:20][CH:21]([O:30][CH3:31])[CH2:22][NH:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.[CH2:32]([N:34]1[CH:38]=[C:37]([C:39]2[CH:40]=[C:41]([CH:50]=[CH:51][CH:52]=2)[CH2:42][CH2:43][O:44][CH2:45][CH2:46][C:47](O)=[O:48])[N:36]=[N:35]1)[CH3:33].C(N(CC)CC)C>C1COCC1.C(#N)C.C(OCC)(=O)C>[CH:24]1([N:23]([CH2:22][CH:21]([O:30][CH3:31])[O:20][CH3:19])[C:47](=[O:48])[CH2:46][CH2:45][O:44][CH2:43][CH2:42][C:41]2[CH:50]=[CH:51][CH:52]=[C:39]([C:37]3[N:36]=[N:35][N:34]([CH2:32][CH3:33])[CH:38]=3)[CH:40]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: COC(CNC1CCCCC1)OC
Reactant: CCn1cc(-c2cccc(CCOCCC(=O)O)c2)nn1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: C1CCOC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCn1cc(-c2cccc(CCOCCC(=O)N(CC(OC)OC)C3CCCCC3)c2)nn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of T3P (1.41 mL) dissolved in THF (1.57M) was added in one portion to a stirred solution of N-(2,2-dimethoxyethyl)cyclohexanamine (0.24 mL), 3-(3-(1-ethyl-1H-1,2,3-triazol-4-yl)phenethoxy)propanoic acid [Example 4, Step iv)] (0.45 g), and triethylamine (1.86 mL) in acetonitrile (5 mL) at 25° C. The resulting solution was stirred at 25° C. for 15 min. The reaction mixture was diluted with ethyl acetate (50 mL), and washed with saturated sodium hydrogen carbonate (20 mL). The organic layer was dried over magnesium sulfate, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0-70% ethyl acetate in isohexane to afford the subtitled compound (0.46 g). 1H NMR (400 MHz, CD3OD) δ 8.32 and 8.31 (2×s, 1H), 7.68 and 7.66 (2×s, 1H), 7.65-7.61 (m, 1H), 7.32 and 7.32 (2×t, J=7.5 Hz, 1H), 7.22-7.18 (m, 1H), 4.52 and 4.36 (2×t, J=5.3 Hz, 1H), 4.47 (q, J=7.3 Hz, 2H), 4.04-3.94 (m, 1H), 3.76-3.61 (m, 4H), 3.34 (s, 3H), 3.32 (s, 3H), 3.25 (d, J=5.1 Hz, 2H), 2.91-2.85 (m, 2H), 2.68-2.62 (m, 2H), 1.79-1.03 (m, 10H), 1.56 (t, J=7.4 Hz, 3H), a ˜1:1 mixture of rotamers is observed.
Reaction SMILES: O[CH:2]=[C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([O:16][CH3:17])=[C:9]([O:14][CH3:15])[CH:10]=2)[N:5]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:4]1[CH3:23].C([O-])(=O)C.[NH4+:28]>C(O)C>[NH2:28][CH:2]=[C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([O:16][CH3:17])=[C:9]([O:14][CH3:15])[CH:10]=2)[N:5]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:4]1[CH3:23]
Reactant: [NH4+]
Reactant: CCOC(=O)N1c2cc(OC)c(OC)cc2C(=O)C(=CO)C1C
Agent: CC(=O)[O-]
Solvent: CCO
Product: CCOC(=O)N1c2cc(OC)c(OC)cc2C(=O)C(=CN)C1C
Temperature: 40 °C

Procedure:
A reaction mixture comprising 58.5 g. of 3-hydroxymethylene-6,7-dimethoxy-2-methyl-4-oxo-1,2,3,4-tetrahydro-1-quinoline carboxylic acid, ethyl ester and 58.5 g. of ammonium acetate in 730 ml. of ethanol is heated to reflux for 10 min. The mixture is cooled to 40° C. and concentrated to a yellow solid. Th residue is taken up in 800 ml. of chloroform which is subsequently washed successively with water (1 × 450 ml.), 1N aqueous sodium hydroxide (2 × 450 ml.) and a brine solution (1 × 450 ml.). The chloroform layer is separated, dried over magnesium sulfate and concentrated to a yellow solid, 87.0 g., m.p. 86°-150° C. The crude product is further purified by recrystallization from ethyl acetate-hexane, 43.3 g., m.p. 160°-161° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8]N=C(CC)CC)=[CH:6][CH:5]=[CH:4][N:3]=1>C1(OC2C=CC=CC=2)C=CC=CC=1>[Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:5]([CH3:4])=[C:6]([CH2:7][CH3:2])[NH:8][C:7]=12
Reactant: CCC(CC)=NNc1cccnc1Cl
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCc1[nH]c2c(Cl)nccc2c1C
Temperature: 25 °C
Yield: 143.2 %

Procedure:
A solution of N-(2-chloropyridin-3-yl)-N′-(1-ethylpropylidene)-hydrazine (1.3 g, 6.1 mmol) prepared in Step 2 in diphenyl ether was stirred for 3 hours at 300□. The reaction mixture was cooled to room temperature and then purified with silica gel column chromatography to give 850 mg of the titled compound as a pale yellow solid. (Yield: 72%).
Reaction SMILES: [H-].[Na+].Cl[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][N:5]=1.[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[CH2:14][OH:15].O1CCCC1>CN(C)C=O>[CH2:18]([O:17][C:13]([CH2:14][O:15][C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][N:5]=1)=[O:16])[CH3:19]
Reactant: CCOC(=O)CO
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)COc1ncccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 5 h
Yield: 85.4 %

Procedure:
11 g of sodium hydride was added to a mixture of 39.63 g of 2-chloro-3-nitropyridine, 31.23 g of ethyl glycolate, 250 ml of tetrahydrofuran and 20 ml of N,N-dimethylformamide at 0° C. The mixture was stirred at room temperature for 5 hours, then, the reaction solution was poured into ice water, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 48.3 g of 2-(ethoxycarbonyl)methoxy-3-nitropyridine.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[OH:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][C:13]=1[O:22][CH3:23].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][C:13]=1[O:22][CH3:23])(=[O:10])[CH3:9]
Reactant: COC(=O)c1ccc(O)c(OC)c1
Reactant: CC(=O)c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Oc2ccccc2C(C)=O)c(OC)c1
Temperature: 100 °C
Reaction time: 15 h
Yield: 41.7 %

Procedure:
2′-Fluoroacetophenone (1.38 g) and methyl 4-hydroxy-3-methoxybenzoate (1.82 g) were dissolved in dimethylformamide (10 ml), and potassium carbonate (1.45 g) was added. The mixture was stirred at 100° C. for 15 hrs. The reaction mixture was cooled to room temperature, and water was added. The mixture was extracted with ethyl acetate. The organic layer was washed successively with water and brine and dried over sodium sulfate. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to give the title compound (1.25 g).
Reaction SMILES: OC1C=CC=CC=1N1CCCCC1.C(OC([N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[O:36]CC2C=CC=CC=2)[CH2:26][CH2:25]1)=O)C1C=CC=CC=1>>[OH:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[CH:27]1[CH2:26][CH2:25][NH:24][CH2:29][CH2:28]1
Reactant: O=C(OCc1ccccc1)N1CCC(c2ccccc2OCc2ccccc2)CC1
Agent: Oc1ccccc1N1CCCCC1
Product: Oc1ccccc1C1CCNCC1

Procedure:
4-(2-Hydroxyphenyl piperidine. 1-Benzyloxycarbonyl-4-(2-benzyloxyphenyl)piperidine was subjected to a procedure similar to that described in Example 10 sub-part c. to give 4-(2-hydroxyphenyl)piperidine as a brown solid (0.36 g); NMR (CDCl3): 1.7-1.9 (m,4), 2.77-2.86 (m,2), 2.99-3.04 (m,1), 3.23 (d,2, J=12), 4.17 (s,2), 6.72 (d,1, J=8), 6.84 (t,1, J=7), 7.05 (m,1); MS: m/z=178(M+1). This material was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[C:12]([N:13]=[C:14]([CH3:15])[C:5]2=[C:4]([CH3:17])[N:3]=1)=[CH:11][CH:10]=[C:9]([F:16])[CH:8]=3.[CH3:18][C:19]1(B(O)O)[CH:23]=[C:22]([CH3:24])[O:21][NH:20]1.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>[CH3:18][C:19]1[C:23]([C:2]2[N:6]3[C:7]4[C:12]([N:13]=[C:14]([CH3:15])[C:5]3=[C:4]([CH3:17])[N:3]=2)=[CH:11][CH:10]=[C:9]([F:16])[CH:8]=4)=[C:22]([CH3:24])[O:21][N:20]=1
Reactant: CC1=CC(C)(B(O)O)NO1
Reactant: Cc1nc(Br)n2c1c(C)nc1ccc(F)cc12
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: Cc1noc(C)c1-c1nc(C)c2c(C)nc3ccc(F)cc3n12
Yield: 77.3 %

Procedure:
Following the general Suzuki coupling procedure, reaction of bromide 5A (75 mg, 0.25 mmol), 3,5-dimethylisoxazolboronic acid (178 mg, 1.25 mmol), K2CO3 (105 mg, 0.75 mmol) and Pd(PPh3)4 (5.8 mg, 0.005 mmol) provided the coupling product as a white powder (60 mg, 77% yield). EIMS 311.1 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH3:13])[CH:5]=1.[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>CN(C=O)C>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([CH2:2][CH2:3][C:4]2[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH3:13])[CH:5]=2)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1ccc(CCCl)cc1OC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(CCN2CCN(C(=O)OC(C)(C)C)CC2)cc1OC
Temperature: 80 °C
Reaction time: 3 h
Yield: 76.5 %

Procedure:
A reaction mixture of 4-(2-chloroethyl)-1,2-dimethoxybenzene (3.6 g, 17.9 mmol), piperazine-1-carboxylic acid t-butyl ester (4.0 g, 21.5 mmol), K2CO3 (4.97 g, 36 mmol), and NaI (2.7 g, 18 mmol) in DMF (20 mL) was stirred at 80° C. for 3 h, cooled to room temperature, and partitioned between water and ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography to afford 4-[2-(3,4-dimethoxy-phenyl)-ethyl]-piperazine-1-carboxylic acid t-butyl ester (4.8 g, 76%) which was dissolved in 4 N HCl in dioxane. This solution was stirred at room temperature for 4 h, concentrated, and dried in a high vacuum oven to give the title compound quantitatively.