Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[C:19]=1[C:20]#[N:21]>CN(C)C=O.N1C=CC=CC=1.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[C:19]=1[C:20]#[N:21]
Reactant: N#Cc1c(CBr)cccc1[N+](=O)[O-]
Reactant: Oc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: N#Cc1c(COc2ccc(F)cc2F)cccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 68.5 %

Procedure:
2,4-Difluorophenol (0.11 g, 0.83 mmol) and potassium carbonate were added to a cooled (0° C.) and stirred solution of 2-bromomethyl-6-nitrobenzonitrile [W. T. Ashton and J. B. Hynes, J. Med. Chem, 16, 1233 (1973)] (0.2 g, 0.83 mmol) in dimethylformamide under nitrogen atmosphere. The reaction mixture was stirred at 0° C. for 1.5 hours, then diluted with pyridine (1.5 mL), water, stirred for 1 hour, filtered and dried. Purification by silica gel chromatography (50% hexanes in dichloromethane) yielded 165 mg of 2-(2,4-difluorophenoxymethyl)-6-nitrobenzonitrile.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH3:18])[CH2:12][CH2:13][CH2:14][C:15]([OH:17])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:38][O:39][C:40]1[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[C:42]([NH2:48])[C:41]=1[NH2:49]>C(Cl)Cl.CN(C1C=CN=CC=1)C.C(Cl)CCl>[CH2:1]([O:8][C:9](=[O:10])[N:11]([CH2:12][CH2:13][CH2:14][C:15](=[O:17])[NH:48][C:42]1[C:43]([O:46][CH3:47])=[CH:44][CH:45]=[C:40]([O:39][CH3:38])[C:41]=1[NH2:49])[CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(OC)c(N)c1N
Reactant: CN(CCCC(=O)O)C(=O)OCc1ccccc1
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COc1ccc(OC)c(NC(=O)CCCN(C)C(=O)OCc2ccccc2)c1N
Reaction time: 0.17 h

Procedure:
To a solution of 3.1 g of 4-(benzyloxycarbonyl-methyl-amino)-butyric acid in 80 mL DCM were added 6.5 mL of DIPEA, 1.8 g of HOBt, 2.6 g of EDC and 154 mg of DMAP. After stirring for 10 min, 2.1 g of 3,6-dimethoxy-benzene-1,2-diamine, dissolved in 20 mL DCM, were added and the mixture was stirred at rt overnight. The reaction was quenched with sat. aq. NaHCO3, the phases were separated and the organic phase was washed with brine, dried over MgSO4 and concentrated in vacuo to yield the crude title compound as black oil.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[O:11].C(C(O)=O)(F)(F)F.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34]Br)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([CH:12]1[CH2:17][CH2:16][N:15]([CH2:34][CH2:33][C:30]2[CH:31]=[CH:32][C:27]([O:26][CH3:25])=[CH:28][CH:29]=2)[CH2:14][CH2:13]1)=[O:11]
Reactant: O=C(c1nc2ccccc2s1)C1CCNCC1
Reactant: COc1ccc(CCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc(CCN2CCC(C(=O)c3nc4ccccc4s3)CC2)cc1
Temperature: 25 °C

Procedure:
Mix (2-benzothiazolyl)(4-piperidinyl)methanone.CF3CO2H (331 g, 9.19 mmol), 2-(4-methoxyphenyl)ethyl bromide (2.07 g, 9.64 mmol), potassium carbonate (3.33 g, 24.1 mmol) and dimethylformamide (35 mL) and heat at 90° C. overnight. Cool to room temperature and partition between a 2:1 mixture of ethyl acetate/toluene and water. Separate the aqueous phase and wash the organic phase with water and brine. Dry (MgSO4) and evaporate the solvent in vacuo. Purify by chromatography (30% ethyl acetate/hexane) and recrystallize (cyclohexane) to give the title compound as a tan powder; mp 119°-120° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][N:23]([CH2:25][CH:26]4[CH2:31]CN(C(OC(C)(C)C)=O)C[CH2:27]4)[CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.FC1C=C2C(=CC=1F)NC=C2C1C=NN(CC2CCNCC2)C=1.CS(OCC1C[CH2:72][O:71][CH2:70]C1)(=O)=O>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][N:23]([CH2:25][CH:26]4[CH2:27][CH2:72][O:71][CH2:70][CH2:31]4)[CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)(=[O:12])=[O:13])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Cn2cc(-c3cn(S(=O)(=O)c4ccccc4)c4cc(F)ccc34)cn2)CC1
Reactant: CS(=O)(=O)OCC1CCOCC1
Agent: Fc1cc2[nH]cc(-c3cnn(CC4CCNCC4)c3)c2cc1F
Product: O=S(=O)(c1ccccc1)n1cc(-c2cnn(CC3CCOCC3)c2)c2ccc(F)cc21

Procedure:
Following the general method as outlined in Intermediate 20, starting from 6-fluoro-1-(phenylsulfonyl)-3-(1H-pyrazol-4-yl)-1H-indole (Intermediate 5; 305 mg; 0.89 mmol) and (tetrahydro-2H-pyran-4-yl)methyl methanesulfonate (226 mg; 1.16 mmol), 398 mg of the title compound was obtained as a white solid, which was used directly without further purification.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6](/[C:9](/[CH3:14])=[CH:10]/[C:11]([OH:13])=O)=[CH:5][CH:4]=1.C(Cl)(=O)C(Cl)=O.[NH2:23][C:24]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:25]=1[CH:26]=[CH:27][N:28]=[CH:29]2.[H-].[Na+]>C(Cl)Cl.CN(C=O)C.O>[CH:29]1[C:30]2[C:25](=[C:24]([NH:23][C:11](=[O:13])/[CH:10]=[C:9](/[C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:16])[F:15])=[CH:8][CH:7]=3)\[CH3:14])[CH:33]=[CH:32][CH:31]=2)[CH:26]=[CH:27][N:28]=1
Reactant: Nc1cccc2cnccc12
Reactant: C/C(=C\C(=O)O)c1ccc(C(F)(F)F)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: C/C(=C\C(=O)Nc1cccc2cnccc12)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
The product from Example 142C (0.23 g, 1.00 mmol) in CH2Cl2 (5 mL) was treated with oxalyl chloride (0.15 g, 1.2 mmol), 1 drop of DMF, and stirred at ambient temperature for 45 minutes. The mixture was treated with a solution of 5-aminoisoquinoline (0.14 g, 1.0 mmol) and 98% NaH (0.048 g, 1.2 mmol) in DMF (5 mL) prepared separately by stirring for 45 minutes. The resulting mixture was stirred for 15 minutes, poured into water, and extracted with CH2Cl2. The organic phase was dried (MgSO4), evaporated, and the residue triturated with diethyl ether. The solid was dried under reduced pressure to provide the title compound. 1H NMR (300 MHz, d6-DMSO) 2.61 (s, 3H), 2.73 (s, 0.45H, DMF)), 2.89 (s, 0.45H (DMF)), 6.82 (br s, 1H), 7.70 (t, 1H), 7.83 (s, 4H), 7.95 (d, 1H), 8.04 (d, 1H), 8.21 (d, 1H), 8.56 (d, 1H), 9.33 (s, 1H), 10.20 (s, 1H); MS (ESI+) 357 (M+H)+; Elemental: Calculated for C20H15N2OF3.HCl.0.15C3H7NO: C66.87, H4.40, N8.20; Found: C66.83, H4.20, N8.27.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17]([C:19]3[N:20]=[CH:21][N:22]([CH2:24][O:25][CH3:26])[CH:23]=3)[S:18][C:11]=12)[NH2:5].[CH3:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[NH:35][C:36](=[O:41])[CH2:37][C:38](O)=[O:39].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:38](=[O:39])[CH2:37][C:36]([NH:35][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[O:28][CH3:27])=[O:41])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17]([C:19]3[N:20]=[CH:21][N:22]([CH2:24][O:25][CH3:26])[CH:23]=3)[S:18][C:11]=12
Reactant: COCn1cnc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)c1
Reactant: COc1ccccc1NC(=O)CC(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COCn1cnc(-c2cc3nccc(Oc4ccc(NC(=O)CC(=O)Nc5ccccc5OC)cc4F)c3s2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.2 %

Procedure:
To a solution of 95 (136 mg, 0.37 mmol) in dry DMF (7 ml) was added the acid 27 (300 mg, 3.0 eq, 1.1 mmol), HOBT (74 mg, 1.5 eq, 0.55 mmol) and EDC (210 mg, 3.0 eq, 1.1 mmol) and the reaction mixture was stirred at RT overnight. The reaction mixture was concentrated to dryness and partitioned between EtOAc and sat NaHCO3 soln, the organic phase was collected, dried over anhydrous sodium sulfate and filtered. The solvent was removed under reduced pressure and the crude was triturated with Et2O to afford title compound 92 (150 mg, 72% yield). 1H NMR (DMSO-d6) δ(ppm): 10.57 (s, 1H), 9.62 (s, 1H), 8.43 (d, J=5.48 Hz, 1H), 8.06 (m, 2H), 7.93 (m, 1H), 7.85 (m, 1H), 7.76 (s, 1H), 7.45 (m, 2H), 7.05 (m, 2H), 6.90 (m, 1H), 6.58 (m, 1H), 5.35 (s, 2H), 3.84 (m, 3H), 3.63 (s, 2H), 3.25 (s, 3H). MS (m/z): 562.1 (M+H).
Reaction SMILES: [NH:1]1[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3].C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1.C([O:42][CH2:43][C@H:44]1[O:48][CH2:47][C@H:46](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:45]1)(=O)C1C=CC=CC=1.C[O-].[Na+]>CN(C=O)C.CO.C(O)(=O)C>[O:3]=[C:2]1[NH:4][C:5](=[O:6])[C:7]([CH3:8])=[CH:9][N:1]1[C@H:46]1[CH2:45][C@@H:44]([CH2:43][OH:42])[O:48][CH2:47]1
Reactant: Cc1c[nH]c(=O)[nH]c1=O
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2CO[C@H](COC(=O)c3ccccc3)C2)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: C[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CO
Solvent: CC(=O)O
Product: Cc1cn([C@@H]2CO[C@H](CO)C2)c(=O)[nH]c1=O
Temperature: 75 °C
Reaction time: 14 h
Yield: 24 %

Procedure:
A mixture of thymine (0.142 g, 1.12 mmol), potassium carbonate (0.208) g, 1.5 mmol), 18-crown-6(0.119 g, 0.45 mmol) and 1,4-anhydro-5-O-benzoyl-3-deoxy-2-O-p-toluenesulfonyl-D-ribitol (0.283 g, 0.75 mmol) in DMF (5 mL) was stirred at 75° C. for 14 h. The solvent was removed under reduced pressure. The residue was purified by flash chromatography using 5% methanol/chloroform as the mobile phase to afford 0.074 g (0.224 mmol, 30%) of the protected isothymidine. To a solution of this nucleoside (0.074 g, 0.22 mmol) in methanol (3.5 mL), was added sodium methoxide (0.018 g, 0.33 mmol). After stirring for 2 h at room temperature, the reaction mixture was neutralized with 5N acetic acid (2 drops). The solvent was removed under reduced pressure and the residue was purified on a silica gel plate with 10% methanol/chloroform to afford the title compound (0.18 mmol, 82%) as a very hygroscopic white solid: 1H NMR (Me2SO-d6): δ1.76 (m,4H),2.35(m,1H),3.45-3.52(m,1H),3.65(m,1H),3.72-3.87(m,3H),4.95(t,1H),5.1(m,1H),7.61(s,1H),11.21(s,1H; UV(MeOH)λmax 271 nm(ε9,554); [α]D =(+)26° (c=0.2,MeOH): FTIR(KBr)1670 cm-1 ; mass spectrum, m/z 226(M+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH2:19]([C:25]1[CH:31]=[CH:30][C:28]([OH:29])=[CH:27][C:26]=1[OH:32])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].Cl>S1(CCCC1)(=O)=O.CO.O>[OH:29][C:28]1[CH:27]=[C:26]([OH:32])[C:25]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:31][C:30]=1[C:2]1[N:7]=[C:6]([C:30]2[CH:31]=[C:25]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:26]([OH:32])=[CH:27][C:28]=2[OH:29])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1
Reactant: CCCCCCc1ccc(O)cc1O
Reactant: Clc1nc(Cl)nc(-c2ccccc2)n1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S1(=O)CCCC1
Solvent: O
Solvent: CO
Product: CCCCCCc1cc(-c2nc(-c3ccccc3)nc(-c3cc(CCCCCC)c(O)cc3O)n2)c(O)cc1O
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
To a 750 mL sulfonation flask equipped with a mechanical stirrer, condenser, dropping funnel and a nitrogen atmosphere are charged 34.0 g (150 mmol) of 2,4-dichloro-6-phenyl-s-triazine, 44.0 g (330 mmol) of aluminum chloride and 100 mL of ligroin (boiling range 110°-140° C.). To that suspension, 60 mL of sulfolane are added dropwise with stirring over a 15 minute period with the temperature rising to 50° C. A solution of 62.1 g (320 mmol) of 4-hexylresorcinol in 60 mL of sulfolane is then added dropwise over a 15 minute period. The temperature rises to 60° C. and hydrogen chloride is evolved. The reaction mixture is heated to 80° C. for four horns. The lower layer of the two-phase mixture is poured into a solution of 50 mL of concentrated hydrochloric acid in 500 mL of methanol and 300 mL of water. The mixture is stirred at room temperature for 14 hours. The product obtained is suspended in 800 mL of water at 80° C. for 1 hour, is isolated by filtration and resuspended under the same conditions, finally isolated and dried at 85° C. under vacuum. The title compound is obtained as a crude orange product (77.0 g) and melts at 230°-238° C. It can be used without further purification.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([OH:27])([CH3:26])[C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[C@@H:11]([CH2:28][N:29]2[CH:34]3[CH2:35][CH2:36][CH2:37][CH:30]2[CH2:31][C:32](=[O:38])[CH2:33]3)[CH2:10]1)(=[O:8])=[O:7].[BH4-].[Na+]>C1COCC1.CO.CCOC(C)=O.O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([OH:27])([CH3:26])[C:22]([F:24])([F:23])[F:25])=[CH:17][CH:16]=2)[C@@H:11]([CH2:28][N:29]2[CH:30]3[CH2:37][CH2:36][CH2:35][CH:34]2[CH2:33][CH:32]([OH:38])[CH2:31]3)[CH2:10]1)(=[O:7])=[O:8]
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CN2C3CCCC2CC(=O)C3)cc1)C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CN2C3CCCC2CC(O)C3)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 27 %

Procedure:
To a solution of racemic 9-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-9-azabicyclo[331]nonan-3-one (81 mg, 0.142 mmol, Example 140) in 1 mL of THF and 0.3 mL of MeOH was added sodium borohydride (10.72 mg, 0.284 mmol, Sigma-Aldrich, St. Louis, Mo.). The mixture was allowed to gradually warm to room temperature and stirred for 16 h. The crude material was then diluted with EtOAc (10 mL) and water (10 mL). The organic layer was separated and the extracts were washed with water (10 mL) and brine (10 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated. The crude material was by purified via reverse-phase preparative HPLC using a Phenomenex Gemini C18 column (150×30 mm, 10 μm) eluting with 0.1% TFA in CH3CN/H2O (5% to 100% over 15 min) to give 9-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-9-azabicyclo[3.3.1]nonan-3-ol (22 mg) as a mixture of two isomers:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[CH:9]=[C:10]([OH:17])[N:11]=[CH:12]3)[CH:4]=[N:3]1.[O:18](S(C(F)(F)F)(=O)=O)[S:19]([C:22]([F:25])([F:24])[F:23])(=O)=[O:20].C(N(CC)CC)C>C(Cl)Cl>[F:23][C:22]([F:25])([F:24])[S:19]([O:17][C:10]1[N:11]=[CH:12][C:13]2[C:8]([CH:9]=1)=[C:7]([C:5]1[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=1)[N:16]=[CH:15][CH:14]=2)(=[O:20])=[O:18]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Cn1cc(-c2nccc3cnc(O)cc23)cn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1cc(-c2nccc3cnc(OS(=O)(=O)C(F)(F)F)cc23)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.2 %

Procedure:
To a solution of 5-(1-methyl-1H-pyrazol-4-yl)-2,6-naphthyridin-3-ol (Preparation 89, 15 mg, 0.066 mmol) in DCM (0.5 mL) was added Tf2O (0.013 mL, 0.080 mmol) and triethylamine (9.3 uL, 0.066 mmol). The reaction mixture was stirred at room temperature under 1 hour. The reaction mixture was concentrated in vacuo. The residue was passed through a SCX-2 cartridge eluting with 100% MeOH—1M NH3 in MeOH to give the title compound (14 mg, 59%).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1)=[O:4].C([O-])([O-])=O.[Ca+2].[I:23]Cl>CO>[F:1][C:2]([F:16])([F:17])[C:3]([NH:5][CH2:6][CH2:7][C:8]1[CH:9]=[C:10]([O:14][CH3:15])[CH:11]=[CH:12][C:13]=1[I:23])=[O:4]
Reactant: COc1cccc(CCNC(=O)C(F)(F)F)c1
Reactant: ClI
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CO
Product: COc1ccc(I)c(CCNC(=O)C(F)(F)F)c1
Reaction time: 8 h
Yield: 99.7 %

Procedure:
A solution of N-trifluoroacetyl-3-methoxyphenethylamine (15.8 g, 64 mmol) in methanol (325 mL) was cooled to −78 C, and treated with CaCO3 (14.7 g, 145 mmol), followed by a solution of ICl (29 g, 181 mmol) in methanol (40 mL). The reaction was allowed to warm to 20 C while stirring overnight and then filtered, concentrated, dissolved in EtOAc (200 mL), washed twice with 5% aqueous sodium bisulfite (100 mL), once with brine (100 mL), dried with Na2SO4 and concentrated to give 23.8 g of a white solid powder. 1H NMR (400 MHz, CDCl3) d 7.68 (d, J=9 Hz, 1H), 6.76 (s, 1H), 6.57 (d, J=9 Hz, 1H), 6.42 (bs, 1H), 3.77 (s, 3H), 3.61 (dd, J=7, 7 Hz, 2H), 2.99 (dd, J=7, 7 Hz, 2H). MS calculated for C11H11F3INO2+H: 374, observed: 374.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[Si]([O:14][C@H:15]([CH2:27][CH2:28][C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1)[CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1)(C(C)(C)C)(C)C.Br[C:36]1[S:40][C:39]([S:41]([NH2:44])(=[O:43])=[O:42])=[CH:38][CH:37]=1.Cl>C(O)C.CO.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>[OH:14][C@H:15]([CH2:27][CH2:28][C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1)[CH2:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([C:36]2[S:40][C:39]([S:41]([NH2:44])(=[O:43])=[O:42])=[CH:38][CH:37]=2)=[CH:22][CH:23]=1
Reactant: NS(=O)(=O)c1ccc(Br)s1
Reactant: CC(C)(C)[Si](C)(C)O[C@H](CCc1cccnc1)COc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: CO
Product: NS(=O)(=O)c1ccc(-c2ccc(OC[C@H](O)CCc3cccnc3)cc2)s1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
2M Aqueous sodium carbonate (2.5 ml), (2R)-4-[2-(tert-butyldimethylsilanyloxy)-4-pyridin-3-yl-butoxy]benzeneboronic acid (Example 7b)), 1.0 g), and tetrakis(triphenylphosphine)palladium(0) (0.1 g) were added to a solution of 5-bromothiophene-2-sulfonic acid amide (1.21 g) in ethanol (25 ml). The mixture was heated at 90° C. for 4 hours. The mixture was cooled to room temperature and solvents were evaporated under reduced pressure. The reaction mixture was triturated with acetone (10 ml) and filtered through a short silica gel column. The column was eluted with a further 10 ml of acetone. The filtrate was evaporated before purification by normal-phase HPLC, eluting with a gradient of 0-10% ethanol in dichloromethane. The oil obtained was dissolved in methanol (25 ml), 2M hydrochloric acid (10 ml) was added and the solution stirred overnight at room temperature. The solid was filtered off, washed with methanol, water, and then diethyl ether. The product was liberated from its hydrochloride salt by stirring in 2M sodium hydrogencarbonate for 30 minutes. The resulting solid was collected by filtration and washed sequentially with water and diethyl ether to afford the title compound as a solid (0.56 g).
Reaction SMILES: FC(F)(F)S(C1C=CC(N)=CC=1)(=O)=O.C(N(CC)CC)C.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.[F:34][C:35]([F:50])([F:49])[S:36]([C:39]1[CH:44]=[CH:43][C:42]([NH:45][C:46](Cl)=[O:47])=[CH:41][CH:40]=1)(=[O:38])=[O:37].[CH3:51][Si:52]([CH3:72])([CH3:71])[CH2:53][CH2:54][O:55][CH2:56][N:57]1[C:61]2=[N:62][CH:63]=[CH:64][CH:65]=[C:60]2[C:59]([CH2:66][NH:67][CH:68]([CH3:70])[CH3:69])=[CH:58]1>>[CH3:70][CH:68]([N:67]([CH2:66][C:59]1[C:60]2[C:61](=[N:62][CH:63]=[CH:64][CH:65]=2)[N:57]([CH2:56][O:55][CH2:54][CH2:53][Si:52]([CH3:71])([CH3:51])[CH3:72])[CH:58]=1)[C:46]([NH:45][C:42]1[CH:43]=[CH:44][C:39]([S:36]([C:35]([F:50])([F:49])[F:34])(=[O:38])=[O:37])=[CH:40][CH:41]=1)=[O:47])[CH3:69]
Reactant: O=C(Cl)Nc1ccc(S(=O)(=O)C(F)(F)F)cc1
Reactant: CC(C)NCc1cn(COCC[Si](C)(C)C)c2ncccc12
Agent: Nc1ccc(S(=O)(=O)C(F)(F)F)cc1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)N(Cc1cn(COCC[Si](C)(C)C)c2ncccc12)C(=O)Nc1ccc(S(=O)(=O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 38 %

Procedure:
To a solution of 4-[(trifluoromethyl)sulfonyl]aniline (180 mg, 0.80 mmol) in 2 mL dichlroethane at 0° C. was added triethylamine (0.250 mL, 1.76 mmol) and triphosgene (71 mg, 0.24 mmol). The solution was allowed to stir at ambient temperature for 10 min. To the crude reaction mixture of {4-[(trifluoromethyl)sulfonyl]phenyl}carbamic chloride was added N-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]propan-2-amine (256 mg, 0.80 mmol) and the reaction was allowed to stir at ambient temperature for 16 h. The mixture was concentrated and partitioned between saturated NaHCO3 and ethylacetate. The organics were washed with water and brine, then dried over Na2SO4, filtered and concentrated. The filtrate was concentrated and purified by silica gel chromatography to give 1-propan-2-yl-3-{4-[(trifluoromethyl)sulfonyl]phenyl}-1-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]urea (38%). LCMS [M+H]+=571.2.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([S:11]([N:14]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[C:15]2[S:16][CH:17]=[CH:18][N:19]=2)(=[O:13])=[O:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[O:29]([Si](C)(C)C)[Na]>C1COCC1>[OH:29][C:2]1[CH:3]=[C:4]([S:11]([N:14]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[C:15]2[S:16][CH:17]=[CH:18][N:19]=2)(=[O:13])=[O:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: C[Si](C)(C)O[Na]
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc([N+](=O)[O-])c(F)c2)cc1
Solvent: C1CCOC1
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc([N+](=O)[O-])c(O)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 103 %

Procedure:
To a solution of 3-fluoro-N-(4-methoxybenzyl)-4-nitro-N-(thiazol-2-yl)benzenesulfonamide (9.0 g, 21.2 mmol) in THF (80 mL) was added a THF solution of NaOSi(Me)3 (4.76 g, 42.5 mmoles, 1 M, Aldrich) at 0° C. and the resulting mixture was stirred at 25° C. for 2 h. After completion of the reaction (monitored by TLC), reaction mass was quenched with 1N HCl (70 mL). The organic compound was then extracted with EtOAc, washed with water, dried over sodium sulfate and concentrated to get the 9.20 g of crude material, 3-hydroxy-N-(4-methoxybenzyl)-4-nitro-N-(thiazol-2-yl)benzenesulfonamide as yellow semi-solid which was used for next step as is.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8](OC)=[O:9])[C:5]([OH:12])=[N:4][CH:3]=1.[NH3:13]>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH2:13])=[O:9])[C:5]([OH:12])=[N:4][CH:3]=1
Reactant: COC(=O)c1nc(Cl)cnc1O
Reactant: N
Product: NC(=O)c1nc(Cl)cnc1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In 5 mL of 25% aqueous ammonia is suspended 0.25 g of methyl 6-chloro-3-hydroxy-2-pyrazinecarboxylate obtained according to the method described in literature [J. Med. Chem., 285-287 (1969)]. The suspension is stirred at ambient temperature for 1 hour. The deposited crystals are collected by filtration to obtain 0.18 g of 6-chloro-3-hydroxy-2-pyrazinecarboxamide.
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:20]2[C:11](=[CH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:10]=[CH:9][CH:8]=1.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:31])(=O)=O)=CC=1>C(OCC)C.O1CCCC1>[F:31][C:7]1[C:20]2[C:11](=[CH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:10]=[CH:9][CH:8]=1
Reactant: Brc1cccc2cc3ccccc3cc12
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: Fc1cccc2cc3ccccc3cc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
1.2 millimoles n-butyl lithium were dropped into a solution of 1 millimole bromoanthracene in 5 milliliters diethyl ether at 5° C. The solution was cooled to 0° C., was stirred for 1 hour, and then was cooled further to -78° C.; 1.2 millimoles N-fluorobenzenesulfonimide prepared according to Example 1 above in 5 milliliters tetrahydrofuran were dropped into the mixture which was stirred for 1 hour. The temperature was allowed to rise to 20° C. while stirring was continued. The reaction mixture was quenched by pouring into saturated ammonium chloride solution and extracted with diethyl ether. Fluoroanthracene was obtained in 76% yield.