Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[CH:7]=[CH:6][NH:5][N:4]=1.[H-].[Na+].F[C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([O:21][C:22]2[N:26]([CH3:27])[N:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[CH:20]=1)[C:16]#[N:17].O>CC(N(C)C)=O>[CH3:27][N:26]1[C:22]([O:21][C:19]2[CH:18]=[C:15]([CH:14]=[C:13]([N:5]3[CH:6]=[CH:7][C:3]([C:2]([F:9])([F:8])[F:1])=[N:4]3)[CH:20]=2)[C:16]#[N:17])=[CH:23][C:24]([C:28]([F:31])([F:30])[F:29])=[N:25]1
Reactant: FC(F)(F)c1cc[nH]n1
Reactant: Cn1nc(C(F)(F)F)cc1Oc1cc(F)cc(C#N)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cn1nc(C(F)(F)F)cc1Oc1cc(C#N)cc(-n2ccc(C(F)(F)F)n2)c1
Temperature: 25 °C
Yield: 68 %

Procedure:
Under an atmosphere of nitrogen, 0.131 g (0.96 mmol) of 3-trifluoromethylpyrazole was initially charged in 5 ml of dimethylacetamide, and 0.033 g (1.1 mmol) of sodium hydride (80%) was added at 0° C. The mixture was allowed to warm to room temperature, and 0.250 g (0.88 mmol) of 3-fluoro-5-(1-methyl-3-trifluoromethylpyrazol-5-yloxy)benzonitrile was added, the mixture was heated at 140° C. for 8 h and cooled to room temperature, water was added to the reaction solution and the solution was stirred for a number of minutes. The mixture was extracted twice with heptane/ethyl acetate (1:1) and twice with ethyl acetate. The combined phases were washed with water and then dried over magnesium sulfate, filtered and concentrated. Column chromatography of the crude product gave 0.240 g of 3-(1-methyl-3-trifluoromethylpyrazol-5-yloxy)-5-(3-trifluoromethylpyrazol-1-yl)benzonitrile in the form of white crystals of melting point of 116-117° C.
Reaction SMILES: [C:1](Cl)(=[O:11])[CH2:2][CH:3]([CH2:7][C:8](Cl)=[O:9])[C:4](Cl)=[O:5].[Br:13][C:14]1[CH:26]=[C:25]([Br:27])[CH:24]=[C:16]([C:17]([O:19]C(C)(C)C)=O)[C:15]=1[OH:28].[H-].[Na+]>O1CCCC1.FC(F)(F)C(O)=O>[Br:13][C:14]1[CH:26]=[C:25]([Br:27])[CH:24]=[C:16]([CH2:17][O:19][C:1](=[O:11])[CH2:2][CH:3]([CH2:7][C:8]([O:19][CH2:17][C:16]2[C:15](=[C:14]([Br:13])[CH:26]=[C:25]([Br:27])[CH:24]=2)[OH:28])=[O:9])[C:4]([O:19][CH2:17][C:16]2[C:15](=[C:14]([Br:13])[CH:26]=[C:25]([Br:27])[CH:24]=2)[OH:28])=[O:5])[C:15]=1[OH:28]
Reactant: O=C(Cl)CC(CC(=O)Cl)C(=O)Cl
Reactant: CC(C)(C)OC(=O)c1cc(Br)cc(Br)c1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC(CC(=O)OCc1cc(Br)cc(Br)c1O)C(=O)OCc1cc(Br)cc(Br)c1O)OCc1cc(Br)cc(Br)c1O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Tricarballylic trichloride (0.01 mol) (see Emery, Ber., 22:2921 (1989)) in dry tetrahydrofuran (THF) (10 ml) was added dropwise to three equivalents of tert-butyl 3,5-dibromosalicylate (see Delaney et al, Arch. Biochem. Biophys., 28:627 (1984)) previously been treated with a stoichiometric amount of NaH in THF. The mixture was stirred for 5 hours at room temperature, and the solvent was then removed under reduced pressure. The residue was dissolved in diethyl ether and extracted several times with water. The extract was dried over MgSO4, filtered and concentrated. Recrystallization from ethanol gave a pure product; m.p. 100-102° C. The resulting product (2 mmol) was dissolved in anhydrous trifluoroacetic acid (10 ml) and allowed to stand at room temperature. After 30 minutes, the solvent was removed under reduced pressure and the precipitate recrystallized from trifluoroacetic acid; m.p. 186° C. (see Razynska et al, supra).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([F:11])[C:5]=1[F:12])[CH3:2].P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH3:37])=[C:31]([F:38])[C:30]=2[F:39])=[CH:25][CH:24]=1>CN(C=O)C>[CH2:36]([O:35][C:32]1[CH:33]=[CH:34][C:29]([C:26]2[CH:27]=[CH:28][C:23]([CH2:22][O:10][C:7]3[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[C:5]([F:12])[C:6]=3[F:11])=[CH:24][CH:25]=2)=[C:30]([F:39])[C:31]=1[F:38])[CH3:37]
Reactant: CCOc1ccc(O)c(F)c1F
Reactant: CCOc1ccc(-c2ccc(CCl)cc2)c(F)c1F
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc(OCc2ccc(-c3ccc(OCC)c(F)c3F)cc2)c(F)c1F
Temperature: 30 °C
Reaction time: 7 h
Yield: 74 %

Procedure:
4-Ethoxy-2,3-difluorophenol (6) (1.5 g) and tripotassium phosphate (K3PO4) (7.5 g) were added to DMF (100 ml) under a nitrogen atmosphere, and the stirring was continued at 70° C. The compound (5) (2.0 g) was added thereto and the stirring was continued at 70° C. for 7 hours. After the reaction mixture obtained had been cooled to 30° C. and then separated from the solid by filtration, toluene (100 ml) and water (100 ml) were added thereto and mixed. The mixture was then allowed to stand until it had separated into two phases of organic and aqueous phases. The extraction into an organic phase was carried out. The organic phase obtained was washed with brine and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off, and the residue obtained was purified by means of column chromatography (silica gel; heptane: toluene=1:2 by volume). The product was further purified by means of recrystallization from a mixed solvent of Solmix A-11 and heptane (Solmix A-11: heptane=1:2 by volume) and dried, giving 2.2 g of 4-ethoxy-2,3-difluoro-4′-(4-ethoxy-2,3-difluorophenoxymethyl)-1,1′-biphenyl (No. 678). The yield based on the compound (5) was 74.0%.
Reaction SMILES: S(Cl)([Cl:3])=O.[O:5]=[C:6]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[O:9][C:8]2[CH:16]=[CH:17][C:18]([C:20]([O-:22])=O)=[CH:19][C:7]1=2.[Na+]>C(Cl)(Cl)(Cl)Cl>[O:5]=[C:6]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[O:9][C:8]2[CH:16]=[CH:17][C:18]([C:20]([Cl:3])=[O:22])=[CH:19][C:7]1=2
Reactant: O=C([O-])c1ccc2oc3ncccc3c(=O)c2c1
Reactant: O=S(Cl)Cl
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(Cl)c1ccc2oc3ncccc3c(=O)c2c1

Procedure:
2.5 g of thionyl chloride is added to a suspension of 4.5 g of sodium 5-oxo-5H-[1]benzopyrano[2,3-b]pyridine-7-carboxylate in 35 ml of carbon tetrachloride with stirring, and the mixture is stirred under reflux for 3 hours. After cooling, the crystals are filtered off, washed with cool water and then with acetone, and dried to give 5-oxo-5H-[1]benzopyrano[2,3-b]pyridine-7-carboxylic acid chloride melting at 234°-235°C.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H](C2C=CC(B3OC(C)(C)C(C)(C)O3)=CC=2)C)[CH2:6][CH2:5]1.BrC1C=CC(=O)N(C(F)F)C=1.C([O-])([O-])=O.[Cs+].[Cs+].O>O1CCOCC1>[OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[NH:7][CH2:6][CH2:5]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Agent: O=C([O-])[O-]
Agent: O=c1ccc(Br)cn1C(F)F
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(O)CC1(c2ccccc2)CCNC(=O)O1
Temperature: 110 °C
Yield: 100.7 %

Procedure:
A microwave vial equipped with a flea stirbar was charged with (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan -2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (20 mg, 0.047 mmol), 5-bromo-1-(difluoromethyl)pyridin-2(1H)-one (25 mg, 0.113 mmol), Cs2CO3 (27 mg, 0.083 mmol), H2O (0.1 mL) and dry dioxane (1 mL). The mixture was sparged with N2 for 10 min and heated at 110° C. in the microwave for 0.5 h. The mixture was diluted with glacial HOAc (0.1 mL) and MeOH (0.5 mL) and filtered. The filtrate was directly purified by prep HPLC to afford (S)-3-(S)-1-(4-(1-(difluoromethyl)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one (11.8 mg, 57%) as an oil. LC-MS Method 1 tR=1.55 min, m/z=497, 248; 1H NMR (CDCl3) 1.13 (s, 3H), 1.19 (s, 3H), 1.56 (d, 3H), 2.15-2.35 (s, 4H), 2.42 (m, 2H), 2.88 (m, 1H), 5.71 (q, 1H), 6.64 (d, 1H), 7.04 (d, 2H), 7.18 (d, 2H), 7.30-7.40 (5H), 7.52 (1H), 7.60 (m, 1H), 7.75 (t, 1H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:27][CH2:26][C:11]2[N:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=3)[N:14]=[C:15]([OH:16])[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:29][C:30]1[CH:39]=[CH:38][C:33]([C:34]([O:36]C)=[O:35])=[CH:32][CH:31]=1>>[CH2:1]([N:8]1[CH2:27][CH2:26][C:11]2[N:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=3)[N:14]=[C:15]([O:16][CH2:29][C:30]3[CH:39]=[CH:38][C:33]([C:34]([OH:36])=[O:35])=[CH:32][CH:31]=3)[C:10]=2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cccc(-c2nc(O)c3c(n2)CCN(Cc2ccccc2)C3)c1
Reactant: COC(=O)c1ccc(CBr)cc1
Product: O=C(O)c1ccc(COc2nc(-c3cccc([N+](=O)[O-])c3)nc3c2CN(Cc2ccccc2)CC3)cc1

Procedure:
The title compound was prepared from 6-benzyl-2-(3-nitro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ol (which was obtained in Intermediate 9) and methyl 4-(bromomethyl)benzoate according to Method A and Method B; LC retention time 3.25 min; MS: m/z (ESI) 494 (M−H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:37][CH3:38])=[C:7]([C:9]2[N:13]([CH:14]([CH3:16])[CH3:15])[C:12]3[CH:17]([C:29]4[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=4[CH3:36])[N:18]([C:21]4[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=4[CH3:28])[C:19](=[O:20])[C:11]=3[N:10]=2)[CH:8]=1.[C:39](Cl)(=[O:41])[CH3:40]>C1COCC1>[Cl:27][C:25]1[CH:24]=[CH:23][C:22]([CH3:28])=[C:21]([N:18]2[C:19](=[O:20])[C:11]3[N:10]=[C:9]([C:7]4[CH:8]=[C:3]([CH:4]=[CH:5][C:6]=4[O:37][CH3:38])[CH2:2][NH:1][C:39](=[O:41])[CH3:40])[N:13]([CH:14]([CH3:15])[CH3:16])[C:12]=3[CH:17]2[C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=2[CH3:36])[CH:26]=1
Reactant: COc1ccc(CN)cc1-c1nc2c(n1C(C)C)C(c1ccc(Cl)cc1C)N(c1cc(Cl)ccc1C)C2=O
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Product: COc1ccc(CNC(C)=O)cc1-c1nc2c(n1C(C)C)C(c1ccc(Cl)cc1C)N(c1cc(Cl)ccc1C)C2=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The product from example 16 (30 mg, 0.05 mmol) was dissolved in THF (0.7 mL) and TEA (10 mL, 0.07 mmol) was added. The reaction was cooled in an ice bath and acetyl chloride (5 mL, 0.06 mmol) was added. The cooling bath was removed and the reaction mixture allowed to stir at rt for 0.5 h. It was then diluted with EtOAc and brine and the aqueous phase extracted with EtOAc. The combined extracts were dried (Na2SO4) and concentrated. The remaining crude product was triturated with acetonitrile to give the title compound as a white solid, which was isolated by filtration and dried under reduced pressure. tR: 1.18/1.21 min (LC-MS 2); ESI-MS: 591.2/593.2 [M+H]+ (LC-MS 2).
Reaction SMILES: [CH:1]([N:4]1[CH:8]=[C:7]([N:9]2[C:21]3[C:20]4[CH:19]=[C:18](B5OC(C)(C)C(C)(C)O5)[CH:17]=[CH:16][C:15]=4[N:14]=[CH:13][C:12]=3[N:11]([CH3:31])[C:10]2=[O:32])[C:6]([CH3:33])=[N:5]1)([CH3:3])[CH3:2].Br[C:35]1[CH:36]=[CH:37][C:38]([C:41]([NH2:43])=[O:42])=[N:39][CH:40]=1>CN(C=O)C.C([O-])([O-])=O.[K+].[K+].CO.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:1]([N:4]1[CH:8]=[C:7]([N:9]2[C:21]3[C:20]4[CH:19]=[C:18]([C:35]5[CH:36]=[CH:37][C:38]([C:41]([NH2:43])=[O:42])=[N:39][CH:40]=5)[CH:17]=[CH:16][C:15]=4[N:14]=[CH:13][C:12]=3[N:11]([CH3:31])[C:10]2=[O:32])[C:6]([CH3:33])=[N:5]1)([CH3:3])[CH3:2]
Reactant: NC(=O)c1ccc(Br)cn1
Reactant: Cc1nn(C(C)C)cc1-n1c(=O)n(C)c2cnc3ccc(B4OC(C)(C)C(C)(C)O4)cc3c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1nn(C(C)C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4ccc(C(N)=O)nc4)cc3c21
Temperature: 105 °C
Reaction time: 2.5 h

Procedure:
A mixture of 1-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Stage 112.1.1, 34 mg, 0.075 mmol), 5-bromo-pyridine-2-carboxylic acid amide (Combi-Blocks, San Diego, USA, 20 mg, 0.099 mmol), and PdCl2(PPh3)2 (3.5 mg, 0.005 mmol) in DMF (0.9 ml) and 1 M aqueous K2CO3 (0.187 ml) was stirred under argon at 105° C. for 2.5 h. The RM was cooled to rt. The mixture was diluted with MeOH+3 drops TFA and purified directly by Prep.HPLC (H2O (0.1% TFA)/CH3CN 97:3 to 55:45). The fractions containing product were collected together and basified with NaHCO3 (0.3 g), before being concentrated. The resulting layer was extracted with DCM, washed with brine, dried over Na2SO4, filtered and evaporated to dryness to give the title compound as a white solid. (HPLC: tR 2.44 min (Method A); M+H=442 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 9.00 (s, 1H), 8.75-8.69 (m, 1H), 8.24-8.19 (m, 1H), 8.18-8.07 (m, 2H), 8.07-7.98 (m, 3H), 7.75-7.67 (m, 1H), 7.61-7.56 (m, 1H), 4.61-4.48 (m, 1H), 3.58 (s, 3H), 1.97 (s, 3H), 1.45 (s, 3H), 1.43 (s, 3H))
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[N:10]=[CH:11][C:12]([NH:15][C:16](=[O:18])[CH3:17])=[N:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:25][N:26]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[N:27]1>O1CCOCC1.O.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>[CH3:25][N:26]1[CH:30]=[C:29]([C:2]2[CH:7]=[C:6]([O:8][C:9]3[N:10]=[CH:11][C:12]([NH:15][C:16](=[O:18])[CH3:17])=[N:13][CH:14]=3)[CH:5]=[CH:4][N:3]=2)[CH:28]=[N:27]1
Reactant: CC(=O)Nc1cnc(Oc2ccnc(Cl)c2)cn1
Reactant: Cn1cc(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: CC(=O)Nc1cnc(Oc2ccnc(-c3cnn(C)c3)c2)cn1
Temperature: 80 °C
Reaction time: 3 h
Yield: 81.8 %

Procedure:
To a degassed solution of N-(5-((2-chloropyridin-4-yl)oxy)pyrazin-2-yl)acetamide (0.25 g, 0.945 mmol) in dioxane (6 mL) was added a solution of K2CO3 (0.261 g, 1.889 mmol) in water (1.5 mL), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.255 g, 1.228 mmol), and Pd(PPh3)4 (0.109 g, 0.094 mmol). The mixture was stirred at 80° C. for 3 h. The mixture was diluted with water (30 mL) and extracted with EtOAc (2×80 mL). The combined organics were washed with brine, dried (Na2SO4) and concentrated in vacuo. The crude product was purified by silica gel chromatography (MeOH/DCM) to afford N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyrazin-2-yl)acetamide (240 mg, 82%) product as white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.86 (s, 1H), 8.97 (d, J=1.4 Hz, 1H), 8.43 (dd, J=5.6, 0.5 Hz, 1H), 8.40 (d, J=1.4 Hz, 1H), 8.27 (s, 1H), 7.98 (d, J=0.7 Hz, 1H), 7.40 (m, 1H), 6.92 (dd, J=5.6, 2.4 Hz, 1H), 3.85 (s, 3H), 2.12 (s, 3H); MS (ESI) m/z: 311.1 (M+H+).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:5]([CH:15]([S:24]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[F:23])=[CH:6][C:7]([NH:10][CH2:11][CH2:12][CH2:13][NH2:14])=[N:8][CH:9]=1.N1C=CC=CC=1.[C:40](OC(=O)C)(=[O:42])[CH3:41]>C(Cl)Cl>[Cl:3][C:4]1[C:5]([CH:15]([S:24]([C:27]2[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=2)(=[O:25])=[O:26])[C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[F:23])=[CH:6][C:7]([NH:10][CH2:11][CH2:12][CH2:13][NH:14][C:40](=[O:42])[CH3:41])=[N:8][CH:9]=1
Reactant: NCCCNc1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)c(Cl)cn1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)NCCCNc1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)c(Cl)cn1
Reaction time: 1 h
Yield: 78.9 %

Procedure:
To a methylene chloride solution (5.0 ml) of N-[5-chloro-4-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-2-yl]propane-1,3-diamine dihydrochloride (47 mg, 0.084 mmol) were added pyridine (17 μl, 0.34 mmol) and acetic anhydride (9.5 μl, 0.10 mmol). The resulting mixture was stirred for 1 hour. The residue obtained by concentrating the reaction mixture was purified by silica gel chromatography (ethyl acetate:methanol=10:1) to give the title compound (35 mg, 79%). The compound was crystallized in ether to afford a white solid (27 mg).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13]([C:15]4[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=4)=[CH:12][C:11]=3[CH:23]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:24]1[CH2:27][CH:26]([C:28]([OH:30])=[O:29])[CH2:25]1.C([BH3-])#N.[Na+]>CO.CS(C)=O>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13]([C:15]4[CH:16]=[CH:17][C:18]([CH2:19][N:24]5[CH2:27][CH:26]([C:28]([OH:30])=[O:29])[CH2:25]5)=[CH:21][CH:22]=4)=[CH:12][C:11]=3[CH:23]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C1CNC1
Reactant: O=Cc1ccc(-c2cc3cc(-c4ccccc4)ccc3o2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CS(C)=O
Product: O=C(O)C1CN(Cc2ccc(-c3cc4cc(-c5ccccc5)ccc4o3)cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 5.6 %

Procedure:
A mixture of 4-(5-phenylbenzofuran-2-yl)benzaldehyde (49 mg, 0.14 mmol) and azetidine-3-carboxylic acid (30 mg, 0.28 mmol) in MeOH (1 mL) was stirred at room temperature for 1 h. Sodium cyanoborohydride (60 mg, 0.28 mmol) was added in two portions and the reaction mixture was stirred for 16 h. Concentration of the solvent under reduced pressure yielded a yellow solid that was dissolved in DMSO (3 mL) and filtered to give a yellow solution that was purified by HPLC to yield 3 mg of desired product [hS1P1 EC50=1200 nM]: 1H NMR (400 MHz, CD3OD) δ 8.03 (d, 2H), 7.84 (br s, 1H), 7.66-7.58 (m, 6H), 7.45 (t, 2H), 7.36-7.32 (m, 2H), 4.47 (s, 2H), 4.40-4.32 (m, 4H), 3.72 (m, 1H). MS (ESI) m/z: Calculated: 383.15; Observed: 383.9 (M++1).
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:12][C:11]([CH3:14])([CH3:13])[CH2:10][C:9]2[N:8]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[N:7]=[C:6]([CH3:21])[C:5]1=2.[CH3:22]I>O1CCCC1>[CH3:22][O:3][CH:4]1[CH2:12][C:11]([CH3:14])([CH3:13])[CH2:10][C:9]2[N:8]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[N:7]=[C:6]([CH3:21])[C:5]1=2
Reactant: CI
Reactant: Cc1nn(-c2ccccn2)c2c1C(O)CC(C)(C)C2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1CC(C)(C)Cc2c1c(C)nn2-c1ccccn1
Reaction time: 0.08 h
Yield: 81.3 %

Procedure:
0.11 g (2.04 mmol) of 55% sodium hydride in oil were added to a solution of 4-hydroxy-1-(2-pyridyl)-3,6,6-trimethyl-4,5,6,7-tetrahydroindazole (0.35 g, 1.36 mmol), prepared as described in example 12, in dry tetrahydrofuran (5 ml) maintained under magnetic stirring and inhert atmosphere at 0° C. After 5 minutes, 0.13 ml (2.04 mmol) of methyl iodide were added, the reaction mixture was allowed to warm to room temperature and after 3.5 hours further 0.13 ml of methyl iodide were added. Stirring was continued for about 24 hours, additional sodium hydride (0.11 g) and methyl iodide (0.13 ml) were added and after 2.5 hours the solvent was evaporated. The residue was chromatographed on silica gel (cyclohexane:ethyl acetate=90:10), to yield the title compound as a colourless solid (0.3 g, 82%): m.p. 66-68° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[C:4]([Cl:9])[N:3]=1.[O:10]1[CH2:15][CH2:14][CH:13]([C:16]#[N:17])[CH2:12][CH2:11]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:13]2([C:16]#[N:17])[CH2:14][CH2:15][O:10][CH2:11][CH2:12]2)[CH:5]=[C:4]([Cl:9])[N:3]=1
Reactant: N#CC1CCOCC1
Reactant: Clc1cc(Cl)nc(Cl)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#CC1(c2cc(Cl)nc(Cl)c2)CCOCC1
Reaction time: 0.08 h

Procedure:
To a stirring solution of 2,4,6-trichloropyridine (4.65 g, 24.7 mmol) and tetrahydropyran-4-carbonitrile (2.29 g, 20.6 mmol) in THF (100 mL, 0.2 M) and under nitrogen at −78° C. was added lithium bis(trimethylsilyl)amide (29 mL, 29 mmol, 1.0 M in THF) and after 5 min, the cooling bath was removed. After stirring a further 40 min, the reaction was quenched by the addition of sat. aq. NH4Cl and then concentrated. The mixture was extracted with CH2Cl2 and organics dried over MgSO4. Following concentration, the residue was purified by flash column chromatography (100:0-70:30 heptanes/EtOAc) but care needed to be taken to prevent compound precipitation on the column. After purification, 4-(2,6-dichloro-4-pyridyl)tetrahydropyran-4-carbonitrile was obtained a white solid (3.75 g, 71%); 1H NMR (400 MHz, CDCl3) δ 7.39 (d, J=0.6 Hz, 2H), 4.17-4.05 (m, 2H), 3.93-3.84 (m, 2H), 2.15-1.99 (m, 4H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][C:10]=1[N+:18]([O-])=O.CN(C=O)C.[F:26][C:27]1[CH:28]=[C:29]([CH:31]=[CH:32][C:33]=1[F:34])[NH2:30]>>[NH2:18][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:9]=1[O:8][CH3:7])[C:13]([NH:30][C:29]1[CH:31]=[CH:32][C:33]([F:34])=[C:27]([F:26])[CH:28]=1)=[O:15]
Reactant: Nc1ccc(F)c(F)c1
Reactant: COc1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Nc2ccc(F)c(F)c2)cc1N
Yield: 87.4 %

Procedure:
Prepared according to the procedure described for Example 1 using oxalyl chloride (3.0 mL, 34.39 mmol), 4-methoxy-3-nitrobenzoic acid (5.00 g, 25.36 mmol), DMF (1.0 mL, 12.92 mmol), and 3,4-difluoroaniline (5.0 mL, 50.42 mmol) to afford the product (6.17 g), m.p. 171-172° C.
Reaction SMILES: Cl[C:2]1[N:3]([CH2:10][C@:11]2([CH3:14])[CH2:13][O:12]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][O:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:18][CH:17]=1.O.[H-].[Na+]>CN(C=O)C>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][O:25][CH:26]2[CH2:27][CH2:28][N:29]([CH2:13][C@:11]3([CH3:14])[O:12][C:2]4=[N:6][C:5]([N+:7]([O-:9])=[O:8])=[CH:4][N:3]4[CH2:10]3)[CH2:30][CH2:31]2)=[CH:18][CH:17]=1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Reactant: Clc1ccc(CCCOC2CCNCC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@]1(CN2CCC(OCCCc3ccc(Cl)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 60 °C
Reaction time: 4 h
Yield: 19.2 %

Procedure:
(R)-2-Chloro-1-(2-methyloxiran-2-ylmethyl)-4-nitroimidazole prepared in Example 12 (0.103 g, 0.473 mmol) and 4-[3-(4-chlorophenyl)propoxy]piperidine (0.109 g, 0.430 mmol) were dissolved in DMF (10 ml), and the solution was stirred at 60° C. for 4 hours. The reaction mixture was added water and extracted with ethyl acetate. The organic phase was combined, washed with water and a saturated saline solution, dried over sodium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=2/3) to afford an oil. The oil was dissolved in DMF (2 ml). To the solution, sodium hydride (15 mg, 0.375 mmol) was added with cooling on ice-bath followed by stirring at room temperature for 3 hours. To the reaction mixture, water was added, and the precipitates were filtered off, purified by silica gel column chromatography (methylene chloride/ethyl acetate=6/1) and then recrystallized from ethyl acetate/n-hexane=1/3 (6 ml) to afford (S)-2-{4-[3-(4-chlorophenyl)propoxy]-piperidin-1-ylmethyl}-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole (36 mg, yield 19%) as a white powder.