Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH3:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1([OH:44])[CH2:21][CH:20]([CH2:22]S(C2C=CC(C)=CC=2)(=O)=O)[CH2:19][CH:18]2[CH:14]1[CH2:15][N:16]([C:33](=[O:43])[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[O:41][CH3:42])[CH2:17]2>CN(C)C=O.O>[N:1]([CH2:22][CH:20]1[CH2:19][CH:18]2[CH:14]([CH2:15][N:16]([C:33](=[O:43])[CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[O:41][CH3:42])[CH2:17]2)[C:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][CH3:5])([OH:44])[CH2:21]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccccc1CC(=O)N1CC2CC(CS(=O)(=O)c3ccc(C)cc3)CC(O)(c3ccccc3OC)C2C1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccccc1CC(=O)N1CC2CC(CN=[N+]=[N-])CC(O)(c3ccccc3OC)C2C1
Temperature: 50 °C
Reaction time: 48 h
Yield: 98.6 %

Procedure:
0.35 g of sodium azide is added to a solution of 2.03 g of (3aRS,4RS,6SR,7aSR)-4-(2-methoxyphenyl)-2-[(2-methoxyphenyl)acetyl]-6-tosylmethylperhydroisoindol-4-ol in 10 cm3 of dimethylformamide. The reaction mixture is heated at 50° C. for 8 hours and stirred at 20° C. for 48 hours and then diluted with 150 cm3 of water and subjected to extraction twice with 40 cm3 of ethyl acetate. The organic phase is washed with 50 cm3 of water, dried over magnesium sulphate and then concentrated to dryness under reduced pressure (2.7 kPa). 1.6 g of (3aRS,4RS,6SR,7aSR)-6-azidomethyl-4-(2-methoxyphenyl)-2-[(2-methoxyphenyl)acetyl]perhydroisoindol-4-ol are obtained in the form of a thick white foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:25])[C:7]=1[NH:8][C:9]1[NH:10][C:11]2[C:17]3[CH:18]=[C:19]([CH3:21])[O:20][C:16]=3[C:15]([C:22](O)=[O:23])=[CH:14][C:12]=2[N:13]=1.F[B-](F)(F)F.[N:31]1(OC(N(C)C)=[N+](C)C)[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2N=N1.C1COCC1.C1(N)CCCCC1>CN(C=O)C>[CH:35]1([NH:31][C:22]([C:15]2[C:16]3[O:20][C:19]([CH3:21])=[CH:18][C:17]=3[C:11]3[NH:10][C:9]([NH:8][C:7]4[C:6]([Cl:25])=[CH:5][N:4]=[CH:3][C:2]=4[Cl:1])=[N:13][C:12]=3[CH:14]=2)=[O:23])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:34]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cc1cc2c(o1)c(C(=O)O)cc1nc(Nc3c(Cl)cncc3Cl)[nH]c12
Agent: F[B-](F)(F)F
Solvent: NC1CCCCC1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1cc2c(o1)c(C(=O)NC1CCCCC1)cc1nc(Nc3c(Cl)cncc3Cl)[nH]c12
Yield: 33.1 %

Procedure:
The title compound was prepared following the procedure as described for Example-1 using 2-[(3,5-dichloropyridin-4-yl)amino]-7-methyl-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-8, 0.050 g, 0.132 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (0.085 g, 0.265 mmol), THF (5.0 mL), DMF (1.0 mL) and cyclohexyl amine (0.026 g, 0.265 mmol) to afford 0.020 g of the desired product. 1HNMR (DMSO-d6): δ 1.23 (s, 3H), 1.36 (t, J=9.6 Hz, 3H), 1.71 (m, 2H), 1.88 (m, 2H), 2.50 (s, 3H), 3.84 (m, 1H), 6.62 (s, 1H), 7.31 (m, 1H), 7.75 (d, J=7.8 Hz, 1H), 8.44 (s, 2H), 11.23 (s, 1H), 11.74 (s, 1H); MS [M+H]+: 458.38.
Reaction SMILES: [CH2:1]([C:12]1[N:16]=[C:15]([C:17]2[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=2)[O:14][N:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[O:25]1[C:29]2[CH:30]=[CH:31][C:32]([NH2:34])=[CH:33][C:28]=2[O:27][CH2:26]1>>[O:25]1[C:29]2[CH:30]=[CH:31][C:32]([NH:34][CH2:21][C:20]3[CH:23]=[CH:24][C:17]([C:15]4[O:14][N:13]=[C:12]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[N:16]=4)=[CH:18][CH:19]=3)=[CH:33][C:28]=2[O:27][CH2:26]1
Reactant: Nc1ccc2c(c1)OCO2
Reactant: CCCCCCCCCCCc1noc(-c2ccc(C=O)cc2)n1
Product: CCCCCCCCCCCc1noc(-c2ccc(CNc3ccc4c(c3)OCO4)cc2)n1

Procedure:
The same procedure as employed in the preparation of Example 357 (step a) but using 4-(3-undecyl-1,2,4-oxadiazol-5-yl)benzaldehyde and 1,3-benzodioxol-5-ylamine gave the title compound as an oil. HPLC (Condition A), Rt: 5.15 min (HPLC purity: 97.2%).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:9][C@@H:10]1[CH2:15][NH:14][CH2:13][CH2:12][NH:11]1>>[Cl:8][C:7]1[C:2]([N:14]2[CH2:13][CH2:12][NH:11][C@H:10]([CH3:9])[CH2:15]2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@@H]1CNCCN1
Reactant: Clc1cccnc1Cl
Product: C[C@@H]1CN(c2ncccc2Cl)CCN1

Procedure:
A mixture of 2,3-dichloropyridine (0.74 g, 5 mmol, Aldrich) and (R)-(−)-2-methylpiperazine (0.6 g. 6 mmol, Aldrich) reacted under the conditions of Example 43a to give the title compound as a off-white solid. MS (ESI, pos. ion) m/z: 212 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2.[CH3:11][N:12]1[CH:16]=[C:15]([C:17]2[N:22]=[N:21][C:20]([N:23]3[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]3)=[CH:19][CH:18]=2)[CH:14]=[N:13]1>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:26]1[CH2:27][CH2:28][N:23]([C:20]3[N:21]=[N:22][C:17]([C:15]4[CH:14]=[N:13][N:12]([CH3:11])[CH:16]=4)=[CH:18][CH:19]=3)[CH2:24][CH2:25]1)[CH2:6][CH2:5]2
Reactant: Cn1cc(-c2ccc(N3CCC(=O)CC3)nn2)cn1
Reactant: Fc1ccc2c(c1)CCN2
Product: Cn1cc(-c2ccc(N3CCC(N4CCc5cc(F)ccc54)CC3)nn2)cn1

Procedure:
The title compound was prepared following the procedure as described in Example 5, STEP 4, reacting 5-fluoroindoline and 1-(6-(1-methyl-1H-pyrazol-4-yl)pyridazin-3-yl)piperidin-4-one.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]2([OH:18])[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH3:21]I>O1CCCC1>[Cl:1][C:2]1[C:3]([C:8]2([O:18][CH3:21])[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1(c2ncccc2Cl)CCC2(CC1)OCCO2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1(c2ncccc2Cl)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 5 h
Yield: 94.6 %

Procedure:
To a solution of the product of Example 1A (2.16 g, 8.00 mmol) in tetrahydrofuran (70 mL) was added 60% sodium hydride (0.96 g, 24.0 mmol) in portions, followed by addition of methyl iodide (1.6 mL, 25.6 mmol). The reaction mixture was stirred at ambient temperature for 5 hours, quenched with saturated ammonium chloride (300 mL), extracted with ethyl acetate (300 mL), washed with water (300 mL), brine, dried with anhydrous sodium sulfate, filtered, and concentrated to a yellow oil. The residue was chromatographed on silica gel, eluting with 0-to-30% ethyl acetate in hexanes to provide 2.147 g (94% yield) of the title compound as a colorless oil. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.59 (d, J=12.55 Hz, 2H), 1.80 (td, J=12.88, 3.73 Hz, 2H), 2.04 (td, J=13.57, 3.73 Hz, 2H), 2.23-2.32 (m, 2H), 2.92 (s, 3H), 3.87 (s, 4H), 7.37 (dd, J=7.97, 4.58 Hz, 1H), 7.88 (dd, J=7.97, 1.53 Hz, 1H), 8.51 (dd, J=4.58, 1.53 Hz, 1H). MS (DCI) m/z 284.13 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7](I)[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][CH3:24])[CH:9]=2)=[O:4].[C:26]([Cu])#[N:27].C(Cl)Cl>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([C:26]#[N:27])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][CH3:24])[CH:9]=2)=[O:4]
Reactant: COC(=O)c1nc(I)c2cc(Oc3ccccc3OC)ccc2c1O
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3OC)ccc2c1O
Temperature: 120 °C
Reaction time: 0.17 h

Procedure:
4-Hydroxy-1-iodo-7-(2-methoxy-phenoxy)-isoquinoline-3-carboxylic acid methyl ester (150 mg, 0.33 mmol) and CuCN (60 mg, 0.67 mmol) were suspended in DMF (1.3 mL). The resulting mixture was heated at 120° C. for 7 minutes and then cooled to room temperature. The reaction crude was poured into CH2Cl2 (30 mL) and stirred vigorously for 10 minutes at room temperature. The resulting suspension was filtered through a pad of celite and the filtrate was washed with H2O and brine sequentially. The organic layer was dried over MgSO4, concentrated, and purified by flash chromatography (0-50% EtOAc/hexanes) to give the title compound in 100 mg. MS: (−) m/z 349.28 (M−1).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[CH2:10][CH2:9]2)CCC.Br[C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[C:27]#[N:28]>O1CCOCC1>[O:15]=[C:11]1[C:12]2[C:8](=[CH:7][C:6]([C:25]3[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=3[C:27]#[N:28])=[CH:14][CH:13]=2)[CH2:9][CH2:10]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc2c(c1)CCC2=O
Reactant: N#Cc1ccccc1Br
Solvent: C1COCCO1
Product: N#Cc1ccccc1-c1ccc2c(c1)CCC2=O
Temperature: 25 °C
Yield: 53.6 %

Procedure:
A mixture of 5-tributylstannanyl-indan-1-one (2.25 grams, 5.8 mmol), 2-bromobenzonitrile (1.06 grams, 5.8 mmol) and PdCl2 (PPh3)2 (421 mg, 0.6 mmol) was heated in dioxane (15 mL) for 20 hours. The reaction was cooled to room temperature, concentrated in vacuo and transferred to a SiO2 -gel column. Flash chromatography using a gradient of 25% ethyl acetate/hexanes to 50% ethyl acetate/hexanes yielded 725 mg of a colorless solid. 1H NMR (250 MHz, CDCl3): d 7.9 (d, 1 H), 7.8 (d, 1 H), 7.69 (m, 2 H), 7.54 (m, 3 H), 3.24 (t, 2 H), 2.78 (t, 2 H).
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:5]2[C:6](OC(=O)[NH:10][C:4]=12)=[O:7]>O.CN(C=O)C>[NH2:10][C:4]1[C:3]([Cl:2])=[CH:14][CH:13]=[C:12]([CH3:15])[C:5]=1[C:6]([NH2:1])=[O:7]
Reactant: N
Reactant: Cc1ccc(Cl)c2[nH]c(=O)oc(=O)c12
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(Cl)c(N)c1C(N)=O
Temperature: 87.5 °C

Procedure:
A solution of 59 ml (0.78 mol) of 25% strength ammonia solution in 207 ml of water and a mixture of 135.2 g (0.64 mol) of 3-chloro-6-methylisatoic anhydride in 705 ml of DMF were added simultaneously to 150 ml of water via 2 dropping funnels in the course of 30 min with stirring at 85 to 90° C., strong evolution of gas occurring. The mixture was stirred at 90° C. for 2 h and at 22° C. for 10 h. The reaction solution was concentrated in vacuo, and the residue was stirred with methyl tert-butyl ether, filtered off with suction and dried. 67.4 g (57% of theory) of the title compound were obtained as a yellowish powder of m.p. 124-128° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][CH:21]=[CH:20][C:4]=1[C:5]([NH:7][S:8]([C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][CH:12]=1)(=[O:10])=[O:9])=[O:6].[CH2:24]([NH:26][CH2:27][CH3:28])[CH3:25].C(N(CC)CC)C>C(#N)C.O>[CH2:24]([N:26]([CH2:27][CH3:28])[C:15](=[O:16])[C:14]1[CH:18]=[CH:19][C:11]([S:8]([NH:7][C:5](=[O:6])[C:4]2[CH:20]=[CH:21][CH:22]=[CH:23][C:3]=2[O:2][CH3:1])(=[O:10])=[O:9])=[CH:12][CH:13]=1)[CH3:25]
Reactant: CCNCC
Reactant: COc1ccccc1C(=O)NS(=O)(=O)c1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: CCN(CC)C(=O)c1ccc(S(=O)(=O)NC(=O)c2ccccc2OC)cc1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
To a suspension of 4-[[(2-methoxybenzoyl)amino]sulfonyl)benzoyl chloride (1 mol) and diethylamine (1 mol) in acetonitrile (1000 ml), was added triethylamine (1 mol) at 10° C. The mixture was stirred for 2 hours at 20° C. and diluted with water (500 ml). The white precipitate was filtered off, washed and dried to give the title compound. The yield of product obtained was 98% of theory, and the purity 98%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[C:5]([F:9])=[CH:4][C:3]=1[OH:10].C1C[O:14][CH2:13]C1.C1N=CN(C(N2C=NC=C2)=O)C=1>CCOC(C)=O>[Br:8][C:6]1[C:5]([F:9])=[CH:4][C:3]2[O:10][C:13](=[O:14])[NH:1][C:2]=2[CH:7]=1
Reactant: Nc1cc(Br)c(F)cc1O
Reactant: C1CCOC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Product: O=c1[nH]c2cc(Br)c(F)cc2o1
Temperature: 60 °C

Procedure:
A flask was charged with 2-amino-4-bromo-5-fluorophenol (3.3 g, 18.84 mmol) and THF (200 mL), and CDI (3.05 g, 18.84 mmol) was added. The mixture was heated to 60° C. for 2 h. The mixture was diluted with EtOAc and washed with 1N HCl in water. The organic phase was dried over Na2SO4 and concentrated to give 5-bromo-6-fluorobenzo[d]oxazol-2(3H)-one. 1H NMR (400 MHz, DMSO-d6) δppm 7.38 (d, J=6.06 Hz, 1H) 7.56 (d, J=8.34 Hz, 1H) 11.88 (br. s., 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[CH3:9][C:10]1[C:15](B2OC(C)(C)C(C)(C)O2)=[CH:14][CH:13]=[CH:12][N:11]=1.C([O-])(=O)C.[K+].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.C(#N)C>[Cl:8][C:6]1[CH:7]=[C:2]([C:15]2[C:10]([CH3:9])=[N:11][CH:12]=[CH:13][CH:14]=2)[N:3]=[CH:4][N:5]=1
Reactant: Cc1ncccc1B1OC(C)(C)C(C)(C)O1
Reactant: Clc1cc(Cl)ncn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: Cc1ncccc1-c1cc(Cl)ncn1
Yield: 24 %

Procedure:
First, 3.01 g of 4,6-dichloropyrimidine, 10.9 g of 2-methylpyridine-3-boronic acid pinacol ester, 60 mL of 1M aqueous solution of potassium acetate, 60 mL of 1M aqueous solution of sodium carbonate, and 60 mL of acetonitrile were put in a 300 mL three-neck flask, and the air in the flask was replaced with argon. To this mixture, 1.40 g of tetrakis(triphenylphosphine)palladium(0) was added, and the mixture was irradiated with microwaves under conditions of 70° C. and 400 W and for 2 hours to cause a reaction. This reaction mixture was extracted with ethyl acetate, and washing with saturated brine was performed. Anhydrous magnesium sulfate was added to the obtained solution of the extract for drying, and the resulting mixture was gravity-filtered to give a filtrate. A residue obtained by condensing the filtrate was purified by flash column chromatography using ethyl acetate as a developing solvent. A solid obtained by condensing the fraction was purified by flash column chromatography using hexane and ethyl acetate in a ratio of 1:1 as a developing solvent, so that 4-chloro-6-(2-methylpyridin-3-yl)pyrimidine was obtained (a yellow white solid, yield of 24%). A synthetic scheme of Step 1 is shown in (c-1) below.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]([Si](C)(C)C)[Si](C)(C)C)=[CH:4][CH:3]=1.[Li]CCCC.[O:22]=[C:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]1>O1CCCC1>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:23]2([OH:22])[CH2:24][CH2:25][N:26]([C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])[CH2:27][CH2:28]2)=[CH:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: C[Si](C)(C)N(c1ccc(Br)cc1)[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(N)cc2)CC1
Temperature: -78 °C

Procedure:
N-(4-Bromophenyl)-1,1,1-trimethyl-N-(trimethylsilyl)silanamine (7 g, 22.12 mmol) in tetrahydrofuran (100 mL) was treated with a solution of n-BuLi (1M, 22 mL) at −78° C. The reaction mixture was stirred an additional hour at −78° C. and then treated with a solution of tert-butyl 4-oxopiperidine-1-carboxylate (3.97 g, 19.91 mmol) in tetrahydrofuran (20 mL). The reaction mixture was stirred at −78° C. for 30 minutes and then warmed to room temperature. The reaction was quenched by addition of saturated ammonium chloride solution (100 mL) and then was extracted with ethyl acetate. The combined organics were washed with water, brine, dried with magnesium sulfate, filtered and concentrated. The crude tert-butyl 4-(4-(bis(trimethylsilyl)amino)phenyl)-4-hydroxypiperidine-1-carboxylate was treated with a solution of tetrabutylammonium fluoride (1M THF, 40 mL) at room temperature for 1 hour. The reaction mixture was diluted with water and extracted with ethyl acetate. The organics were washed with water and brine, dried with magnesium sulfate, filtered and concentrated. Purification by normal phase chromatography provided the title compound.
Reaction SMILES: N1C=CC=CC=1.[C:7]([C:10]1[CH:11]=[N:12][C:13]([OH:16])=[CH:14][CH:15]=1)(=O)[CH3:8].Cl.[NH2:18][O:19][CH2:20][CH2:21][O:22][C:23]1[CH:36]=[CH:35][C:26]([CH2:27][CH:28]2[S:32][C:31](=[O:33])[NH:30][C:29]2=[O:34])=[CH:25][CH:24]=1>C(O)C>[OH:16][C:13]1[CH:14]=[CH:15][C:10]([C:7](=[N:18][O:19][CH2:20][CH2:21][O:22][C:23]2[CH:24]=[CH:25][C:26]([CH2:27][CH:28]3[S:32][C:31](=[O:33])[NH:30][C:29]3=[O:34])=[CH:35][CH:36]=2)[CH3:8])=[CH:11][N:12]=1
Reactant: NOCCOc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: CC(=O)c1ccc(O)nc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CC(=NOCCOc1ccc(CC2SC(=O)NC2=O)cc1)c1ccc(O)nc1
Temperature: 25 °C
Yield: 62.6 %

Procedure:
124 μl of pyridine were added at room temperature to a suspension of 100 mg of 3-acetyl-6-hydroxypyridine and 232 mg of 5-[4-(2-aminooxyethoxy)benzyl]thiazolidine-2,4-dione hydrochloride [prepared as described in step (e) above] in 10 ml of ethanol, and the resulting mixture was stirred and heated under reflux for 1 hour. At the end of this time, the reaction mixture was cooled to room temperature and the precipitate was collected by filtration to give 183 mg of the title compound as a crystalline powder, melting at 240°-242° C.
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH2:13].C(Br)(Br)(Br)[Br:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH2:1]([Br:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH2:13]
Reactant: C=CCCCCCCCCCCCO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C=CCCCCCCCCCCCBr
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 12-tridecen-1-ol (2.11 g, 10.7 mmol) and carbon tetrabromide (4.37 g, 13.1 mmol) in dichloromethane (15 mL) at 0° C. was added triphenyl phosphine (3.45 g, 13.1 mmol) in portions over 5 minutes. After stirring for 1.5 hours at 25° C. the solvent was evaporated and the residue extracted with hexane (3×30 mL), filtering off any solids. The solvent was evaporated to afford 12-tridecenyl bromide as a clear oil which was used without further purification.
Reaction SMILES: C([O:3][C:4](=[O:25])[C:5]([CH2:17][C:18]1[CH:23]=[CH:22][C:21](O)=[CH:20][CH:19]=1)([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:6][CH2:7][CH2:8][CH3:9])C.[CH3:26][C:27]1[O:31][C:30]([C:32]2[CH:37]=[CH:36][C:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[CH:34][CH:33]=2)=[N:29][C:28]=1[CH2:44][CH2:45][O:46]S(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[K+].[K+].[OH-].[Na+]>C(O)C>[C:35]1([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:36]=[CH:37][C:32]([C:30]2[O:31][C:27]([CH3:26])=[C:28]([CH2:44][CH2:45][O:46][C:21]3[CH:22]=[CH:23][C:18]([CH2:17][C:5]([O:10][C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)([CH2:6][CH2:7][CH2:8][CH3:9])[C:4]([OH:25])=[O:3])=[CH:19][CH:20]=3)[N:29]=2)=[CH:33][CH:34]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)cc1
Reactant: CCCCC(Cc1ccc(O)cc1)(Oc1ccccc1)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Product: CCCCC(Cc1ccc(OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)cc1)(Oc1ccccc1)C(=O)O

Procedure:
A mixture of 2-(4-hydroxybenzyl)-2-phenoxyhexanoic acid ethyl ester (0.030 mmol), toluene-4-sulfonic acid 2-(5-methyl-2-biphenyl-4-yl-oxazol-4-yl)ethyl ester (0.030 mmol) (see Ex. 1, Part I) and 325 mesh K2CO3 (0.084 g, 0.60 mmol) in ethanol (2 mL) was heated to reflux for 24 h under N2. Aqueous 5N NaOH (0.5 mL) and additional ethanol (1 mL) was added to the reaction mixture and it was heated at reflux for an additional 2 h. The reaction was cooled and the solvent removed in vacuo. The residue was acidified with aqueous 1 N HCl (5 mL), extracted with water and CH2Cl2 and the organic layer dried by passing it through a Varian Chem Elut 1003 cartridge. The solvent was removed in vacuo to give 2-{4-[2-(2-biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-benzyl}-2-phenoxy-hexanoic acid. 1H NMR (400 MHz, CDCl3) δ 8.02 (d, 2H, J=8.60 Hz), 7.65–7.61 (m, 4H), 7.46 (t, 2H, J=7.62 Hz), 7.38–7.26 (m, 3H), 7.07–6.96 (m, 5H), 6.76 (d, 2H, J=8.60 Hz), 4.18 (t, 2H, J=6.65 Hz), 3.29 (s, 2H), 2.97 (t, 2H, J=6.65 Hz), 2.38 (s, 3H), 2.08–1.98 (m, 2H), 1.42–1.18 (m, 4H), 0.79 (t, 3H, J=7.04 Hz); MS (ES+) calcd for C37H38NO5: Found m/e 576.3 (M+1, 100%).
Reaction SMILES: C([NH:8][C:9]1[CH:10]=[C:11]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:12][C:13]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14]1)C1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[NH2:8][C:9]1[CH:10]=[C:11]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:12][C:13]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15]1
Reactant: CC(C)(C)OC(=O)C1(Cc2ccc(Cl)c(NCc3ccccc3)c2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C1(Cc2ccc(Cl)c(N)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
50.0 g (134.4 mmol) of tert-butyl 1-[3-(benzylamino)-4-chlorobenzyl]cyclopropanecarboxylate were dissolved in 1.5 liters of ethyl acetate, and 1.43 g (1.34 mmol) of palladium (10% on carbon) were added. The reaction mixture was stirred at RT overnight under a hydrogen atmosphere at atmospheric pressure. The reaction mixture was then filtered off with suction through kieselguhr and the filtrate was concentrated. The crude product was purified by chromatography on silica gel (mobile phase petroleum ether/ethyl acetate 10:1). The product obtained was triturated using a methanol/water mixture (70:30) and the solid was isolated. This gave 24.3 g (64.1% of theory) of the target compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:30])[CH2:9][NH:10][C:11]2[CH:16]=[CH:15][NH:14][C:13](=[O:17])[C:12]=2[C:18]2[NH:19][C:20]3[CH:26]=[C:25]([C:27]#N)[CH:24]=[C:23]([CH3:29])[C:21]=3[N:22]=2)[CH:5]=[CH:6][CH:7]=1.C([Al]CC(C)C)C(C)C.C(OCC)(=[O:42])C.O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:30])[CH2:9][NH:10][C:11]2[CH:16]=[CH:15][NH:14][C:13](=[O:17])[C:12]=2[C:18]2[NH:19][C:20]3[CH:26]=[C:25]([CH:27]=[O:42])[CH:24]=[C:23]([CH3:29])[C:21]=3[N:22]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(C)=O
Reactant: Cc1cc(C#N)cc2[nH]c(-c3c(NCC(O)c4cccc(Cl)c4)cc[nH]c3=O)nc12
Agent: CC(C)C[Al]CC(C)C
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(C=O)cc2[nH]c(-c3c(NCC(O)c4cccc(Cl)c4)cc[nH]c3=O)nc12
Temperature: -78 °C
Reaction time: 6 h
Yield: 2.5 %

Procedure:
To a suspension of (±)-2-{4-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-7-methyl-3H-benzimidazole-5-carbonitrile (76 mg, 0.18 mmol) in toluene (anhydrous, 20 mL) was added diisobutylaluminium (1.4 M toluene solution) (0.65 mL, 0.97 mmol) at −78° C. under nitrogen. The mixture was stirred at −78° C. for 6 h. Ethyl acetate (1 mL) was then added followed by water (0.5 mL). The mixture was stirred at room temperature for 20 min. The mixture was then passed through a pad of celite and the filtrate was concentrated. The crude product was purified by prep. HPLC to yield the title compound (4 mg, 2.5%) as a brown solid. 1H NMR (300 MHz, CD3OD) δ 7.65 (1H, s), 7.57 (1H, s), 7.24–7.50 (5H, m), 6.26 (1H, d, J=7.6 Hz), 5.49 (1H, s), 4.96 (1H, m), 3.53–3.79 (2H, m), 2.62 (3H, s). LCMS (M+H)+ m/z 423 (t=1.79 min.).
Reaction SMILES: [Br:1][CH2:2][C:3]1[N:7]2[C:8]3[C:13]([NH:14][C:15](=[O:16])[C:6]2=[N:5][C:4]=1[C:21]([O:23]CC)=[O:22])=[CH:12][C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][CH:9]=3>Br>[Br:1][CH2:2][C:3]1[N:7]2[C:8]3[C:13]([NH:14][C:15](=[O:16])[C:6]2=[N:5][C:4]=1[C:21]([OH:23])=[O:22])=[CH:12][C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][CH:9]=3
Reactant: CCOC(=O)c1nc2c(=O)[nH]c3cc(C(F)(F)F)ccc3n2c1CBr
Agent: Br
Product: O=C(O)c1nc2c(=O)[nH]c3cc(C(F)(F)F)ccc3n2c1CBr
Temperature: 80 °C
Reaction time: 16 h
Yield: 72.6 %

Procedure:
A suspension of 1-bromomethyl-2-ethoxycarbonyl-7-trifluoromethylimidazo[1,2-a]quinoxalin-4-(5H)-one (Example 3) (500 mg, 1.2 mmol) in hydrobromic acid (48% in water) (25 ml) was stirred at 80° C. for 16 h. The mixture was concentrated in vacuo, and the residue stirred with water to give 340 mg (73%) of the title compound, which was isolated by filtration. M.p. >250° C.