Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[F:12][C:13]([F:23])([F:22])[C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17]Cl.[CH3:24][C:25]([NH:28][C:29]1[O:30][C:31]([C:38]([OH:40])=[O:39])=[C:32]([C:34]([F:37])([F:36])[F:35])[N:33]=1)([CH3:27])[CH3:26]>O>[CH3:27][C:25]([NH:28][C:29]1[O:30][C:31]([C:38]([O:40][CH2:17][C:16]2[CH:19]=[CH:20][CH:21]=[C:14]([C:13]([F:23])([F:22])[F:12])[CH:15]=2)=[O:39])=[C:32]([C:34]([F:35])([F:37])[F:36])[N:33]=1)([CH3:24])[CH3:26]
Reactant: CC(C)(C)Nc1nc(C(F)(F)F)c(C(=O)O)o1
Reactant: FC(F)(F)c1cccc(CCl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)Nc1nc(C(F)(F)F)c(C(=O)OCc2cccc(C(F)(F)F)c2)o1
Temperature: 25 °C
Yield: 161.3 %

Procedure:
A reaction vessel was charged with 50 ml of dimethylformamide, 2.6 g (18.8 mmol) of potassium carbonate, and 5.36 g (28 mmol) of m-trifluoromethyl benzyl chloride. With this mixture stirred at ambient temperature under a nitrogen atmosphere, there was added 4.03 g (17 mmol) of 2-[(1,1-dimethylethyl)amino]-4-trifluoromethyl-5-oxazolecarboxylic acid (prepared by Example 26). The reaction mixture was stirred at ambient temperature for 36 hours. Then, the mixture was added to water and extracted four times with ethyl ether. The ether extracts were washed with large amounts of water, then dried over magnesium sulfate, and concentrated under reduced pressure to yield 11.25 g of a yellow oily solid material. This solid material was dissolved in ethyl ether, washed with large amounts of water, dried over magnesium sulfate, and concentrated under reduced pressure to yield 10.8 g of a gold viscous oil. Then, 5.0 g of this oil was subjected to Kugelrohr distillation (83°-85° C. @ 0.5 mm Hg) to yield 1.38 g of a gold viscous oil which upon standing overnight formed an oily solid product identified in Table I.
Reaction SMILES: Cl[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[N:5]=[C:4]([C:17]([F:20])([F:19])[F:18])[C:3]=1[C:21]#[N:22].[NH:23]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.[F-].[K+].O>CS(C)=O>[N:23]1([C:2]2[N:6]([C:7]3[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=3)[N:5]=[C:4]([C:17]([F:20])([F:19])[F:18])[C:3]=2[C:21]#[N:22])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)c(C#N)c2Cl)cc1
Reactant: C1CCCNCC1
Agent: [F-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)c(C#N)c2N2CCCCCC2)cc1
Temperature: 20 °C
Reaction time: 48 h

Procedure:
5—Chloro-(4-methanesulfonyl-phenyl)-3-trifluoromethyl-1H-pyrazole-4-carbonitrile (70 mg, 0.2 mmol) and azepane (40 mg, 0.4 mmol) were dissolved in dry dimethylsulfoxide (DMSO) (2 ml) and potassium fluoride (0.35 mg, 0.6 mmol) was added to the DMSO solution. The resulting mixture was stirred at 20° C. for a period of 48 hours. Analytical HPLC indicated the reaction completion. The reaction mixture was poured into water (15 ml) and the resulting mixture was extracted with ethyl acetate (20 ml). The organic extract was dried over magnesium sulfate and concentrated with a rotary evaporator. The desired product was isolated by chromatography on silica gel column. MS:395, r.t.: 2.6 min.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([Cl:12])=[CH:4][N:3]=1.O.[NH2:14][NH2:15]>C(O)(C)C>[Cl:12][C:5]1[C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][C:2]([NH:14][NH2:15])=[N:3][CH:4]=1
Reactant: NN
Reactant: FC(F)(F)c1cc(Cl)ncc1Cl
Solvent: O
Solvent: CC(C)O
Product: NNc1cc(C(F)(F)F)c(Cl)cn1
Temperature: 70 °C
Reaction time: 16 h
Yield: 96 %

Procedure:
To a solution of 2,5-dichloro-4-(trifluoromethyl)pyridine (1 g, 4.63 mmol) in isopropanol (20 mL) was added hydrazine monohydrate (2.021 mL, 41.7 mmol). The mixture was stirred at 70° C. for 16 h. The reaction was concentrated. The residue was taken up in ethyl acetate and the insoluble material was removed by filtration. The filtrate was concentrated to give the title compound as a tan solid (0.94 g). LCMS m/z=212.0 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 4.39 (s, 2H), 7.11 (s, 1H), 8.19 (s, 1H), 8.25 (s, 1H).
Reaction SMILES: [CH:1]([NH:4][C:5]1[O:6][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([S:19]([C:22]2[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:14]=[C:13]3B2OC(C)(C)C(C)(C)O2)=[N:8][N:9]=1)([CH3:3])[CH3:2].Br[C:39]1[CH:40]=[N:41][CH:42]=[C:43]([CH:47]=1)[C:44]([OH:46])=[O:45].O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:1]([NH:4][C:5]1[O:6][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([S:19]([C:22]2[CH:23]=[CH:24][C:25]([CH3:26])=[CH:27][CH:28]=2)(=[O:20])=[O:21])[CH:14]=[C:13]3[C:39]2[CH:40]=[N:41][CH:42]=[C:43]([CH:47]=2)[C:44]([OH:46])=[O:45])=[N:8][N:9]=1)([CH3:3])[CH3:2]
Reactant: O=C(O)c1cncc(Br)c1
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(-c4nnc(NC(C)C)o4)ccc32)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cncc(C(=O)O)c3)c3cc(-c4nnc(NC(C)C)o4)ccc32)cc1
Temperature: 90 °C
Yield: 75.7 %

Procedure:
To a solution of N-isopropyl-5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine (4.0 g, 7.662 mmol) and 5-bromonicotinic acid (2.3 g, 11.49 mmol, Sigma-Aldrich) in DME (75 mL)/water (18 mL) was added Na2CO3 (2.7 g, 22.98 mmol) and Pd(PPh3)4 (878 mg, 0.76 mmol) and Ar gas was bubbled for 5 min. The reaction mixture was heated at 90° C. for 4 h. The reaction was quenched with water (200 mL) to get a brown precipitate. The precipitate was filtered, washed with water (2×100 mL) and dried to give crude product (3.0 g), which was used in the next step without further purification. MS (ESI, pos. ion) m/z: 518.2 (M+1).
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:15])[C:7]2=[O:16])[CH2:3][CH2:2]1.C(N1C2C(=CC=CC=2)C(=O)C1=O)CCCC.O1C2C=CC(O)=CC=2OC1.[CH3:43][C:44]1[S:45][C:46]2[CH:52]=[CH:51][C:50]([OH:53])=[CH:49][C:47]=2[N:48]=1>>[OH:15][C:8]1([C:51]2[C:50]([OH:53])=[CH:49][C:47]3[N:48]=[C:44]([CH3:43])[S:45][C:46]=3[CH:52]=2)[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:6]([CH2:5][CH2:4][CH2:1][CH2:3][CH3:2])[C:7]1=[O:16]
Reactant: O=C1C(=O)N(CCC2CC2)c2ccccc21
Reactant: Cc1nc2cc(O)ccc2s1
Agent: CCCCCN1C(=O)C(=O)c2ccccc21
Agent: Oc1ccc2c(c1)OCO2
Product: CCCCCN1C(=O)C(O)(c2cc3sc(C)nc3cc2O)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 2B, and making non-critical variations to replace 1-(2-cyclopropylethyl)-1H-indole-2,3-dione with 1-pentyl-1H-indole-2,3-dione, and 1,3-benzodioxol-5-ol with 2-methyl-1,3-benzothiazol-5-ol, the title compound was obtained (81%) as a colorless solid: 1H NMR (300 MHz, DMSO-d6) δ 9.90 (br, 1H), 9.05 (br, 1H), 7.78 (d, 1H), 7.25 (dd, 1H), 7.10-6.95 (m, 2H), 6.90-6.80 (m, 2H), 3.81-3.58 (m, 2H), 2.75 (br, 3H), 1.80-1.60 (m, 2H), 1.50-1.31 (m, 4H), 0.90 (t, 3H); MS (ES+) m/z 383.4 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([CH2:9][S:10]([CH3:13])(=[O:12])=[O:11])[CH:6]=[CH:5][C:3]=1[NH2:4].O[CH2:15][CH:16]([CH2:18]O)O>>[CH3:13][S:10]([CH2:9][C:7]1[CH:6]=[C:5]2[C:3](=[C:2]([Br:1])[CH:8]=1)[N:4]=[CH:18][CH:16]=[CH:15]2)(=[O:12])=[O:11]
Reactant: OCC(O)CO
Reactant: CS(=O)(=O)Cc1ccc(N)c(Br)c1
Product: CS(=O)(=O)Cc1cc(Br)c2ncccc2c1

Procedure:
2-bromo-4-(methylsulfonylmethyl)aniline and glycerol can be combined to form 6-(methylsulfonylmethyl)-8-bromoquinoline.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].N([O-])=O.[Na+].[I:9][C:10]1[CH:11]=[C:12]([O:16][CH3:17])[CH:13]=[CH:14][CH:15]=1.[I:18]I>C(O)(=O)C>[I:9][C:10]1[CH:11]=[C:12]([O:16][CH3:17])[C:13]([I:18])=[CH:14][C:15]=1[N+:1]([O-:4])=[O:2]
Reactant: II
Reactant: O=[N+]([O-])O
Reactant: COc1cccc(I)c1
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1cc(I)c([N+](=O)[O-])cc1I
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Nitric acid (68-70%, 125 mL) was slowly mixed with glacial acetic acid (125 ml) at room temperature, followed by addition of NaNO2 (400 mg, 5.8 mmol) and 3-iodoanisole (10 g, 42.7 mmol). After the reaction was stirred at room temperature for 24 hours, I2 (10.8 g, 42.7 mmol) was added and the mixture was stirred at 60° C. overnight. The reaction mixture was poured into ice-water (500 ml) and extracted by CH2Cl2 (100 ml) three times. The combined organic phase was neutralized with saturated NaHCO3 solution (500 ml), washed with aqueous solution of Na2S2O3 (20%, 100 ml), dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography to yield crude 3,6-diiodo-4-nitroanisole (5.4 g), which is mixed with one unknown by-product (20%) and used in the next step without further purification. 1H NMR (400 MHz, CDCl3): δ 8.42 (s, 1H, Ph-H), 7.33 (s, 1H, Ph-H), 3.97 (s, 3H, OCH3).
Reaction SMILES: C(OC([N:11]1[CH2:15][C@H:14]([OH:16])[CH2:13][C@H:12]1[CH2:17][O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])=O)C1C=CC=CC=1.O[C@H]1[C@@H]2CC(=C)CN2C(=O)C2C=C(I)C=CC=2N1NC(OCC(Cl)(Cl)Cl)=O.C(OC(N1C[C@H](O)C[C@H]1CO[Si](C(C)(C)C)(C)C)=O)C=C>C(OCC)(=O)C.C(O)C.[Pd]>[Si:19]([O:18][CH2:17][C@@H:12]1[CH2:13][C@@H:14]([OH:16])[CH2:15][NH:11]1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Agent: [Pd]
Agent: C=C1C[C@H]2[C@H](O)N(NC(=O)OCC(Cl)(Cl)Cl)c3ccc(I)cc3C(=O)N2C1
Agent: C=CCOC(=O)N1C[C@H](O)C[C@H]1CO[Si](C)(C)C(C)(C)C
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](O)CN1

Procedure:
A slurry of 10% Pd/C (190 mg) in ethyl acetate (20 mL) was added to a solution of TBDMS ether (43) (1.90 g, 5.19 mmol) in ethanol (100 mL). The reaction mixture was hydrogenated (Parr apparatus) for 16 h. The catalyst was removed by vacuum filtration through Celite and excess solvent was evaporated under reduced pressure to give a yellow oil in quantitative yield (1.20 g, 100%). [α]22.2D=+35.6° (c 0.042,CHCl3). 1H NMR (CDCl3): δ −(0.07-0.08) (m, 6H, H1=, H2=), 0.82 (s, 9H, H3=, H4=, H5=), 1.68-1.73 (m, 2H, H1,), 2.99-3.11 (m, 2H, H11), 3.47-3.50 (m, 3H, H11a, H3), 4.09 (bs, 1H, NH or OH), 4.32 (bs, 1H, NH or OH). 13C NMR (CDCl3): δ −5.4 (C3=, C5=, C6=), 18.1 (C4=), 25.8 (C1=, C2=), 37.4 (C1), 54.6 (C11), 58.1 (C2), 64.6 (C3), 72.2 (C11a). IR (thin film): v=3330 (OH), 2928, 2857, 1557, 1421, 1331 (C—CH3), 1249 (CH3-Si), 1204 (t-Bu), 1191 (t-Bu), 1100 (Si—O), 1073, 993, 713 cm−1. MS (Cl) m/e (relative intensity): 232 (M+., 100), 230 (13), 174 (5), 133 (6), 86 (6).
Reaction SMILES: [CH3:1][Si](C)(C)N[Si](C)(C)C.[Na].[CH:11]([C:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=1[C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:35])[C:27]2[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=2[F:34])=[CH:21][CH:20]=1)=O>C1COCC1>[CH:11]([C:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=1[C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:35])[C:27]2[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=2[F:34])=[CH:21][CH:20]=1)=[CH2:1]
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: O=CC1=C(c2ccc(NC(=O)c3c(F)cccc3F)cc2)CCCC1
Agent: [Na]
Solvent: C1CCOC1
Product: C=CC1=C(c2ccc(NC(=O)c3c(F)cccc3F)cc2)CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.9 %

Procedure:
To the solution of Ph3PCH3Br (75 mg, 0.21 mmol) in THF (4 mL) was added sodium hexamethyidisilazane (NaHMDS) (1 N, 0.21 mL, 0.21 mmol) at −78° C. After stirring at this temperature for 30 min, Compound 100 (70 mg, 0.21 mmol) was added. The reaction solution was allowed to warm up to room temperature and stirred overnight. The solution was quenched with NH4Cl (20 mL) and extracted with EtOAc (30 mL). The organic portion was collected, dried and concentrated. Column chromatography afforded Compound 101 (42 mg, 60%). 1H NMR (300 MHz, CDCl3) δ 7.63-7.51 (m, 3 H), 7.45-7.38 (m, 1 H), 7.26-7.15 (m, 2 H), 7.04-6.97 (m, 2 H), 6.45 (dd, J=17.4 and 11.1 Hz, 1 H), 5.14 (d, J=17.4 Hz, 1 H), 4.86 (d, J=11.4 Hz, 1 H), 2.37-2.29 (m, 4 H), 1.79-1.72 (m, 4 H); ESMS cacld (C21H19F2NO): 339.1; found: 340.1 (M+H).
Reaction SMILES: [O:1]([CH2:3][CH2:4][O:5][C:6]1[N:14]=[C:13]2[C:9]([NH:10][CH:11]=[N:12]2)=[C:8]([NH2:15])[N:7]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH:23]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:24]([O:26][CH2:27][CH3:28])=[O:25]>CN(C=O)C>[CH2:27]([O:26][C:24](=[O:25])[CH:23]([N:12]1[CH:11]=[N:10][C:9]2[C:13]1=[N:14][C:6]([O:5][CH2:4][CH2:3][O:1][CH3:2])=[N:7][C:8]=2[NH2:15])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH3:28]
Reactant: CCOC(=O)C(Br)c1ccccc1
Reactant: COCCOc1nc(N)c2[nH]cnc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(c1ccccc1)n1cnc2c(N)nc(OCCOC)nc21

Procedure:
To a suspension of 2-methoxylethoxyadenine (500 mg, 2.39 mmol) in DMF (5 ml), was added K2CO3 (329 mg, 2.39 mmol) and ethyl α-bromophenylacetate (460 μl, 2.68 mmol). The reaction mixture was allowed to react at 70° C. for 2 h. The reaction mixture was washed with water and extracted by DCM. The organic later was dried over Na2SO4. The organic layer then was filtered, concentrated and purified by silica gel column, using dichlormethane and MeOH as the solvent in a linear gradient. 1H NMR (CDCl3): δ 1.31 (t, 3H), δ 3.45 (s, 3H), δ 3.78 (t, 2H), δ 4.29-4.33 (m, 2H), δ 4.51 (t, 2H), δ 5.83 (bs, 2H), δ 7.41-7.42 (m, 5H), δ 7.78 (s, 1H); MS: 372.1 (M+H)+, 370.1 (M−1).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([O:11][C:12](=[O:21])[NH:13][CH2:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)([CH3:10])([CH3:9])[CH3:8].Br[C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][N:24]=1>CO>[C:7]([O:11][C:12](=[O:21])[NH:13][CH2:14][CH:15]1[CH2:16][CH2:17][N:18]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][N:24]=2)[CH2:19][CH2:20]1)([CH3:10])([CH3:8])[CH3:9]
Reactant: FC(F)(F)c1ccc(Br)nc1
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)(C)OC(=O)NCC1CCN(c2ccc(C(F)(F)F)cn2)CC1
Temperature: 120 °C
Yield: 80.8 %

Procedure:
In a 5-ml microwave vial equipped was placed potassium carbonate (1.38 g), tert-butyl(piperidin-4-ylmethyl)carbamate (1.07 g), and 2-bromo-5-trifluoromethylpyridine (1.13 g) in methanol. This was heated to 120° C. for 30 min in a microwave reactor. The mixture was cooled and concentrated in vacuo, and the residue was taken up in ethyl acetate. This was filtered through a plug of silica gel, and the eluent was concentrated in vacuo to provide tert-butyl({1-[5-(trifluoromethyl)pyridin-2-yl]piperidin-4-yl}methyl)carbamate (1.45 g, 81%). This compound was taken up in 15 ml of dichloromethane and 15 ml of trifluoroacetic acid. The resultant mixture was stirred at room temperature for 2 h, and then concentrated and taken up in dichloromethane (20 ml) and saturated aqueous sodium bicarbonate. The mixture was extracted and the organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to provide 1.31 g (87%) of the title compound. Mass spectrum (ESI) 260.1 (M+1).
Reaction SMILES: CCN(C(C)C)C(C)C.CS(Cl)(=O)=O.CS(O[CH2:20][CH2:21][CH:22]([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=1)(=O)=O.[I-:38].[Na+]>C(Cl)Cl.CC(C)=O>[Cl:29][C:25]1[CH:24]=[C:23]([CH:22]([NH:30][C:31](=[O:32])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:21][CH2:20][I:38])[CH:28]=[CH:27][CH:26]=1
Reactant: [I-]
Reactant: CC(C)(C)OC(=O)NC(CCOS(C)(=O)=O)c1cccc(Cl)c1
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC(CCI)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
To a solution of Intermediate 9C (61 mg, 0.213 mmol) in DCM (5 mL) was added DIEA (0.080 mL, 0.458 mmol) followed by the addition of MeSO2Cl (0.030 mL, 0.385 mmol). The reaction mixture was then stirred at rt for 0.5 h. After 30 min., the reaction mixture was concentrated. The residue was dissolved in EtOAc and washed with aqueous NaHCO3 solution followed by brine. The organic layers were then dried over MgSO4 and concentrated in vacuo to yield a clear oily residue, which was subjected to the next step without further purification. To a solution of 3-((tert-butoxycarbonyl)amino)-3-(3-chlorophenyl)propyl methanesulfonate in acetone (5 mL) was added sodium iodide (128 mg, 0.854 mmol). The yellow suspension was refluxed for ˜4 h, and then stirred at rt for overnight. The reaction mixture was then concentrated followed by addition of small amount of water and DCM. The aqueous layer was then re-extracted with DCM (2×). The combined organic layers were concentrated and then purified by chromatography to give tert-butyl (1-(3-chlorophenyl)-3-iodopropyl)carbamate (68 mg, 81%) as yellow oil which solidified upon standing. MS (ESI) m/z: 395.9 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH:5](O)[C:6]1[N:10]2[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:9]2=[N:8][C:7]=1[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[CH3:2]>C(Cl)Cl.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[N:10]2[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:9]2=[N:8][C:7]=1[C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)[CH3:2]
Reactant: CCOC(=O)C(O)c1c(-c2ccc(OC)cc2)nc2ccc(C)cn12
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1c(-c2ccc(OC)cc2)nc2ccc(C)cn12
Temperature: 25 °C
Reaction time: 4 h
Yield: 42.4 %

Procedure:
To a magnetically stirred solution of hydroxy-[2-(4-methoxy-phenyl)-6-methyl-imidazo[1,2-a]pyridin-3-yl]-acetic acid ethyl ester 13b (0.72 g, 2.11 mmol) in DCM (21 mL) under Ar atmosphere was added P2I4 (0.84 g mg, 1.48 mmol). The reaction mixture was stirred at room temperature for 4 h. Aqueous NaH2CO3 (100 mL) was added, and the aqueous phase was extracted with dichloromethane (20 mL). The combined organic layers were washed with water (100 mL), dried (MgSO4), and concentrated in vacuo to the crude product. The pure product was obtained by column chromatography over silica gel (40:60 EtOAc/hexane, then 100% EtOAc as eluent), which gave the title compound (0.29 g, 42%) as an off white solid. 1H NMR (400 MHz, CDCl3) δ 1.25 (t, J=7.3 Hz, 3H), 2.33 (s, 3H), 3.82 (s, 3H), 3.96 (s, 2H), 4.19 (q, J=7.3 Hz, 2H), 6.97 (d, J=8.8 Hz, 2H), 7.04 (dd, J=1.4, 9.1 Hz, 1H), 7.53 (d, J=9.1 Hz, 1H), 7.73 (d, J=8.8 Hz, 2H), 7.85 (s, 1H).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[C:13](=[O:15])[CH3:14])(=O)C.[CH2:16]([OH:18])[CH3:17]>>[CH2:1]([N:8]1[C:13](=[O:15])[C:14]2[C:17](=[N:8][CH:1]=[CH:2][CH:3]=2)[C:16]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: CCO
Reactant: CC(=O)OC(C)=O
Product: O=C1c2cccnc2C(=O)N1Cc1ccccc1
Temperature: 180 °C
Reaction time: 0.5 h

Procedure:
To 100 g of 2,3-pyridinedicarboxylic acid was added dropwise 170 ml of acetic anhydride at room temperature, and the mixture was heated up to 110° C., and stirred for 4 hours. After completion of the reaction, the solvent was removed under reduced pressure. To a residue was added 200 ml of diethyI ether, and a precipitated crystal was collected by filtration and washed with diethyl ether (100 ml×4) to yield 86 g of an acid anhydride compound. To the product was added dropwise 76 ml of benzylamine while cooling with ice, and the mixture was stirred at 180° C. for 30 minutes. To the reaction mixture was added dropwise 170 ml of acetic anhydride while cooling with ice, followed by stirring at 110° C. for 2 hours. After completion of the reaction, the reaction mixture was allowed to cool, and 500 ml of ethanol was added thereto. The thus formed crystal was collected by filtration and washed with ethanol (100 ml×3) to yield 89.4 g of the titled compound.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([NH2:20])=[CH:12][CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:21](=O)(O)[O-:22].[Na+].C(Cl)(Cl)=O.[C:30]([C:34]1[CH:35]=[C:36]([NH:43][S:44]([CH3:47])(=[O:46])=[O:45])[C:37]([O:41][CH3:42])=[C:38]([CH:40]=1)[NH2:39])([CH3:33])([CH3:32])[CH3:31]>ClCCl>[C:30]([C:34]1[CH:35]=[C:36]([NH:43][S:44]([CH3:47])(=[O:46])=[O:45])[C:37]([O:41][CH3:42])=[C:38]([NH:39][C:21]([NH:20][C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:10]([O:9][CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[CH:11][CH:12]=2)=[O:22])[CH:40]=1)([CH3:33])([CH3:31])[CH3:32]
Reactant: Nc1ccc(OCCN2CCOCC2)c2ccccc12
Reactant: O=C([O-])O
Reactant: COc1c(N)cc(C(C)(C)C)cc1NS(C)(=O)=O
Agent: O=C(Cl)Cl
Agent: [Na+]
Solvent: ClCCl
Product: COc1c(NC(=O)Nc2ccc(OCCN3CCOCC3)c3ccccc23)cc(C(C)(C)C)cc1NS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
4-[2-(Morpholin-4-yl)ethoxy]napth-1-yl-amine (Example 5) (1.0 mmol) is dissolved in dichloromethane (15 mL). An equal volume of sat. aqueous sodium bicarbonate is added, and the biphasic solution is cooled to 0° C. During the addition of phosgene (1.93 M in toluene, 1.0 mL), stirring is stopped. Immediately afterward, stirring is resumed for 15 min with the reaction mixture at 0° C. The layers are separated, the organics dried over solid magnesium sulfate and concentrated to approximately 5 mL of solution. 5-tert-Butyl-3-methanesulfonamido-2-methoxyaniline (Example 4) (0.9 mmol) in dichloromethane (5 mL) is added, and the reaction mixture is stirred overnight at ambient temperature. The solvent is removed by rotary evaporation and the resulting product purified by flash chromatography over silica gel with a suitable elutant such as CH2Cl2:MeOH (95:5) to give the title compound.
Reaction SMILES: O(P(O[C:18]1[N:19]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:21][O:22][CH:23]=1)(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[C:31]([O:35][C:36]([NH:38][C:39]1[N:44]=[CH:43][C:42](B(O)O)=[CH:41][CH:40]=1)=[O:37])([CH3:34])([CH3:33])[CH3:32]>>[C:31]([O:35][C:36]([NH:38][C:39]1[N:44]=[CH:43][C:42]([C:18]2[N:19]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:20][CH2:21][O:22][CH:23]=2)=[CH:41][CH:40]=1)=[O:37])([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)Nc1ccc(B(O)O)cn1
Reactant: CC(C)(C)OC(=O)N1CCOC=C1OP(=O)(Oc1ccccc1)Oc1ccccc1
Product: CC(C)(C)OC(=O)Nc1ccc(C2=COCCN2C(=O)OC(C)(C)C)cn1
Yield: 26 %

Procedure:
This compound was prepared from tert-butyl 5-((diphenoxyphosphoryl)oxy)-2H-1,4-oxazine-4(3H)-carboxylate and 6-(tert-butoxycarbonylamino)pyridin-3-ylboronic acid using a procedure similar to that described in Example 2 (Steps 1-3a) above. The product was isolated as a white solid (26% yield); 1H-NMR (d6-DMSO) 1.10 (9H, s), 1.46 (9H, s), 3.69 (2H, t), 4.10 (2H, t), 6.43 (1H, s), 7.51-7.54 (1H, m), 7.73 (1H, m), 8.06 (1H, s), 9.75 (1H, s); 13C-NMR (d6-DMSO) 27.9, 28.3, 41.7, 66.8, 111.3, 132.3, 133.1, 135.0, 143.9; MS ES(+) 378.0 M++1); HRMS m/z calcd for C19H27N3O5+H+ 378.2029 [M+H+]. Found 378.2035. IR λmax=1699 cm−1.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]([CH3:18])[N:10]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.C(O)(=O)C.[Cl:23]Cl>CCCCCC.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([C:9]2[C:13]([Cl:23])=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]([CH3:18])[N:10]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: ClCl
Reactant: Cn1nc(-c2ncc(Cl)cc2Cl)cc1C(F)(F)F
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cn1nc(-c2ncc(Cl)cc2Cl)c(Cl)c1C(F)(F)F
Yield: 90 %

Procedure:
2.0 g of 3-(3,5-dichloro-2-pyridyl)-5-trifluoromethyl-1-methyl-[1H]-pyrazole (Example P11) are introduced into glacial acetic acid at 40° C. and, with stirring, chlorine gas is slowly passed over the solution. The reaction can be monitored analytically by means of thin-layer chromatography (silica gel 60 F254, eluant: n-hexanelethyl acetate 4/1, UV). Once starting material can no longer be detected, glacial acetic acid is removed in vacuo and the residue is partitioned between dilute aqueous sodium hydroxide solution and ethyl acetate. After extraction by shaking, the separated organic phase is washed with brine, dried over sodium sulfate, filtered and concentrated. The yellow oil is purified by means of flash chromatography (silica gel; eluant: n-hexane/ethyl acetate 5/1). 1.6 g of of the desired compound are obtained in the form of a yellow oil (70% of the theoretical yield).