Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[OH:13][CH:14]([CH3:51])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:28](=[O:29])[C:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[C:38]([C:43]#[N:44])=[CH:39][CH:40]=[CH:41][CH:42]=4)=[CH:33][CH:32]=3)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]3[N:48]=[CH:49][CH:50]=[C:24]23)=[CH:19][CH:18]=1>C(OCC)(=O)C>[OH:13][CH:14]([CH3:51])[CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[C:28](=[O:29])[C:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=4[C:43]4[NH:3][C:4](=[O:7])[O:5][N:44]=4)=[CH:33][CH:32]=3)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]3[N:48]=[CH:49][CH:50]=[C:24]23)=[CH:21][CH:22]=1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(-c2ccc(OCC(C)O)cc2)c2ccnn12
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(-c2ccc(OCC(C)O)cc2)c2ccnn12
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 38.9 %

Procedure:
A mixture of hydroxylammonium chloride (0.48 g), sodium hydrogen carbonate (0.72 g) and dimethyl sulfoxide (3 mL) was stirred at 50° C. for 30 min, 4′-({4-[4-(2-hydroxypropoxy)phenyl]-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.30 g) was added, and the mixture was stirred at 90° C. for 15 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (3 mL). N,N′-Carbonyldiimidazole (0.092 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.072 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid, then with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.13 g, 38%).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:7][CH2:6][C@H:5]([OH:8])[C@@H:4]1[OH:9].[CH3:10][C:11]1([CH3:35])[CH2:20][CH2:19][C:18]([CH3:22])([CH3:21])[C:17]2[CH:16]=[C:15]([C:23]3[N:24]=[C:25]([N:28]4[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]4)[S:26][CH:27]=3)[CH:14]=[CH:13][C:12]1=2.Cl>>[CH3:10][C:11]1([CH3:35])[CH2:20][CH2:19][C:18]([CH3:21])([CH3:22])[C:17]2[CH:16]=[C:15]([C:23]3[N:24]=[C:25]([N:28]4[CH2:33][CH2:32][CH:31]([NH:2][C@@H:3]5[CH2:7][CH2:6][C@H:5]([OH:8])[C@@H:4]5[OH:9])[CH2:30][CH2:29]4)[S:26][CH:27]=3)[CH:14]=[CH:13][C:12]1=2
Reactant: N[C@@H]1CC[C@H](O)[C@@H]1O
Reactant: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCC(=O)CC4)n3)ccc21
Agent: Cl
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCC(N[C@@H]5CC[C@H](O)[C@@H]5O)CC4)n3)ccc21

Procedure:
The preparation is carried out analogously starting from 24 mg (0.16 mmol) of (1S,2R,3R)-3-aminocyclopentane-1,2-diol hydrochloride and 60 mg (0.16 mmol) of 1-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]-piperidin-4-one. The product is in the form of the hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][N:5]([CH3:27])[C:6]2[C:7]=1[CH:8]=[N:9][C:10]1[N:19]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:18][CH:17]=[C:12]3[NH:13][C:14](=[O:16])[C:15]=2[C:11]=13.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:61][C:62]1[CH:67]=[CH:66][C:65]([F:68])=[CH:64][C:63]=1[CH2:69][C:70](O)=[O:71]>CN(C)C(=O)C>[Cl:61][C:62]1[CH:67]=[CH:66][C:65]([F:68])=[CH:64][C:63]=1[CH2:69][C:70]([NH:1][C:2]1[CH:3]=[CH:4][N:5]([CH3:27])[C:6]2[C:7]=1[CH:8]=[N:9][C:10]1[N:19]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:18][CH:17]=[C:12]3[NH:13][C:14](=[O:16])[C:15]=2[C:11]=13)=[O:71]
Reactant: O=C(O)Cc1cc(F)ccc1Cl
Reactant: CN1C=CC(N)=c2cnc3c4c([nH]c(=O)c-4c21)=CCN3c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CN1C=CC(NC(=O)Cc2cc(F)ccc2Cl)=c2cnc3c4c([nH]c(=O)c-4c21)=CCN3c1ccc(F)cc1
Yield: 30 %

Procedure:
A stock solution of Example 14e and N,N-diisopropylethylamine (0.11 M and 0.33 M in N,N-dimethylacetamide, respectively, 350 μL, 0.038 mmol Example 14e and 0.11 mmol N,N-diisopropylethylamine), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.13 M in N,N-dimethylacetamide, 350 μL, 0.046 mmol), and 2-(2-chloro-5-fluorophenyl)acetic acid (0.40 M in N,N-dimethylacetamide, 113 μL, 0.050 mmol) were aspirated from their respective source vials, mixed through a perfluoroalkoxy mixing tube (0.2 mm inner diameter), and loaded into an injection loop. The reaction segment was injected into the flow reactor (Hastelloy coil, 0.75 mm inner diameter, 1.8 mL internal volume) set at 100° C., and passed through the reactor at 180 μL per minute (10 minute residence time). Upon exiting the reactor, the reaction mixture was loaded directly into an injection loop and purified by reverse phase HPLC(C8, acetonitrile/water (0.1% ammonium acetate), 5-100%) to give 0.0062 g (30%) of the title compound. 1H NMR (400 MHz, DMSO-d6/D2O) δ 8.54 (d, J=2.75 Hz, 1H), 8.44 (d, J=2.75 Hz, 1H), 7.76 (s, 1H), 7.53 (dd, J=8.85, 5.19 Hz, 1H), 7.37 (dd, J=9.46, 3.05 Hz, 1H), 7.21 (m, 1H), 7.07 (s, 1H), 6.87 (m, 2H), 6.58 (m, 2H), 4.62 (m, 2H), 4.05 (s, 3H), 3.94 (s, 2H). MS (APCI+) m/z 532.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH:8]2SC)=[O:4]>C(O)(=O)C.[Zn]>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)=[O:4]
Reactant: COC(=O)c1ccc2c(c1)C(SC)C(=O)N2
Agent: [Zn]
Solvent: CC(=O)O
Product: COC(=O)c1ccc2c(c1)CC(=O)N2
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
A solution of 2.66 g (20.0 mmol) of ethyl (methylthio)acetate dissolved in 200 mL of dichloromethane was cooled with stirring to −70° C. and 2.7 g (20.0 mmol) of sulfuryl chloride was added. The reaction was stirred for 30 min. at −70° C., and a solution of 3.0 g (20 mol) of methyl 4-aminobenzoate and 4.39 (20 mmol) of Proton Sponge® in 250 mL of dichloromethane was added dropwise over 1 h. The resulting pink slurry was treated with 2.3 g (23 mmol) of TEA in one portion, and the solution was allowed to warm to rt. The solution was washed with three 250-mL portions of water, dried over MgSO4, and concentrated to give an oil. This was chromatographed on silica gel eluting with hexane:EtOAc (1:1) to yield 2.0 g (42% yield) of 3-methylthio-2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid methyl ester: 1H NMR (DMSO-d6): δ 1.97 (s, 3H), 3.35 (s, 3H), 4.67 (s, 1H), 6.97 (d, J=8.2 Hz, 1H), 7.84 (s, 1H). 7.91 (d, J=8.2 Hz, 1H), 10.97 (s, 1H). A solution of 2.0 g (8.4 mmol) of 3-methylthio-2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid methyl ester in 20 mL of acetic acid was treated with 10 g of zinc powder. The reaction mixture was stirred for 2 h at rt, filtered through celite and concentrated to dryness. The residue was chromatographed on silica gel eluting with hexane:EtOAc (1:1) to yield 1.6 g (99% yield) of 2oxo-2,3-dihydro-1H-indole-5-carboxylic acid methyl ester as a pink solid: 1H NMR (DMSO-d6): δ 3.52 (s, 2H), 3.77 (s, 3H), 6.87 (d, J=8.2 Hz, 1H), 7.74 (s, J=1H), 7.80 (d, J=8.2 Hz, 1H), 10.72 (br s, 1H). Conversion to the 3-dimethylaminomethylene-2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid methyl ester (mixture of E and Z isomers) was carried out via Procedure G in 49% yield: 1H NMR (DMSO-d6): δ 3.29 Z (s, 6H), 3.31 E (s, 6H), 3.76 Z (s, 3H), 3.76 E (s, 3H), 6.74 Z (d, J=8.1 Hz, 1H), 6.81 E (d. J=8.2 Hz, 1H), 7.47-7.50 Z (m, 1H), 7.50-7.52 E (m, 1H), 7.57 E (dd, J=1.3, 8.2 Hz, 1H), 7.74 Z (s, 1H), 7.89 Z (s, 1H), 7.94 E (s, 1H), 10.33 Z (bs, 1H), 10.43 E (bs, 1H). The title compound was prepared in 41% yield from 3-[(dimethylamino)methylene]oxindole-5-carboxylic acid methyl ester and 4-aminobenzenesulfonamide according to Procedure J: 1H NMR (DMSO-d6): δ 3.81 (s, 3H), 6.92 (d, J=8.2 Hz, 1H), 7.26 (s, 2H), 7.60 (d, J=8.4 Hz, 2H), 7.69 (d, J=8.2 Hz, 1H). 7.75 (d, J=8.4 Hz, 2H), 8.29 (s, 1H), 8.86 (d, J=12.4 Hz, 1H), 10.80 (d, J=12.4 Hz, 1H), 10.94 (s, 1H); APCI−MS m/z 372 (M−1)−. Anal. Calcd for C17H15N3O5S: C, 54.68, H, 4.05; N, 11.25; S, 8.59. Found C, 54.65, H, 4.12; N, 11.17; S. 8.49.
Reaction SMILES: N1C=CC=C1[C:6]1[CH:7]=[C:8]([NH:12][C:13]2[C:14]3[CH:21]=[C:20]([C:22]4[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:26][CH:27]=4)[NH:19][C:15]=3[N:16]=[CH:17][N:18]=2)[CH:9]=[CH:10][CH:11]=1.[S:35]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36]1>>[S:35]1[CH:39]=[CH:38][C:37]([C:6]2[CH:7]=[C:8]([NH:12][C:13]3[C:14]4[CH:21]=[C:20]([C:22]5[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[CH2:26][CH:27]=5)[NH:19][C:15]=4[N:16]=[CH:17][N:18]=3)[CH:9]=[CH:10][CH:11]=2)=[CH:36]1
Reactant: OB(O)c1ccsc1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Nc4cccc(-c5ccc[nH]5)c4)ncnc3[nH]2)CC1
Product: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Nc4cccc(-c5ccsc5)c4)ncnc3[nH]2)CC1

Procedure:
The title compound was prepared following the procedure for tert-butyl 4-{4-[3-(1H-pyrrol-2-yl)phenylamino]-7H-pyrrolo[2,3-d]pyrimidin-6-yl}-3,6-dihydro-2H-pyridine-1-carboxylate, but using 3-thienylboronic acid. 1H-NMR (CD3OD, 400 MHz): δ=1.50 (s, 9H), 2.56 (m, 2H), 3.67 (m, 2H), 4.13 (m, 2H), 6.30 (s, br, 1H), 6.66 (s, 1H), 7.37-7.42 (m, 2H), 7.47-7.50 (m, 2H), 7.63-7.66 (m, 2H), 8.01-8.02 (m, 1H), 8.23 (s, 1H). MS (ES+): m/z 474.04 [MH+]. HPLC: tR=3.58 min (ZQ2000, polar—5 min).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.C1C(=O)N([Br:19])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:19][CH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2ncccc2c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc2ncccc2c1
Yield: 54 %

Procedure:
To a solution of 6-methylquinoline (2.15 g, 15.0 mmol) in CCl4 (30 mL) was added NBS (2.92 g, 16.5 mmol) and benzoyl peroxide (BP, 0.36 g, 1.5 mmol) at room temperature. The mixture was heated at reflux for 2 hours. After cooling, the mixture was evaporated under vacuum to give a yellow solid, which was extracted with Petroleum Ether (30 mL×5). The extracts were concentrated under vacuum to give crude 6-bromomethylquinoline (1.8 g), which was used directly in the next step.
Reaction SMILES: [OH-].[Na+].[C:3]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([C:15]([O:17]C)=[O:16])=[CH:12]2)=[CH:7][CH:6]=1)#[N:4]>O.CCO.C(Cl)Cl>[C:3]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([C:15]([OH:17])=[O:16])=[CH:12]2)=[CH:7][CH:6]=1)#[N:4]
Reactant: COC(=O)c1ccc2ccc(C#N)cc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: N#Cc1ccc2ccc(C(=O)O)cc2c1
Reaction time: 15 h
Yield: 97.2 %

Procedure:
A solution of NaOH (1.36 g, 34 mmol) in water (35 mL) was added dropwise to a solution of 191 (4.95 g, 24 mmol) in EtOH (100 mL) and CH2Cl2 (30 mL) and the mixture was stirred for 15 h. Water was added to dissolve the white solid and the mixture was extracted with CH2Cl2 (×2) and EtOAc. The aqueous portion was acidified (pH 2) with aqueous HCl (2N) and the resulting precipitate was filtered off, washed with water, and dried in a vacuum desiccator to give 7-cyano-2-naphthoic acid (192) (4.60 g, 99%), as a colorless powder: mp 279-283° C.; lit. mp [Aust. J. Chem., 1965, 18, 1351] 286-288° C.; 1H NMR [(CD3)2SO] δ 13.25 (br s, 1H), 8.81 (s, 1H), 8.75 (s, 1H), 8.20 (d, J=8.5 Hz, 1H), 8.17 (d, J=8.5 Hz, 2H), 8.15 (d, J=8.5 Hz, 2H), 7.92 (dd, J=8.5, 1.3 Hz, 1H).
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:12]([CH2:15][CH3:16])=[N:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH:17]1([NH2:20])[CH2:19][CH2:18]1.ClC1C2N(C(CCC)=NN=2)C2C(N=1)=CC=CC=2.C1(N)CCCC1>>[CH:17]1([NH:20][C:2]2[C:3]3[N:4]([C:12]([CH2:15][CH3:16])=[N:13][N:14]=3)[C:5]3[C:10]([N:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:19][CH2:18]1
Reactant: CCc1nnc2c(Cl)nc3ccccc3n12
Reactant: NC1CC1
Agent: CCCc1nnc2c(Cl)nc3ccccc3n12
Agent: NC1CCCC1
Product: CCc1nnc2c(NC3CC3)nc3ccccc3n12

Procedure:
The title compound was prepared essentially as described in Example 4 substituting 4-chloro-1-ethyl[1,2,4]triazolo[4,3-a]quinoxaline and cyclopropyl amine for 4-chloro-1-n-propyl[1,2,4]triazolo[4,3-a]quinoxaline and cyclopentanamine respectively; mp 190°-192° C.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)[OH:4].[NH2:19][C:20]1[N:25]=[C:24](Cl)[CH:23]=[C:22]([Cl:27])[N:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>O1CCOCC1>[Cl:27][C:22]1[CH:23]=[C:24]([O:4][CH:3]([C:5]2[CH:6]=[CH:7][C:8]([C:11]3[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=3)=[CH:9][CH:10]=2)[C:2]([F:1])([F:17])[F:18])[N:25]=[C:20]([NH2:19])[N:21]=1
Reactant: OC(c1ccc(-c2ccncc2)cc1)C(F)(F)F
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Nc1nc(Cl)cc(OC(c2ccc(-c3ccncc3)cc2)C(F)(F)F)n1
Temperature: 110 °C
Yield: 82.9 %

Procedure:
The mixture of 2,2,2-trifluoro-1-(4-pyridin-4-yl-phenyl)ethanol (100 mg, 0.40 mmol), 2-amino-4,6-dichloropyrimidine (60 mg, 0.38 mmol), and cesium carbonate (468 mg, 1.44 mmol) was dissolved in 2 ml of 1,4-dioxane in a 50 ml sealed tube. The mixture was heated at 110° C. overnight, then was cooled to room temperature; 10 ml of ethyl acetate was added and then filtered through Celite. The filtrate was concentrated to give 120 mg of 4-chloro-6-[2,2,2-trifluoro-1-(4-pyridin-4-yl-phenyl)-ethoxy]-pyrimidin-2-ylamine, yield: 80%.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]1[NH:10][C:9](=[O:11])[NH:8][C:7](=[O:12])[C:6]=1[N+:13]([O-])=O>C(O)(=O)C.[Zn]>[NH:10]1[C:5]2[CH:4]=[CH:3][NH:13][C:6]=2[C:7](=[O:12])[NH:8][C:9]1=[O:11]
Reactant: CN(C)/C=C/c1[nH]c(=O)[nH]c(=O)c1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Product: O=c1[nH]c(=O)c2[nH]ccc2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.5 %

Procedure:
A suspension of 6-[(e)-2-(dimethylamino)vinyl]-5-nitropyrimidine-2,4(1H,3H)-dione (1.43 g, 6.36 mmol) in acetic acid (23 mL) was heated to 80° then zinc dust (2 g, 30.77 mmol) was added slowly over 1 h. The resulting suspension was heated for a further 1 h then allowed to cool to room temperature. The solid was collected by filtration then washed with acetic acid. The solid was transferred to a beaker and washed with water (25 mL), collected then dissolved in sodium hydroxide (5%, 10 mL). This solution was warmed to 70° and stirred for 30 min. Acetic acid was added until pH 5-6 then the precipitate collected and washed with cold water then ethanol. The resultant solid was dried in vacuo to furnish 1H-pyrrolo[3,2-d]pyrimidine-2,4(3H,5H)-dione (0.62 g, 65%).
Reaction SMILES: CC(C)([O-:4])C.[K+].Cl[C:8]1[N:9]=[CH:10][C:11]([C:14]([OH:16])=[O:15])=[N:12][CH:13]=1.[F:17][C:18]([F:21])(O)[CH3:19]>CN(C=O)C>[F:17][CH:18]([F:21])[CH2:19][O:4][C:8]1[N:9]=[CH:10][C:11]([C:14]([OH:16])=[O:15])=[N:12][CH:13]=1
Reactant: CC(O)(F)F
Reactant: CC(C)(C)[O-]
Reactant: O=C(O)c1cnc(Cl)cn1
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)c1cnc(OCC(F)F)cn1
Temperature: 100 °C
Reaction time: 8 h
Yield: 91.6 %

Procedure:
Potassium tert-butoxide (4.25 g, 37.84 mmol) is added to a solution of 5-chloropyrazine-2-carboxylic acid (1.00 g, 6.31 mmol) and difluoroethanol (2.59 g, 31.54 mmol) in DMF (20 mL) and the mixture is heated at 100° C. for 2 hours. The reaction is cooled to room temperature and stirred overnight under nitrogen. The reaction is quenched with 1 M HCl (30 mL) and extracted with ethyl acetate (3 times). The combined organic layers are dried over sodium sulfate, filtered, and concentrated to give the crude product. The crude product is purified by silica gel flash chromatography, eluting with a gradient of 0.5% to 10% methanol in dichloromethane and azeotroped with xylenes to remove residual DMF to give the title product (1.18 g, 91%). ES/MS (m/e): 205.0 (M+1).
Reaction SMILES: C(N(CC)CC)C.[SH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([NH2:18])(=[O:17])=[O:16].Cl[CH2:20][CH2:21][F:22]>CO>[F:22][CH2:21][CH2:20][S:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([NH2:18])(=[O:17])=[O:16]
Reactant: NS(=O)(=O)c1ccccc1S
Reactant: FCCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: NS(=O)(=O)c1ccccc1SCCF
Reaction time: 23 h
Yield: 74.5 %

Procedure:
A mixture of 5.8 g of the 2-mercaptophenylsulfonamide triethylamine salt obtained in accordance with Example H6 and 1.7 g of 2-chloro-1-fluoroethane in 40 ml of methanol is stirred in a bomb tube for 23 hours at a temperature of +50° to +55° C. The reaction mixture is then evaporated and water is added to the residue which remains. The mixture is extracted with ethyl acetate, and the organic phase is washed and dried. Evaporation of the solution gives 3.5 g of 2-(2-fluoroethylthio)-phenylsulfonamide (74.5% of theory) having a melting point of +83° to +85° C.
Reaction SMILES: [C:1]([O:9][CH2:10][CH:11]1[CH2:13][O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:14][C:15]1[CH:16]=[C:17]([CH2:22][C@H:23]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:24]([OH:26])=[O:25])[CH:18]=[CH:19][C:20]=1[OH:21]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[OH:14][C:15]1[CH:16]=[C:17]([CH2:22][C@H:23]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:24]([O:26][CH2:13][CH:11]([OH:12])[CH2:10][O:9][C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:8])=[O:25])[CH:18]=[CH:19][C:20]=1[OH:21]
Reactant: O=C(OCC1CO1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)c(O)c1)C(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)c(O)c1)C(=O)OCC(O)COC(=O)c1ccccc1
Yield: 25.7 %

Procedure:
A solution of oxiran-2-ylmethyl benzoate (3.0 g, 16.8 mmol), (2S)-3-(3,4-dihydroxyphenyl)-2-[(tert-butoxy)carbonylamino]propanoic acid (6.0 g, 20.2 mmol), and tetrabutylammonium bromide (542 mg, 1.7 mmol) in anhydrous toluene was heated to 90° C. for 18 hrs. The reaction mixture was concentrated to dryness under reduced pressure, diluted with ethyl acetate, and washed with water twice followed by the addition of a saturated NaHCO3 solution and brine. The organic layer was dried through MgSO4 and concentrated under reduced pressure. Chromatography (silica gel, 1:1 ethyl acetate/hexane) of the residue afforded 2.05 g (26%) of 2-Hydroxy-3-phenylcarbonyloxypropyl (2S)-3-(3,4-dihydroxyphenyl)-2-[(tert-butoxy)carbonylamino]propanoate.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.C(O)C.[CH2:30]([NH2:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)Cl>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=[C:2]([NH:37][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:3]=1)=[O:15]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: NCc1ccccc1
Solvent: ClCCl
Solvent: CCO
Product: Cc1cc(C)c(CNC(=O)c2cc(NCc3ccccc3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 135 °C
Reaction time: 12 h

Procedure:
To a 10 mL microwave vial were sequentially added 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (0.100 g, 0.267 mmol), ethanol (2.0 mL) and then benzylamine (0.350 mL, 3.21 mmol) via syringe at once. The sealed contents were irradiated at 140° C. for 3 hr. The contents were transferred to a heat block and heated at 135° C. for 16 hr., and then at 145° C. for an additional 12 h. After cooling to room temperature, the contents were diluted with CH2Cl2 and pre-absorbed onto silica gel. The crude product was purified by silica gel chromatography (dry loaded, eluent; gradient of 5-80% DCM and chloroform containing 10% 2M Ammonia (in methanol)). The isolated solid was triturated with MTBE, filtered, and washed with additional MTBE. The collected solid was dried in vacuum oven at 45° C. overnight to afford the final product as 0.067 g (55%). LCMS E-S (M+H)=445.3. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.38 (d, J=6.57 Hz, 6 H), 2.12 (s, 3 H), 2.20 (s, 3 H), 4.31 (d, J=5.05 Hz, 2 H), 4.56 (d, J=6.06 Hz, 2 H), 4.92 (quin, J=6.69 Hz, 1 H), 5.88 (s, 1 H), 6.69 (s, 1 H), 7.18-7.25 (m, 1 H), 7.26-7.35 (m, 2 H), 7.35-7.43 (m, 2 H), 7.77 (t, J=5.94 Hz, 1 H), 7.83 (s, 1H), 8.47 (t, J=5.05 Hz, 1 H), 11.55 (br. s., 1 H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[C:21]3[CH:20]=[CH:19][C:18]4[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=4[C:16]=3[N:15]=[C:14]3[C:9]=2[CH:10]=[CH:11][C:12]2[CH:29]=[CH:28][CH:27]=[CH:26][C:13]=23)[CH:5]=[CH:6][CH:7]=1.[C:30]1(B(O)O)[C:43]2[C:44]3=[C:45]4[C:40](=[CH:41][CH:42]=2)[CH:39]=[CH:38][CH:37]=[C:36]4[CH:35]=[CH:34][C:33]3=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>C(O)C>[C:30]1([C:2]2[CH:3]=[C:4]([C:8]3[C:21]4[CH:20]=[CH:19][C:18]5[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=5[C:16]=4[N:15]=[C:14]4[C:9]=3[CH:10]=[CH:11][C:12]3[CH:29]=[CH:28][CH:27]=[CH:26][C:13]=34)[CH:5]=[CH:6][CH:7]=2)[C:43]2[C:44]3=[C:45]4[C:40](=[CH:41][CH:42]=2)[CH:39]=[CH:38][CH:37]=[C:36]4[CH:35]=[CH:34][C:33]3=[CH:32][CH:31]=1
Reactant: Brc1cccc(-c2c3ccc4ccccc4c3nc3c2ccc2ccccc23)c1
Reactant: OB(O)c1ccc2ccc3cccc4ccc1c2c34
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: c1cc(-c2c3ccc4ccccc4c3nc3c2ccc2ccccc23)cc(-c2ccc3ccc4cccc5ccc2c3c45)c1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
10 (700 mg, 1.61 mmol), pyren-1-ylboronic acid (434 mg, 1.76 mmol), Palladium tetrakis triphenylphoshine (186 mg, 0.16 mmol) and potassium carbonate (1.34 g, 9.66 mmol) were introduced in a flask together with 17 mL toluene, 8.8 mL ethanol and 2.6 mL distilled water. This mixture is stirred at 80° C. during 24 hours before being filtered. The solid is then washed with hexane, water and some mL of chloroform before being dried.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16]([C:18]2[C:19]([N:24]([CH:26]([CH3:28])[CH3:27])[CH3:25])=[N:20][CH:21]=[CH:22][CH:23]=2)=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.O1CCOCC1.CO>O>[CH:26]([N:24]([CH3:25])[C:19]1[C:18]([C:16]([NH:15][C:6]2([C:4]([OH:5])=[O:3])[CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7]2)=[O:17])=[CH:23][CH:22]=[CH:21][N:20]=1)([CH3:28])[CH3:27]
Reactant: CCOC(=O)C1(NC(=O)c2cccnc2N(C)C(C)C)Cc2ccccc2C1
Solvent: C1COCCO1
Solvent: CO
Solvent: O
Product: CC(C)N(C)c1ncccc1C(=O)NC1(C(=O)O)Cc2ccccc2C1
Reaction time: 16 h
Yield: 97.6 %

Procedure:
A 100 mL round bottom flask which contains 2-{[2-(isopropyl-methyl-amino)-pyridine-3-carbonyl]-amino}-indan-2-carboxylic acid ethyl ester (341, 220 mg, 0.58 mmol) is charged with 1,4-dioxane (2 mL) and MeOH (2 mL). A stirring bar is added and stirring is initiated. After dissolution, water (1 mL) is added followed by the LiOH monohydrate (61 mg, 1.46 mmol). After 16 h, tlc analysis (silica, 50% EtOAc/heptanes) indicates that the starting material is completely consumed. Amberlyst highly acidic exchange resin (0.5 g) is added to the reaction vial. The reaction is capped and allowed to stir at ambient temperature. After 4 days, the contents of the flask are filtered through a pad of Celite. The solvent is removed from the filtrate. The residue is reconstituted with iPrOH/toluene (20+20 mL) and the solvent is removed. This process is repeated 1 time. Pumping to constant weight provides white solid (0.2 g, 98%).