Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][N:12]=1>>[C:1]1([C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Brc1ccc(Br)nc1
Reactant: OB(O)c1ccccc1
Product: Brc1ccc(-c2ccccc2)nc1
Yield: 86 %

Procedure:
To explain the synthesis in more detail, the Suzuki reaction between phenylboronic acid and 2,5-dibromopyridine gave 2-phenyl-5-bromopyridine in an 86% yield (see scheme 1 above). The reaction occurred preferentially on the 2 position on the pyridine ring, which is activated by the adjacent nitrogen. Reaction of 2-phenyl-5-bromopyridine with trimethylsilylacetylene under Sonogashira conditions gave the 2-phenyl-5-(trimethylsilylethynyl)pyridine (2) in an 88% yield, which could be deprotected to 2-phenyl-5-ethynylpyridine (3) in a yield of 93% using tetra-n-butylammonium hydroxide. The Diels-Alder reaction between (3) and the difluorenylcyclopentadienone (10) gave the dendronised ligand in a 48% yield, after purification by precipitation of the ligand from a dichloromethane solution by pouring the solution into ethanol. The complex was formed by the two-step procedure via the bis(chloro)-bis(iridium) dimer in a yield of 50%. This yield is no lower than those obtained from the complexation of ligands dendronised only on the phenyl ring, showing that the presence of the bulky dendron on the pyridine ring does not inhibit complexation.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6]([C@:9]23[CH2:14][C@H:13]2[CH2:12][NH:11][CH2:10]3)=[CH:5][CH:4]=1.CC(C)[O-].[CH3:21][C:22]1[S:23][C:24]([C:28]2[C:29](=[O:39])[NH:30][C:31](=[O:38])[N:32]([CH2:34][CH2:35][CH:36]=O)[CH:33]=2)=[C:25]([CH3:27])[N:26]=1>C(#N)C>[CH3:21][C:22]1[S:23][C:24]([C:28]2[C:29](=[O:39])[NH:30][C:31](=[O:38])[N:32]([CH2:34][CH2:35][CH2:36][N:11]3[CH2:12][C@H:13]4[C@:9]([C:6]5[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:15])[F:16])=[CH:8][CH:7]=5)([CH2:14]4)[CH2:10]3)[CH:33]=2)=[C:25]([CH3:27])[N:26]=1
Reactant: FC(F)(F)c1ccc([C@@]23CNC[C@@H]2C3)cc1
Reactant: Cc1nc(C)c(-c2cn(CCC=O)c(=O)[nH]c2=O)s1
Agent: CC(C)[O-]
Solvent: CC#N
Product: Cc1nc(C)c(-c2cn(CCCN3C[C@@H]4C[C@]4(c4ccc(C(F)(F)F)cc4)C3)c(=O)[nH]c2=O)s1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 41.3 %

Procedure:
To a solution of (1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane (269 mg, 1.186 mmol) in acetonitrile (4 mL), Titanuim (IV) isopropoxide (0.434 mL, 1.482 mmol) and a solution of 3-[5-(2,4-dimethyl-1,3-thiazol-5-yl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]propanal (Prep36, 276 mg, 0.988 mmol) in acetonitrile (6 mL) were added and the mixture was stirred at rt for 20 minutes. Afterwards, it was cooled to 0° C. and Sodiumtriacetoxyboronhydride (314 mg, 1.482 mmol) was added. The mixture was stirred at rt for 1.5 h, then quenched with water. Acetonitrile was eliminated under reduced pressure and the aqueous residue was extracted with DCM. Organic phase was washed with NaHCO3 saturated solution, dried and concentrated under vacuum. Crude product was purified by flash chromatography (eluent: DCM/MeOH/NH3 97:3:0.1) affording the title compound (E37, 200 mg, 0.408 mmol) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[C:19]([O:24][CH3:25])[CH:18]=3)[C:15]([S:26][CH2:27][C:28]3[C:36]([F:37])=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][C:29]=3[F:38])=[N:14][CH:13]=2)([CH3:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[CH3:40][O:41][C:42](=[O:46])[CH2:43][CH2:44][NH2:45].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[C:19]([O:24][CH3:25])[CH:18]=3)[C:15]([S:26][CH2:27][C:28]3[C:36]([F:37])=[CH:35][C:31]([C:32]([NH:45][CH2:44][CH2:43][C:42]([O:41][CH3:40])=[O:46])=[O:33])=[CH:30][C:29]=3[F:38])=[N:14][CH:13]=2)([CH3:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)CCN
Reactant: COc1cc(-n2c(C(C)(C)c3ccc(Cl)c(Cl)c3)cnc2SCc2c(F)cc(C(=O)O)cc2F)ccc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCNC(=O)c1cc(F)c(CSc2ncc(C(C)(C)c3ccc(Cl)c(Cl)c3)n2-c2ccc(F)c(OC)c2)c(F)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4-((5-(2-(3,4-dichlorophenyl)propan-2-yl)-1-(4-fluoro-3-methoxyphenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorobenzoic acid (0.85 mmol from previous step) and β-alanine methyl ester hydrochloride (139 mg, 1.0 mmol) in DCM (10 mL) was treated with Et3N (0.36 mL, 2.6 mmol) and HATU (390 mg, 1.0 mmol) at ambient temperature. After stirring for 16 h at ambient temperature the reaction mixture was quenched by the addition of H2O, 1N HCl, and DCM. The aqueous layer was extracted with DCM. The combined extracts were washed with satd NaHCO3, dried over Na2SO4 and concentrated under reduced pressure to afford crude product. This material was purified by flash chromatography (silica gel, EtOAc/Hex, 0:100 to 100:0) to give methyl 3-(4-((5-(2-(3,4-dichlorophenyl)propan-2-yl)-1-(4-fluoro-3-methoxyphenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorobenzamido)propanoate as a clear syrup, that was carried on to the next step directly. 1H NMR (400 MHz, CDCl3) δ 7.31-7.23 (m, 2H), 7.19 (s, 1H), 7.09 (d, J=2.2 Hz, 1H), 6.99 (t, J=5.5 Hz, 1H), 6.88 (ddd, J=10.7, 9.6, 5.4 Hz, 2H), 6.26 (ddd, J=8.5, 3.8, 2.5 Hz, 1H), 5.91 (dd, J=7.5, 2.4 Hz, 1H), 4.16-4.08 (m, 2H), 3.76-3.66 (m, 5H), 3.50 (s, 3H), 2.66 (t, J=5.9 Hz, 2H), 1.89 (s, 1H), 1.54 (s, 3H), 1.47 (s, 3H); MS (EI) m/z 666 (MH+).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]([N:16]3[CH2:21][CH2:20][C@@:19]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)([CH2:22][CH2:23][CH2:24][OH:25])[O:18][C:17]3=[O:33])[CH3:15])=[CH:10][CH:9]=2)[CH:3]=1.[OH-:34].[Na+]>>[F:32][C:29]1[CH:30]=[CH:31][C:26]([C@:19]2([CH2:22][CH2:23][CH2:24][OH:25])[O:18][C:17](=[O:33])[N:16]([C@H:14]([C:11]3[CH:12]=[CH:13][C:8]([C:4]4[N:5]=[CH:6][NH:7][C:2](=[O:34])[CH:3]=4)=[CH:9][CH:10]=3)[CH3:15])[CH2:21][CH2:20]2)=[CH:27][CH:28]=1
Reactant: [OH-]
Reactant: C[C@@H](c1ccc(-c2cc(Cl)ncn2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Agent: [Na+]
Product: C[C@@H](c1ccc(-c2cc(=O)[nH]cn2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Temperature: 110 °C
Yield: 78 %

Procedure:
A mixture of (R)-3-((S)-1-(4-(6-chloropyrimidin-4-yl)phenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one (20 mg, 0.0426 mmol) in 15% aq NaOH (5 mL) was heated to 110° C. overnight. Then the solvent was evaporated, and the residue was washed with EtOAc. The solid was filted off and the filtrate was dried, and condensed in vacuum to give the crude product, which was purified by preparative HPLC to afford (R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(6-oxo-1,6-dihydropyrimidin-4-yl)phenyl)ethyl)-1,3-oxazinan-2-one (15 mg, 78%). LC-MS Method 2 tR=0.91 min, m/z=452, 408. 1H NMR (CD3OD): δ=1.31 (m, 1H), 1.59 (m, 3H), 1.95 (m, 2H), 2.25 (m, 1H), 2.35 (m, 1H), 2.46 (m, 1H), 3.15 (m, 1H), 3.48 (m, 2H), 5.59 (m, 1H), 6.81 (s, 1H), 7.12 (m, 4H), 7.33 (m, 2H), 7.79 (m, 2H), 8.25 (s, 1H).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].IC.[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:20]=1[O:21][CH3:22])[CH:17]=[N:16][CH:15]=[C:14]2[CH2:23][C:24]1[NH:32][C:31]2[C:30](=[O:33])[N:29]([CH3:34])[C:28](=[O:35])[N:27]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:26]=2[N:25]=1>CN(C=O)C>[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:20]=1[O:21][CH3:22])[CH:17]=[N:16][CH:15]=[C:14]2[CH2:23][C:24]1[N:32]([CH3:1])[C:31]2[C:30](=[O:33])[N:29]([CH3:34])[C:28](=[O:35])[N:27]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:26]=2[N:25]=1
Reactant: COc1cc2cncc(Cc3nc4c([nH]3)c(=O)n(C)c(=O)n4CC(C)C)c2cc1OC
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cc2cncc(Cc3nc4c(c(=O)n(C)c(=O)n4CC(C)C)n3C)c2cc1OC
Reaction time: 8 h

Procedure:
Potassium carbonate (48 mg, 0.35 mmol) and iodomethane (0.018 ml,0.295 mmol) are added to a solution of the product of Example 10, 8-(6,7-dimethoxy-isoquinolin-4-ylmethyl)-3-isobutyl-1-methyl-3,7-dihydro-purine-2,6-dione (0.100 g, 0.24 mmol) in DMF (2 ml). The reaction is stirred overnight and purified by preparative HPLC to afford 8-(6,7-dimethoxy-isoquinolin-4-ylmethyl)-3-isobutyl-1,7-dimethyl-3,7-dihydro-purine-2,6-dione, [MH]+ 438.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[S:15][C:14](=[S:16])[NH:13][N:12]=1.[OH-].[Na+].I[CH3:20]>CO>[CH3:20][S:16][C:14]1[S:15][C:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[N:12][N:13]=1
Reactant: CI
Reactant: S=c1[nH]nc(-c2ccc3ccccc3c2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CSc1nnc(-c2ccc3ccccc3c2)s1
Reaction time: 2 h

Procedure:
To a solution of 5-naphthalen-2-yl-3H-[1,3,4]thiadiazole-2-thione (2.8 g, 11.5 mmol) in methanol (100 ml) was added dropwise 1 N sodium hydroxide (12 ml, 12 mmol) at 0° C. After stirred for 10 min. at 0° C. iodomethane (2.0 g, 13.8 mmol) was added dropwise and stirring was continued at 0° C. for 5 min. and at room temperature for 2 h. The volatiles were evaporated in vacuo and to the residue was added water (100 ml). The precipitate was filtered off and dried in vacuo at 50° C. The dried compound (2.4 g) was recrystallised from ethyl acetate (60 ml) affording after drying in vacuo at 50° C. 0.7 g (23%) of the title compound as a solid.
Reaction SMILES: [C-:1]#[N:2].[K+].O.[CH2:5]([N:12]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:14][CH:13]1[CH2:25]Cl)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(O)C>[CH2:5]([N:12]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:14][CH:13]1[CH2:25][C:1]#[N:2])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: [C-]#N
Reactant: ClCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N#CCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Yield: 80 %

Procedure:
A mixture of 4.57 g (70.2 mmol) of potassium cyanide and 10 ml of water is heated to reflux. When the potassium cyanide has dissolved, 17 g (54 mmol) of the chloride obtained in Step b dissolved in 10 ml of ethanol are added slowly. When the addition is complete, the mixture is heated under reflux for 3 hours. After evaporation of the solvent, the mixture is taken up in chloroform and washed with water until the pH is neutral. The chloroform phase is dried over magnesium sulfate, filtered and evaporated off. The resulting residue is crystallised from hexane and yields 13.2 g of white crystals.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:23]=[CH:22]4)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl[CH2:36][C:37]1[O:38][CH:39]=[CH:40][N:41]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[O:38]1[CH:39]=[CH:40][N:41]=[C:37]1[CH2:36][O:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:23]=[CH:22]4)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: ClCc1ncco1
Reactant: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(O)c4)nc4ccccc34)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(OCc5ncco5)c4)nc4ccccc34)ccc21
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A suspension of tert-butyl 5-(2-(3-hydroxyphenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (100 mg, 0.22 mmol), 2-(chloromethyl)oxazole (31 mg, 0.26 mmol), KI (44 mg, 0.27 mmol), and K2CO3 (122 mg, 0.88 mmol) in dry DMF (1.5 mL) was stirred at 70° C. for 1 h. The mixture was poured into water, filtered, dried under high vacuum for several hours to afford tert-butyl 5-(2-(3-(oxazol-2-ylmethoxy)phenyl)-quinazolin-4-ylamino)-1H-indazole-1-carboxylate.
Reaction SMILES: Br[CH2:2][C:3]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:4]=1[O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1.[NH:21]1[CH:25]=[CH:24][N:23]=[CH:22]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[Cl:20][C:18]1[CH:17]=[CH:16][C:4]([O:5][C:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8][CH:7]=2)=[C:3]([CH:19]=1)[CH2:2][N:21]1[CH:25]=[CH:24][N:23]=[CH:22]1
Reactant: c1c[nH]cn1
Reactant: Clc1ccc(Oc2cccc3ccccc23)c(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Clc1ccc(Oc2cccc3ccccc23)c(Cn2ccnc2)c1
Yield: 70.1 %

Procedure:
1-(2-Bromomethyl-4-chlorophenoxy)naphthalene (400 mg) from Example 3 was dissolved in acetonitrile (20 ml), followed by addition of imidazole (235 mg) and cesium carbonate (1.1 g) under reflux for 10 minutes. After leaving the solution to stand at room temperature, the solvent was removed under reduced pressure. The residue was purified by chromatography on a silica gel column (methylene chloride:methanol=99:1) to give the title compound (270 mg; 70%). The purity of the compound was determined by HPLC, which was of 99.9%.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]([CH3:17])[CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]2[N+:14]([O-])=O)=[CH:4][CH:3]=1>CO.O.[Ni]>[F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]([CH3:17])[CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]2[NH2:14])=[CH:4][CH:3]=1
Reactant: CN(Cc1ccc(F)cc1)C1CCCCC1[N+](=O)[O-]
Agent: [Ni]
Solvent: O
Solvent: CO
Product: CN(Cc1ccc(F)cc1)C1CCCCC1N
Reaction time: 16 h
Yield: 8.5 %

Procedure:
To crude (4-fluoro-benzyl)-methyl-(2-nitro-cyclohexyl)-amine (1.0 mMol) in (5:1) MeOH/H2O (30 mL) was added Raney-Nickel. The reaction mixture was placed under H2 (1 atm) and stirred for 16 h. The slurry was filtered through Celite and the volatiles removed in vacuo to yield N-(4-Fluoro-benzyl)-N-methyl-cyclohexane-1,2-diamine (20 mg).
Reaction SMILES: [CH3:1][N:2]([C:17]([O:19][C@@H:20]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])=[O:18])[CH2:3][CH2:4][C:5]([O:7]CC(C1C=CC=CC=1)=O)=[O:6]>C(O)(=O)C.[Zn]>[CH3:1][N:2]([C:17]([O:19][C@@H:20]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])=[O:18])[CH2:3][CH2:4][C:5]([OH:7])=[O:6]
Reactant: CN(CCC(=O)OCC(=O)c1ccccc1)C(=O)O[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Agent: [Zn]
Solvent: CC(=O)O
Product: CN(CCC(=O)O)C(=O)O[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 70.9 %

Procedure:
To a solution of benzyl 2(S)-[N-methyl-N-(2-phenacyloxycarbonylethyl)aminocarbonyloxy]-3-phenylpropionate (1.0 g) in acetic acid (10 ml) was added zinc dust (1.0 g) portionwise at ambient temperature. After being stirred for 2 hours, zinc dust (0.2 g) was added thereto. The reaction mixture was stirred overnight at the same temperature and filtered, and the filtrate was evaporated in vacuo. The residue was dissolved in ethyl acetate (30 ml) and 0.5 N hydrochloric acid (30 ml). The organic layer was extracted with 1 N sodium hydroxide solution (20 ml×3). The combined aqueous extract was acidified to pH 2 with 1 N hydrochloric acid and extracted with chloroform (50 ml×3). The extract was washed with brine and dried over magnesium sulfate. Evaporation of the solvent gave benzyl 2(S)-[N-methyl-N-(2-carboxyethyl)aminocarbonyloxy]-3-phenylpropionate (543 mg) as an oil.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH:11]=O)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[N+:13]([CH3:16])([O-:15])=[O:14].C([O-])(=O)C.[NH4+].O>C(O)(=O)C>[N+:13]([CH:16]=[CH:11][C:9]1[CH:8]=[CH:7][C:6]2[O:1][CH2:2][CH2:3][O:4][C:5]=2[CH:10]=1)([O-:15])=[O:14]
Reactant: O=Cc1ccc2c(c1)OCCO2
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])C=Cc1ccc2c(c1)OCCO2
Temperature: 110 °C
Yield: 61 %

Procedure:
To 1,4-benzodioxane-6-carboxaldehyde (10.0 g, 60 mmol) in acetic acid (50 mL) was added nitromethane (6.3 mL, 1.9 eq.) and ammonium acetate (5.1 g, 1.1 eq.). After heating at 110° C. for 4 hours the mixture was cooled to ambient temperature, water (150 mL) was added, and the solid precipitate was collected by filtration. The solid was crystallized from methylene chloride-hexane (1:1, 45 mL) to obtain 7.6 g (61%) of 6-(2-nitroethenyl)-1,4-benzodioxane. To a portion of the solid (3.58 g) dissolved in MeOH-EtOH-AcOEt (1:1:1, 450 mL) was added 10% Pd/C (1.7 g) and concentrated HCl (3.3 mL, 2.3 eq). After shaking on a Parr hydrogenator at 45 psi for 5 hours, the catalyst was removed by filtration through Celite and washed with methanol. Evaporation of the filtrate gave 3.59 g (96%) of 1,4-benzodioxan-6-ethanamine, hydrochloride.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=O)=[CH:3][CH:2]=1.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][C:20]#[N:21]>>[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1/[C:19](=[CH:11]/[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=[CH:2][CH:3]=1)/[C:20]#[N:21]
Reactant: O=Cc1ccnc2ccccc12
Reactant: N#CCc1ccccn1
Product: N#C/C(=C\c1ccnc2ccccc12)c1ccccn1
Yield: 53.7 %

Procedure:
4-Quinolinecarboxaldehyde (157 mg) was condensed with 2-pyridineacetonitrile (118 mg) through Method B (production step 3), to thereby yield the target product (yield: 138 mg, 54%).
Reaction SMILES: [CH3:1][N:2]([S:22]([C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)(=[O:24])=[O:23])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][C:14]([CH2:17][CH2:18][C:19](O)=[O:20])=[CH:15][N:16]=1)=[CH:8]2.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:42][S:43]([NH2:46])(=[O:45])=[O:44].C1CCN2C(=NCCC2)CC1>O1CCCC1>[CH3:42][S:43]([NH:46][C:19](=[O:20])[CH2:18][CH2:17][C:14]1[S:13][C:12]([C:9]2[NH:10][C:11]3[C:7]([CH:8]=2)=[CH:6][CH:5]=[CH:4][C:3]=3[N:2]([CH3:1])[S:22]([C:25]2[S:26][CH:27]=[CH:28][CH:29]=2)(=[O:23])=[O:24])=[N:16][CH:15]=1)(=[O:45])=[O:44]
Reactant: CS(N)(=O)=O
Reactant: CN(c1cccc2cc(-c3ncc(CCC(=O)O)s3)[nH]c12)S(=O)(=O)c1cccs1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CN(c1cccc2cc(-c3ncc(CCC(=O)NS(C)(=O)=O)s3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
A mixture of 3-(2-{7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-1,3-thiazol-5-yl)propanoic acid (0.3.0 g), 1,1′-carbonylbis-1H-imidazole (0.27 g) and tetrahydrofuran (10 mL) was heated under reflux for 2 hr. The reaction mixture was cooled to room temperature, methanesulfonamide (0.32 g) and 1,8-diazabicyclo[5.4.0]-7-undecene (0.50 mL) were added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated and 10% aqueous citric acid solution was added. The resulting crystals were collected by filtration, washed with water and dried. The obtained crystals were subjected to silica gel column chromatography and the title compound (0.21 g, yield 60%) was obtained as yellow crystals from a fraction eluted with tetrahydrofuran-hexane (3:1, volume ratio). The crystals were recrystallized from ethyl acetate. melting point 217-218° C.
Reaction SMILES: [C:1]([O:4][CH:5]([C@@H:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]1/[CH:18]=[CH:19]/[CH:20]=[CH:21]/[CH:22]([O:31][Si](C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:23][C:24]#[C:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10])(=[O:3])[CH3:2].[OH-].[K+].S(=O)(=O)(O)O>>[C:1]([O:4][CH:5]([C@@H:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]1/[CH:18]=[CH:19]/[CH:20]=[CH:21]/[CH:22]([OH:31])[CH2:23][C:24]#[C:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10])(=[O:3])[CH3:2]
Reactant: CCCCCC#CCC(/C=C/C=C/[C@H]1CCCC[C@H]1C(CCCC(=O)O)OC(C)=O)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Product: CCCCCC#CCC(O)/C=C/C=C/[C@H]1CCCC[C@H]1C(CCCC(=O)O)OC(C)=O
Yield: 55.2 %

Procedure:
90 mg of (±)-(5RS)-5-acetoxy-5-[cis-(2RS)-2-((1E,3E)-(5RS)-5-tert-butyldiphenylsilyloxy-trideca-1,3-dien-7-inyl)-(1RS)-cyclohex- 1-yl]-pentanoic acid (produced in example 59) is stirred together with 1.8 ml of ethanolic potassium hydroxide solution (5 g of potassium hydroxide in 62.5 ml of water and 187.5 ml of ethanol) for 4 days at 24° C. Then, it is acidified with 10% sulfuric acid to pH 5, extracted several times with ethyl acetate, the organic phase is washed with brine, dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel with hexane/10-70% of ethyl acetate. 32 mg of (±)-(5RS)-5-acetoxy-5-[cis-(2RS)-2-((1E,3E)-(5RS)-5-hydroxy-trideca-1,3-dien-7-inyl)-(1RS)-cyclohex-1-yl]-pentanoic acid is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([NH2:9])=[C:4]([F:10])[CH:3]=1.Cl.[CH3:12][C:13](=O)CC(=O)C.C(=O)(O)[O-].[Na+]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([F:10])[C:5]2[N:9]=[C:12]([CH3:13])[NH:8][C:6]=2[CH:7]=1
Reactant: CC(=O)CC(C)=O
Reactant: Nc1cc(Br)cc(F)c1N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1nc2c(F)cc(Br)cc2[nH]1
Reaction time: 3 h
Yield: 82 %

Procedure:
A round bottomed flask was charged with 5-bromo-3-fluorobenzene-1.2 diamine (400 mg, 2 mmol) and 30 mL ethanol. 5 N hydrochloric acid (8 mL, 40 mmol) was then added. This mixture was heated to reflux and 2,4-pentanedione was added. The reaction mixture turned deep purple in color then slowly turned back to tan. Reaction was allowed to proceed for 3 hours and then cooled and neutralized with saturated sodium bicarbonate solution. The reaction mixture was then extracted three times with dichloromethane. The combined organic layers were washed with brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The crude mixture was triturated in diethyl ether then filtered to give 6-bromo-4-fluoro-2-methyl-1H-benzo[d]imidazole (375 mg, 82%) as a tan solid, 1H NMR (400 MHz, CDCl3) δ ppm 7.44 (br. s., 1H), 7.10 (d, J=11.22 Hz, 1H), 2.63 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([N:15]2[C:19]3=[N:20][CH:21]=[C:22]([C:24]4[N:25]=[N:26][N:27]([CH:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)[CH:28]=4)[CH:23]=[C:18]3[N:17]=[CH:16]2)[CH:12]=[C:11]([NH2:35])[CH:10]=1.N1C=CC=CC=1.[CH2:42]([S:44](Cl)(=[O:46])=[O:45])[CH3:43]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([N:15]2[C:19]3=[N:20][CH:21]=[C:22]([C:24]4[N:25]=[N:26][N:27]([CH:29]5[CH2:30][CH2:31][O:32][CH2:33][CH2:34]5)[CH:28]=4)[CH:23]=[C:18]3[N:17]=[CH:16]2)[CH:12]=[C:11]([NH:35][S:44]([CH2:42][CH3:43])(=[O:46])=[O:45])[CH:10]=1
Reactant: CCS(=O)(=O)Cl
Reactant: Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(-c4cn(C5CCOCC5)nn4)cnc32)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCS(=O)(=O)Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(-c4cn(C5CCOCC5)nn4)cnc32)c1
Yield: 42 %

Procedure:
To a solution of 2′,4′-difluoro-5-(6-(1-(tetrahydro-2H-pyran-4-yl)-1H-1,2,3-triazol-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-[1,1′-biphenyl]-3-amine (65 mg, 0.136 mmol) in DCM was added pyridine (21 mg, 2.72 mmol, 2.0 eq.) followed by ethanesulfonyl chloride (21 mg, 0.164 mmol, 1.2 eq.). After completion of the reaction the solvent was distilled off and the crude product was purified by preparative HPLC to give the product in 42% yield (30 mg). 1H NMR (300 MHz, DMSO): δ 10.4 (s, 1H) 9.04 (s, 1H), 8.99-8.98 (d, 1H), 8.90 (d, 1H), 8.63-8.61 (d, 1H) 7.95 (d, 1H), 7.76-7.70 (m, 2H), 7.49 (m, 2H), 7.35 (d, 1H), 4.82 (m, 1H), 3.95 (d, 2H), 3.58-3.55 (t, 2H), 3.36-3.28 (m, 2H), 2.12 (m, 2H), 1.29-1.24 (t, 3H), 1.08-1.06 (t, 2H); LC-MS (ESI): Calculated mass: 565.5; Observed mass: 565.9 [M+H]+ (rt: 1.44 min).