Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[C:11]([O:13][C:14]3[CH:15]=[N:16][C:17]([N+:20]([O-])=O)=[CH:18][CH:19]=3)[CH:10]=[CH:9][N:8]=2)[CH:6]=1.C1COCC1>CO.[Pd]>[CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[C:11]([O:13][C:14]3[CH:19]=[CH:18][C:17]([NH2:20])=[N:16][CH:15]=3)[CH:10]=[CH:9][N:8]=2)[CH:6]=1
Reactant: Cc1cn(-c2cc(Oc3ccc([N+](=O)[O-])nc3)ccn2)cn1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cn(-c2cc(Oc3ccc(N)nc3)ccn2)cn1
Yield: 91.3 %

Procedure:
A solution of 2-(4-methyl-1H-imidazol-1-yl)-4-((6-nitropyridin-3-yl)oxy)pyridine (0.73 g, 2.46 mmol) in MeOH (10 mL)/THF (10 mL) was treated with 10% Pd/C (50% wet, 0.261 g, 0.122 mmol) and the mixture was hydrogenated (50 psi) for 16 h at RT. The mixture was filtered through diatomaceous earth and washed with 10% methanol-DCM (3×10 mL). The combined filtrate was concentrated to afford 5-((2-(4-methyl-1H-imidazol-1-yl)pyridin-4-yl)oxy)pyridin-2-amine (0.6 g, 91%) as an off-white solid. MS (ESI) m/z: 268.2 (M+H+).
Reaction SMILES: [CH2:1]([N:3]([CH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)[C:4]1[C:5]([CH3:33])=[C:6]([CH:22]=[C:23]([C:25]2[CH:26]=[N:27][C:28]([CH:31]=O)=[CH:29][CH:30]=2)[CH:24]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:21])[NH:13][C:14]([CH3:20])=[CH:15][C:16]=1[CH:17]([CH3:19])[CH3:18])=[O:8])[CH3:2].[NH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH2:1]([N:3]([CH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)[C:4]1[C:5]([CH3:33])=[C:6]([CH:22]=[C:23]([C:25]2[CH:26]=[N:27][C:28]([CH2:31][N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)=[CH:29][CH:30]=2)[CH:24]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:21])[NH:13][C:14]([CH3:20])=[CH:15][C:16]=1[CH:17]([CH3:18])[CH3:19])=[O:8])[CH3:2]
Reactant: CCN(c1cc(-c2ccc(C=O)nc2)cc(C(=O)NCc2c(C(C)C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CCN(c1cc(-c2ccc(CN3CCOCC3)nc2)cc(C(=O)NCc2c(C(C)C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 37.8 %

Procedure:
To a stirred solution of 3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-5-(6-formylpyridin-3-yl)-N-((4-isopropyl-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methylbenzamide (0.28 g, 0.528 mmol) and morpholine (0.07 g, 0.79 mmol) in dichloroethane (3 mL), acetic acid (0.19 g, 3.16 mmol) was added and reaction stirred at room temperature for 20 minutes. Then sodium triacetoxyborohydride (0.33 g, 1.55 mmol) was added at 0° C. and reaction stirred at room temperature for 2 h. On completion, reaction was quenched with aqueous sodium bicarbonate, organic phase was separated and aqueous phase was extracted with dichloromethane. Combined organic layers were dried over sodium sulphate and concentrated under reduced pressure to give crude material was purified by prep. HPLC to afford the title compound (0.12 g, 38.70%).
Reaction SMILES: C(OC([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][N:12]([CH2:16][C:17]3[S:18][C:19]4[C:24]([N:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[N:23][C:22]([Cl:31])=[N:21][C:20]=4[N:32]=3)[CH2:13]2)[CH2:9]1)=O)(C)(C)C.N1CCC(N2C[CH2:43][O:42][CH2:41][CH2:40]2)CC1>>[Cl:31][C:22]1[N:23]=[C:24]([N:25]2[CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)[C:19]2[S:18][C:17]([CH2:16][N:12]3[CH2:13][CH2:14][CH:9]([N:8]4[CH2:40][CH2:41][O:42][CH2:43][CH2:15]4)[CH2:10][CH2:11]3)=[N:32][C:20]=2[N:21]=1
Reactant: C1CC(N2CCOCC2)CCN1
Reactant: CC(C)(C)OC(=O)N1CC2CN(Cc3nc4nc(Cl)nc(N5CCOCC5)c4s3)CC2C1
Product: Clc1nc(N2CCOCC2)c2sc(CN3CCC(N4CCOCC4)CC3)nc2n1

Procedure:
Prepared according to the method used in the preparation of 5-(5-chloro-7-morpholin-4-ylthiazolo[4,5-d]pyrimidin-2-ylmethyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester using 4-piperidin-4-ylmorpholine in place of hexahydro-pyrrolo[3,4-e]pyrrole-2-carboxylic acid tert-butyl ester. The title compound was obtained as a yellow solid (220 mg, 39%).
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([Br:23])[CH:21]=4)C(=O)C3=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([NH:14][C:22]3[CH:17]=[CH:18][CH:19]=[C:20]([Br:23])[CH:21]=3)[CH2:10][CH2:9]2)=[CH:26][CH:27]=1
Reactant: O=C1C(=O)N(C2CCN(CCc3ccc(F)cc3)CC2)c2cc(Br)ccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Fc1ccc(CCN2CCC(Nc3cccc(Br)c3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.2 %

Procedure:
Under ice cooling, a 1 M solution (69 ml) of a borane/tetrahydrofuran complex in tetrahydrofuran was added dropwise into a solution of 1-[1-(4-fluorophenethyl)-piperidin-4-yl]-2,3-dioxo-6-bromoindoline (7.4 g) in tetrahydrofuran (150 ml) followed by stirring at room temperature overnight and heating under reflux for 3 hr. Into the reaction solution was carefully added dropwise a saturated aqueous solution of sodium bicarbonate. Then ethyl acetate was added to the resultant mixture and the organic layer was separated. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was then diluted with pyridine (50 ml) and stirred at room temperature for 4 hr. Next, a saturated aqueous solution of sodium bicarbonate and ethyl acetate were added thereto and the layers were separated. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography (hexane/ethyl acetate system) to give the title compound (3.9 g) as a yellow oil (yield: 57%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23](=[O:25])[CH3:24])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12][C:11]2=[O:26])[CH3:9])=[CH:4][CH:3]=1.[CH3:27][Mg]Br>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23]([OH:25])([CH3:27])[CH3:24])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12][C:11]2=[O:26])[CH3:9])=[CH:6][CH:7]=1
Reactant: CC(=O)C[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)C1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)CC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.5 %

Procedure:
To a solution of (R)-1-((S)-1-(4-bromophenyl)ethyl)-4-(2-oxopropyl)-4-phenyl piperidin-2-one (82 mg, 0.2 mmol) in anhydrous THF (20 mL) was added dropwise methylmagnesium bromide (0.4 mL, 3M) at −78° C. under nitrogen. The formed mixture was stirred at rt for 1 h. The reaction mixture was quenched with aq NaHCO3 solution (5 mL). The layers were separated. The aqueous layer was extracted with EtOAc (3×8 mL). The combined organic phase was washed with a satd aq NaCl (5 mL), dried over Na2SO4 and concentrated in vacuo to give the crude product, which was purified by preparative HPLC to afford (R)-1-((S)-1-(4-bromophenyl)ethyl)-4-(2-hydroxy-2-methylpropyl)-4-phenylpiperidin-2-one (60 mg, 70.5%). LC-MS Method 2, tR=2.131 min, m/z=454. 1H NMR (CDCl3): δ 0.85 (s, 3H), 1.05 (s, 3H), 1.46 (m, 3H), 1.85-1.89 (m, 1H), 1.96-2.18 (m, 4H), 2.73-2.76 (m, 1H), 2.89-2.94 (m, 1H), 3.58-3.63 (m, 1H), 5.91-5.96 (m, 1H), 6.95-6.97 (m, 1H), 7.21-7.34 (m, 7H).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[CH:3]([CH3:12])[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1.[C:15](OC(OC)=O)(OC)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C(Cl)Cl>[CH3:15][NH:11][C:8]1[CH:7]=[CH:6][C:5]([O:4][CH:3]([CH3:12])[C:2]([F:13])([F:14])[F:1])=[CH:10][CH:9]=1
Reactant: COC(=O)OC(=O)OC
Reactant: CC(Oc1ccc(N)cc1)C(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: ClCCl
Product: CNc1ccc(OC(C)C(F)(F)F)cc1

Procedure:
This material was prepared from (rac)-4-(2,2,2-trifluoro-1-methyl-ethoxy)-phenylamine by, first an standard methoxycarbonylation reaction with dimethyl dicarbonate in methylene chloride (at RT and 12 h stirring) followed by reduction with LiAlH4 according to standard literature procedures.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:4]=1[NH2:5])[CH3:2].[N:13]([O-])=O.[Na+]>C(O)(=O)C.O>[CH3:2][C:1]1[C:3]2[C:4](=[CH:6][C:7]([N+:10]([O-:12])=[O:11])=[CH:8][CH:9]=2)[NH:5][N:13]=1
Reactant: CCc1ccc([N+](=O)[O-])cc1N
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1n[nH]c2cc([N+](=O)[O-])ccc12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 40.1 %

Procedure:
Following generally the procedure reported by Organic Synthesis 1955, Coll. Vol. 3, 660; 1940, 20, 73, 2-ethyl-5-nitroaniline (1.021 g, 6.14 mmol) was dissolved in glacial acetic acid (40 ml) and the mixture was cooled to 0° C. A solution of sodium nitrite (1 eq, 424 mg) in water (1 ml) was added all at once. Stirring was continued for 15 minutes at 25° C. After 3 hours, residual solids were filtered off and discarded, and the filtrate was allowed to stand for 3 days at room temperature. The solution was concentrate in vacuo, and the residue was diluted with 2 ml of water and stirred vigorously. The solid product was filtered and washed thoroughly with cold water, dried and purified by flash chromatography (4:1 hexanes/ethyl acetate) to give 3-methyl-6-nitro-1H-indazole (436 mg, 40.5%) as a solid.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:7][O:8][C:9]=1[CH3:10])=O.[CH2:17]1[CH:19]([C:20]([NH2:22])=[NH:21])[CH2:18]1.Cl>>[CH:19]1([C:20]2[NH:21][CH:2]=[C:3]([C:5]3[C:6]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[N:7][O:8][C:9]=3[CH3:10])[N:22]=2)[CH2:17][CH2:18]1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)CBr
Reactant: N=C(N)C1CC1
Agent: Cl
Product: Cc1onc(-c2ccccc2)c1-c1c[nH]c(C2CC2)n1
Yield: 85 %

Procedure:
As described for Example 57, 4-(bromoacetyl)-5-methyl-3-phenylisoxazole (commercially available) (1.5 g, 5 mmol) using cycloproylcarbamidine HCl instead of acetamidine HCl was converted to the title compound (1.2 g, 85%) which was obtained as an off-white solid. MS: m/e=266.3 [M+H]+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:22]([NH:24][NH:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10].C1(=O)N(CCS(Cl)(=O)=O)C(=O)C2=CC=CC=C12.N1C=CC=CC=1.[O:57]=[C:58]([S:72](Cl)(=[O:74])=[O:73])[CH2:59][N:60]1[C:64](=[O:65])[CH:63]2[C:66](=[O:70])[CH:67]=[CH:68][CH:69]=[C:62]2[C:61]1=[O:71]>ClCCl>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:22]([NH:24][N:25]([CH2:26][CH:27]([CH3:28])[CH3:29])[S:72]([C:58](=[O:57])[CH2:59][N:60]1[C:64](=[O:65])[CH:63]2[C:66](=[O:70])[CH:67]=[CH:68][CH:69]=[C:62]2[C:61]1=[O:71])(=[O:73])=[O:74])=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10]
Reactant: CC(C)CNNC(=O)[C@H](CC(C)C)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Reactant: O=C1C=CC=C2C(=O)N(CC(=O)S(=O)(=O)Cl)C(=O)C12
Agent: O=C1c2ccccc2C(=O)N1CCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)C[C@@H](C(=O)NN(CC(C)C)S(=O)(=O)C(=O)CN1C(=O)C2=CC=CC(=O)C2C1=O)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.4 %

Procedure:
A solution of 0.459 g of (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-4-methylvalerohydrazide in 8 ml of dichloromethane was treated with 0.287 g of 2-phthalimidoethanesulphonyl chloride and 0.1 ml of pyridine at room temperature under a nitrogen atmosphere. The mixture was stirred for 2 hours at room temperature and a further 0.287 g of 1,3-dioxo-2-phthalimidoethanesulphonyl chloride was added. The mixture was stirred overnight at room temperature and evaporated. The residue was dissolved in ethyl acetate and washed in sequence with water, 5% aqueous citric acid, water, 5% aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride. Drying over anhydrous magnesium sulphate and evaporation gave a residue which was triturated with diethyl ether to give 0.47 g of (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-2′-(1,3-dioxo-2-phthalimidoethanesulphonyl)-4-methylvalerohydrazide in the form of a pale yellow solid.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[C:10]1([SH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+].C(O)CO>[Cu]I.CC(O)C>[C:10]1([S:16][C:2]2[CH:9]=[CH:8][CH:7]=[C:4]([C:5]#[N:6])[CH:3]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: N#Cc1cccc(I)c1
Reactant: Sc1ccccc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: CC(C)O
Product: N#Cc1cccc(Sc2ccccc2)c1
Yield: 85.7 %

Procedure:
The general procedure in example 39 was followed. 3-Iodobenzonitrile (229 mg, 1.0 mmol), thiophenol (103 μL, 1.0 mmol), CuI (10 mg, 0.05 mmol), K2CO3 (276 mg, 2.0 mmol), ethylene glycol (111 μL, 2.0 mmol) and 2-propanol (1.0 mL) were used to obtain the 3-cyanophenyl phenyl sulfide (181 mg, 86% yield) as colorless liquid. Column chromatography solvent (hexane/ethyl acetate=25/1). Rf=0.4 (hexane/ethyl acetate=20/1). 1H NMR (CDCl3, 300 MHz) δ 7.30-7.45 (m, 9 H). 13C NMR (CDCl3, 75 MHz) δ 140.2, 133.6, 132.9, 132.3, 131.7, 130.0, 129.7, 129.6, 129.1, 118.5, 113.5. MS (EI) m/z (relative intensity) 211 (30), 185 (20), 134 (100).
Reaction SMILES: C([O:8][C:9](=[O:40])[CH:10]([O:37][CH2:38][CH3:39])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19](=[O:35])[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:23][CH:22]=2)=[C:14]([CH3:36])[CH:13]=1)C1C=CC=CC=1.CO>CCOC(C)=O>[C:31]([O:30][C:28]([NH:27][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][C:19]([O:18][C:15]2[CH:16]=[CH:17][C:12]([CH2:11][CH:10]([O:37][CH2:38][CH3:39])[C:9]([OH:40])=[O:8])=[CH:13][C:14]=2[CH3:36])=[O:35])=[CH:26][CH:25]=1)=[O:29])([CH3:32])([CH3:34])[CH3:33]
Reactant: CCOC(Cc1ccc(OC(=O)Cc2ccc(NC(=O)OC(C)(C)C)cc2)c(C)c1)C(=O)OCc1ccccc1
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(Cc1ccc(OC(=O)Cc2ccc(NC(=O)OC(C)(C)C)cc2)c(C)c1)C(=O)O

Procedure:
The title compound was prepared from 3-{4-[2-(4-tert-butoxycarbonylamino-phenyl)-acetoxy]-3-methyl-phenyl}-2-ethoxy-propionic acid benzyl ester (0.035 g, 0.064 mmol) in the same manner as described for example 1 with the difference that MeOH was used as the solvent instead of EtOAc. The crude product was purified by column chromatography using DCM/iPrOH (95:5) as the eluent and the title compound was obtained as a solid (0.02 g, 68.4%). 1H NMR (500 MHz, CD3OD): δ 7.40-7.42 (d, 2H), 7.29-7.31 (d, 2H), 7.10-7.15 (m, 2H), 6.86-6.87 (d, 1H), 3.84-3.88 (m, 3H), 3.60-3.62 (m, 1H), 3.26-3.29 (m, 1H), 2.96-3.02 (dd, 1H), 2.80-2.86 (dd, 1H), 1.53 (s, 9H), 1.10-1.13 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.Br[C:18]1[CH:32]=[CH:31][C:21]([C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=2)=[O:23])=[CH:20][CH:19]=1>>[Cl:30][C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=1)[C:22]([C:21]1[CH:31]=[CH:32][C:18]([NH:1][C:2]2[N:7]=[C:6]([C:8]3[N:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:11]4=[N:10][CH:9]=3)[CH:5]=[CH:4][N:3]=2)=[CH:19][CH:20]=1)=[O:23]
Reactant: Nc1nccc(-c2cnc3ccccn23)n1
Reactant: O=C(c1ccc(Br)cc1)c1cccc(Cl)c1
Product: O=C(c1ccc(Nc2nccc(-c3cnc4ccccn34)n2)cc1)c1cccc(Cl)c1
Yield: 21 %

Procedure:
The title compound was prepared from 2-amino-4-(imidazo-[1,2-a]pyridin-3-yl)pyrimidine and 4-bromo-3′-chlorobenzophenone following the general method of Example 2. The crude product was purified by column chromatography on silica gel using chloroform/ethanol, 99:1, as the eluent affording 51 mg (21% yield) of the title compound as a yellow solid: mp 194.7-196.7° C.; 1H NMR (400 MHz, DMSO-d6) δ 10.26 (s, 1 H), 10.17 (d, J=7.0 Hz, 1 H), 8.69 (s, 1 H), 8.54 (d, J=5.4 Hz, 1 H), 8.01 (d, J=8.7Hz, 2 H), 7.83-7.79 (m, 3 H), 7.76-7.72 (m, 2 H), 7.70-7.66 (m, 1 H), 7.62-7.59 (m, 1 H), 7.56-7.51 (m, 2 H), 7.21 (t, J=6.9 Hz, 1 H); 13C NMR (400 MHz, DMSO-d6) δ 193.2, 159.3, 157.7, 157.4, 148.4, 145.7, 140.4, 139.4, 133.7, 132.0, 131.8, 130.8, 129.8, 129.1, 129.0, 128.3, 127.6, 121.3, 118.3, 117.8, 114.3, 108.8; MS (ESP) m/z 426 (M+1).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14]C)=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.Br[CH2:17][CH2:18][CH2:19][CH3:20]>CN(C=O)C.C(OCC)(=O)C>[CH2:17]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([OH:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4]1)[CH2:18][CH2:19][CH3:20]
Reactant: COC(=O)c1ccc2[nH]ccc2c1
Reactant: CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCn1ccc2cc(C(=O)O)ccc21
Reaction time: 12 h

Procedure:
Sodium hydride (50% in oil, 1.4 g) was added to methyl 1H-indole-5-carboxylate (5.0 g) in DMF (100 ml) and, after gas evolution ceased, bromobutane (3.9 g) was added. After 12 hours, the reaction solution was diluted with ethyl acetate and washed three times with water. The organic phase was dried over magnesium sulfate and concentrated. The residue was purified by chromatography on silica gel (mobile phase ethyl acetate/heptane 1:6). The resulting ester was dissolved in methanol (10 ml) and boiled under reflux with sodium hydroxide (0.6 g ) in water (10 ml) for 12 hours. The mixture was diluted with water and acidified with hydrochloric acid, followed by extraction with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated. This resulted in the product with the molecular weight of 217.27 (C13H15NO2); MS (ESI): 218 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C@H:8]([CH3:23])[C@@H:9]([OH:22])[CH2:10][NH:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)([CH3:4])([CH3:3])[CH3:2].[C:25]1(=O)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.C([BH3-])#N.[Na+]>CO>[C:1]([O:5][C:6](=[O:24])[NH:7][C@H:8]([CH3:23])[C@@H:9]([OH:22])[CH2:10][N:11]([CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)[CH2:12][CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCCCC1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)[C@@H](O)CNCCCc1ccc(F)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: C[C@@H](NC(=O)OC(C)(C)C)[C@@H](O)CN(CCCc1ccc(F)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The material from step d (623 mg, 1.83 mMol) and cyclohexanone (179 mg, 1.83 mMol) were dissolved in methanol (5 ml), 4 A molecular sieves were added, and the mixture was stirred at room temperature for 2 hours. To this mixture, sodium cyanoborohydride (173 mg, 2.75 mMol) was added, and the mixture was stirred overnight. Analysis of the reaction mixture by ESI MS showed an M+H which was two AMU higher than that of the desired product, indicating that the imine or aminal hadn't been reduced by sodium cyanoborohydride. The reaction mixture was filtered, the solids were rinsed with EtOAc, and the combined filtrates were concentrated in-vacuo. The residue was dissolved in EtOAc (30 ml), washed with water (2×10 ml), dried over sodium sulfate, and concentrated in-vacuo. The residue was dissolved in methylene chloride (5 ml), sodium triacetoxyborohydride (583 mg, 2.75 mMol) followed by two drops of glacial acetic acid were added, and the mixture was stirred at room temperature for three days. The reaction was worked up by diluting with water (50 ml), adjusting the pH of the mixture to >10 with 1N NaOH, and extracting with EtOAc (3×30 ml). The combined organic phases were dried over sodium sulfate, and concentrated to a yellow oil. This oil was purified via flash chromatography, eluting with EtOAc to yield 310 mg of a colorless oil as product. ESI+MS detects 423 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([OH:28])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][CH:17]=2)[C:5]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[N:6][C:7]=1[CH3:8].C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][CH2:37][CH2:38][OH:39]>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:28][CH2:36][CH2:37][CH2:38][OH:39])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][CH:17]=2)[C:5]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[N:6][C:7]=1[CH3:8]
Reactant: OCCCBr
Reactant: COc1cc2c(Oc3cc(C)c(C)nc3-c3cccnc3)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc(C)c(C)nc3-c3cccnc3)ccnc2cc1OCCCO
Temperature: 25 °C
Reaction time: 8 h
Yield: 24 %

Procedure:
4-(5,6-Dimethyl-[2,3′]bipyridin-3-yloxy)-6-methoxy-quinolin-7-ol (compound 345) (45 mg) was dissolved in N,N-dimethylformamide (2 ml) to prepare a solution, potassium carbonate (50 mg) and 3-bromo-1-propanol (0.03 ml) were added to the solution, and the mixture was stirred at room temperature overnight. The solvent was removed by distillation under the reduced pressure, water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-acetone to give the title compound (13 mg, yield 24%).
Reaction SMILES: [CH2:1]([C:4]1[C:9]([F:10])=[C:8]([F:11])[CH:7]=[C:6]([Br:12])[C:5]=1[OH:13])[CH:2]=C.[O:14]=[O+][O-]>ClCCl.CO>[OH:13][C:5]1[C:6]([Br:12])=[CH:7][C:8]([F:11])=[C:9]([F:10])[C:4]=1[CH2:1][CH:2]=[O:14]
Reactant: O=[O+][O-]
Reactant: C=CCc1c(O)c(Br)cc(F)c1F
Solvent: ClCCl
Solvent: CO
Product: O=CCc1c(O)c(Br)cc(F)c1F
Temperature: 25 °C

Procedure:
A solution of 7.8 gm (31.45 mMol) 2-allyl-3,4-difluoro-6-bromophenol in 100 mL dichloromethane and 20 mL methanol was cooled to −78° C. and was then saturated with ozone. After 20 minutes the reaction mixture was purged with nitrogen for 10 minutes and was then treated with 5 mL dimethylsulfide. The reaction mixture was allowed to warm gradually to room temperature. After 15 hours the reaction mixture was concentrated under reduced pressure to provide the title compound.
Reaction SMILES: [F:1][CH:2]([F:38])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[N:15]=[C:14](/[CH:16]=[CH:17]/[C:18]3[CH:19]=[C:20]4[C:25](=[CH:26][CH:27]=3)[N:24]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[C:23](=[O:36])[CH:22]=[CH:21]4)[O:13][N:12]=2)=[CH:6][C:5]=1[CH3:37].[N+](=[CH2:41])=[N-]>C(OCC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:38][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[N:15]=[C:14]([C@@H:16]3[CH2:41][C@H:17]3[C:18]3[CH:19]=[C:20]4[C:25](=[CH:26][CH:27]=3)[N:24]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[C:23](=[O:36])[CH:22]=[CH:21]4)[O:13][N:12]=2)=[CH:6][C:5]=1[CH3:37]
Reactant: Cc1cc(Nc2noc(/C=C/c3ccc4c(ccc(=O)n4COCC[Si](C)(C)C)c3)n2)ccc1OC(F)F
Reactant: C=[N+]=[N-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOCC
Product: Cc1cc(Nc2noc([C@@H]3C[C@H]3c3ccc4c(ccc(=O)n4COCC[Si](C)(C)C)c3)n2)ccc1OC(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.6 %

Procedure:
To a solution of (E)-6-(2-(3-((4-(difluoromethoxy)-3-methylphenyl)amino)-1,2,4-oxadiazol-5-yl)vinyl)-1-((2-(trimethylsilyl)ethoxy)methyl)quinolin-2(1H)-one (65 mg, 0.120 mmol) in diethylether (20 mL) were added palladium (II) acetate (2.70 mg, 0.012 mmol) and a diazomethane solution [prepared from N-nitroso-N-methylurea (62.0 mg, 0.601 mmol) and KOH (33.7 mg, 0.61 mmol)]. The reaction was stirred at room temperature overnight, The reaction mixture was filtered through celite and concentrated to give trans-6-(2-(3-((4-(difluoromethoxy)-3-methylphenyl)amino)-1,2,4-oxadiazol-5-yl)cyclopropyl)-1-((2-(trimethylsilyl)ethoxy)methyl)quinolin-2(1H)-one (45 mg, 67%). LCMS, RT 2.25 min; LCMS (ES-API), m/z 555.