Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)CC.Cl.Cl[CH2:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([O-:23])=[O:22])=[CH:17][CH:16]=1.[Na+].C([O-])(=O)C.[K+]>CCCCCC.C(OCC)(=O)C>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: ClCc1ccncc1
Reactant: O=S([O-])c1ccc(Cl)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCCCCC
Solvent: CCCO
Solvent: CCOC(C)=O
Product: O=S(=O)(Cc1ccncc1)c1ccc(Cl)cc1
Temperature: 70 °C
Yield: 61.5 %

Procedure:
A 1-propanol (50 ml) solution of 4-chloromethylpyridine hydrochloride (1.26 g, 7.65 mmol), sodium 4-chlorobenzenesulfinate (1.52 g, 7.65 mmol) and potassium acetate (1.50 g, 15.3 mmol) was stirred under heating at 70° C. for 8 hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The residue thus obtained was caused to pass through a short column (silica gel, ethyl acetate) and the eluate was concentrated under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography, and the fraction obtained from the hexane:ethyl acetate (=2:3) eluate was concentrated under reduced pressure to give the title compound (1.26 g, 62%) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:9]1[NH:30][C:12]2=[CH:13][C:14]3[C:15](=[O:29])[N:16]([CH:22]4[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]4)[C:17](=[O:21])[C:18]=3[C:19]([CH3:20])=[C:11]2[N:10]=1.[F:31][C:32]1[C:37]([F:38])=[CH:36][C:35]([F:39])=[C:34]([F:40])[C:33]=1[CH2:41][CH:42]([NH2:44])[CH3:43].CCN(C(C)C)C(C)C>C(O)CCC>[CH3:20][C:19]1[C:18]2[C:17](=[O:21])[N:16]([CH:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)[C:15](=[O:29])[C:14]=2[CH:13]=[C:12]2[NH:30][C:9]([C:3]3[C:4](=[O:8])[NH:5][CH:6]=[CH:7][C:2]=3[NH:44][CH:42]([CH3:43])[CH2:41][C:33]3[C:34]([F:40])=[C:35]([F:39])[CH:36]=[C:37]([F:38])[C:32]=3[F:31])=[N:10][C:11]=12
Reactant: Cc1c2c(cc3[nH]c(-c4c(Cl)cc[nH]c4=O)nc13)C(=O)N(C1CCN(C)CC1)C2=O
Reactant: CC(N)Cc1c(F)c(F)cc(F)c1F
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c2c(cc3[nH]c(-c4c(NC(C)Cc5c(F)c(F)cc(F)c5F)cc[nH]c4=O)nc13)C(=O)N(C1CCN(C)CC1)C2=O
Yield: 78.5 %

Procedure:
A mixture of 2-(4-chloro-2-oxo-1,2-dihydropyridin-3-yl)-4-methyl-6-(1-methylpiperidin-4-yl)imidazo[4,5-f]isoindole-5,7(1H,6H)-dione (1.00 g, 2.35 mmol), 1-(2,3,5,6-tetrafluorophenyl)propan-2-amine (0.54 g, 2.58 mmol), Hunig's base (1.52 g, 0.011 mol), and 20 mL of anhydrous 1-butanol was heated at reflux for 14-15 h under an argon atmosphere. Product was purified by a silica gel column using methylene chloride and methanol (9:1 v/v) as eluent to afford 1.10 g of the designed compound as yellowish solid. 1H NMR (500 MHz, DMSO-d6) δ 13.35 (s, 1H, NH), 11.35 (d, J=6.0 Hz, 1H, NH), 11.02 (d, J=8.5 Hz, 1H, NH), 7.93 (s, 1H, ArH), 7.81-7.77 (m, 1H, ArH), 7.42 (t, J=7.0 Hz, 1H, ArH), 6.22 (d, J=8.0 Hz, 1H, ArH), 4.34-4.29 (m, 1H, CH), 4.12 (m, 1H, CH), 3.17 (m, 2H, CH2), 3.08 (d, J=5.5 Hz, 21-1, CH2), 2.72 (s, 3H, CH3), 2.48 (s, 3H, CH3), 1.77-1.76 (m, 2H, CH2), 1.37 (d, J=6.5 Hz, 3H, CH3), 1.29-1.24 (m, 6H, 2×CH2); Mass (ESI, positive) m/z 597.2 [M+H]+.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:39][CH2:40][CH:41]([CH3:43])[CH3:42]>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:39][CH2:40][CH:41]([CH3:43])[CH3:42])[CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)CCBr
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Agent: Cl
Product: CC(C)CCn1cc(CN(C(=O)C2CCCc3c(OCc4ccccc4)cccc32)c2ccc(C(C)C)nc2)cn1

Procedure:
By the reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.83 g) and 1-bromo-3-methylbutane (0.359 mL) as starting materials, 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-{[1-(3-methylbutyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.60 g) was obtained. By the reaction and treatment of this compound in the same manner as in Example 139, 5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-{[1-(3-methylbutyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.45 g) was obtained.
Reaction SMILES: S1[C:5]2C=CC=C[C:4]=2N=C1NC(C1C=CC=C2C=1CN(C1SC(CCCI)=C(C(OCC)=O)N=1)CC2)=O.[S:37]1[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=2[N:39]=[C:38]1[NH:46][C:47]([C:49]1[CH:50]=[CH:51][CH:52]=[C:53]2[C:58]=1[CH2:57][N:56]([C:59]1S[C:61]([CH2:67][CH2:68][CH2:69][O:70][C:71]3[CH:76]=[CH:75][C:74]([N:77]4[CH2:82][CH2:81][N:80]([CH3:83])[CH2:79][CH2:78]4)=[CH:73][C:72]=3[F:84])=[C:62]([C:64]([OH:66])=[O:65])[N:63]=1)[CH2:55][CH2:54]2)=[O:48].S1C2C=CC=CC=2N=C1NC(C1C=CC=C2C=1CN(C1N=C(C(OC(C)(C)C)=O)C(CCCI)=CC=1)CC2)=O>>[S:37]1[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=2[N:39]=[C:38]1[NH:46][C:47]([C:49]1[CH:50]=[CH:51][CH:52]=[C:53]2[C:58]=1[CH2:57][N:56]([C:59]1[N:63]=[C:62]([C:64]([OH:66])=[O:65])[C:61]([CH2:67][CH2:68][CH2:69][O:70][C:71]3[CH:76]=[CH:75][C:74]([N:77]4[CH2:78][CH2:79][N:80]([CH3:83])[CH2:81][CH2:82]4)=[CH:73][C:72]=3[F:84])=[CH:5][CH:4]=1)[CH2:55][CH2:54]2)=[O:48]
Reactant: CCOC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)sc1CCCI
Reactant: CN1CCN(c2ccc(OCCCc3sc(N4CCc5cccc(C(=O)Nc6nc7ccccc7s6)c5C4)nc3C(=O)O)c(F)c2)CC1
Agent: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)ccc1CCCI
Product: CN1CCN(c2ccc(OCCCc3ccc(N4CCc5cccc(C(=O)Nc6nc7ccccc7s6)c5C4)nc3C(=O)O)c(F)c2)CC1

Procedure:
The title compound 101 was prepared using the same procedure described in step 2 of Example 54 by replacing compound 54A and compound 2C with compound 93 and compound 96D, respectively: 1H NMR (400 MHz, DMSO-D6) δ ppm 12.80 (1H, s), 9.61 (1H, s), 8.03 (1H, d), 7.79 (1H, d), 7.60 (1H, d), 7.55 (1H, d), 7.44-7.51 (1H, m), 7.39-7.43 (1H, m), 7.33-7.38 (2H, m), 7.02 (1H, t), 6.90-6.98 (2H, m), 6.70 (1H, dd), 4.93 (2H, s), 3.93 (2H, t), 3.86 (2H, t), 3.67-3.75 (2H, m), 3.26-3.37 (2H, m), 3.06-3.20 (2H, m), 2.99 (2H, t), 2.76-2.93 (7H, m), 1.86-1.99 (2H, m); LCMS (APCI) m/e 681 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[C:28]1[CH:36]=[C:35]2[C:31]([CH:32]=[CH:33][N:34]2[S:37]([C:40]2[CH:45]=[CH:44][C:43]([O:46]C)=[CH:42][CH:41]=2)(=[O:39])=[O:38])=[CH:30][CH:29]=1.B(Br)(Br)Br>ClCCl.C(OCC)(=O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[C:28]1[CH:36]=[C:35]2[C:31]([CH:32]=[CH:33][N:34]2[S:37]([C:40]2[CH:41]=[CH:42][C:43]([OH:46])=[CH:44][CH:45]=2)(=[O:38])=[O:39])=[CH:30][CH:29]=1
Reactant: COc1ccc(S(=O)(=O)n2ccc3ccc(-c4c(N)ncnc4N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)cc32)cc1
Agent: BrB(Br)Br
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3ccc4ccn(S(=O)(=O)c5ccc(O)cc5)c4c3)n(-c3ccccc3)c(=O)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.8 %

Procedure:
(S)-2-(1-((6-Amino-5-(1-((4-methoxyphenyl)sulfonyl)-1H-indol-6-yl)pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (100 mg, 0.14 mmol) was dissolved in dichloromethane (1 ml). A solution of boron tribromide (1M in dichloromethane, 952 μL, 0.95 mmol) was added dropwise and the reaction was stirred at room temperature overnight. A solution of boron tribromide (1M in dichloromethane, 1.4 ml, 1.4 mmol) was added dropwise and the reaction was heated at 60° C. overnight. The mixture was diluted with ethyl acetate and washed with a 4% solution of sodium bicarbonate, water, brine and dried over sodium sulphate, filtered and evaporated under reduced pressure. The product was purified by reverse phase chromatography using SP1® Purification System to give 53 mg (61% yield) of the title compound. Purity 99%. LRMS (m/z): 633 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[OH:12].Br[C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[C:17]#[N:18].C(=O)([O-])[O-].[Cs+].[Cs+].CC(C)(C(=O)CC(=O)C(C)(C)C)C>[Cu]Cl.CN1C(=O)CCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[O:12][C:14]1[CH:21]=[CH:20][CH:19]=[C:16]([C:17]#[N:18])[CH:15]=1
Reactant: O=C(O)Cc1ccc(Cl)c(O)c1
Reactant: N#Cc1cccc(Br)c1
Agent: Cl[Cu]
Agent: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Product: N#Cc1cccc(Oc2cc(CC(=O)O)ccc2Cl)c1
Temperature: 120 °C
Yield: 1.9 %

Procedure:
The product from example 1 step (iii) (0.5 g), 3-bromobenzonitrile (0.73 g), cesium carbonate (2.61 g), copper(I) chloride (0.13 g), 2,2,6,6-tetramethyl-3,5-heptanedione (0.06 ml) and NMP (10 ml) were charged to a flask and heated at 120° C. for 16 h. The mixture was partitioned between ether and 2M NaOH, the aqueous layer was acidified then extracted with EtOAc, dried (MgSO4) and evaporated under reduced pressure. The residue was purified by RPHPLC to give the title compound (0.015 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:8]([C:16]3[CH:17]=[C:18]([NH2:22])[CH:19]=[CH:20][CH:21]=3)=[N:9][N:10]3[CH2:15][CH2:14][CH2:13][S:12][C:11]=23)=[CH:3][CH:2]=1.[F:23][C:24]1[CH:25]=[C:26]([S:30](Cl)(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1.CN1CCOCC1>C(Cl)Cl>[F:23][C:24]1[CH:25]=[C:26]([S:30]([NH:22][C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([C:8]3[C:7]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)=[C:11]4[S:12][CH2:13][CH2:14][CH2:15][N:10]4[N:9]=3)[CH:17]=2)(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1
Reactant: Nc1cccc(-c2nn3c(c2-c2ccncc2)SCCC3)c1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: O=S(=O)(Nc1cccc(-c2nn3c(c2-c2ccncc2)SCCC3)c1)c1cccc(F)c1
Reaction time: 2 h
Yield: 92.8 %

Procedure:
3-(3-Pyridin-4-yl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]thiazin-2-yl)-phenylamine (prepared as described in Example 3) (30 mg, 0.097 mmol) was dissolved in dry DCM (1 mL). At room temperature 3-fluorobenzensulfonylchloride (0.013 mL, 0.097 mmol, 1 eq) was added followed by NMM (0.011 mL, 0.097 mmol, 1 eq) and the mixture was stirred for 2 hours. It was then diluted with DCM and washed with water and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (eluant DCM/MeOH/NH3 7 N in MeOH 95:5:0.5) to give 42 mg (93%) of 3-fluoro-N-[3-(3-pyridin-4-yl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]thiazin-2-yl)-phenyl]-benzenesulfonamide.
Reaction SMILES: [CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[NH:9][C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].[CH3:29][C:30]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([CH3:33])[CH2:31]O.C(P(CCCC)CCCC)CCC.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1COCC1.O>[CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[N:9]([CH2:29][C:30]([CH3:33])([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH3:31])[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CC(C)(CO)c1ccccc1
Reactant: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: O
Solvent: C1CCOC1
Product: CCc1cc2c(=O)n(CC(C)(C)c3ccccc3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.9 %

Procedure:
To a solution of 4′-[(6-ethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)methyl]biphenyl-2-carbonitrile (1.5 g), 2-methyl-2-phenylpropan-1-ol (0.64 g), tributylphosphine (0.86 g) in THF (50 ml) was added ADDP (1.2 g) under ice-cooling, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 4′-{[6-ethyl-3-(2-methyl-2-phenylpropyl)-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}biphenyl-2-carbonitrile (0.2 g). This was dissolved in dimethyl sulfoxide (2 mL), and the mixture was added to a mixture of hydroxylammonium chloride (0.27 g), sodium hydrogencarbonate (0.32 g) and dimethyl sulfoxide (20 mL), which had been stirred at 40° C. for 30 min in advance. The reaction mixture was stirred at 90° C. for 16 hr, diluted with chloroform, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography, dissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.075 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.070 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed successively with saturated aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.073 g, 33%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:27])[C:10]([C:16]1[CH:17]=[CH:18][C:19]2[O:23][C:22](=[O:24])[N:21]([CH3:25])[C:20]=2[CH:26]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[CH3:28][O:29][C:30](=[O:39])[C:31]1[C:36]([Cl:37])=[CH:35][C:34](Cl)=[N:33][CH:32]=1>>[CH3:28][O:29][C:30](=[O:39])[C:31]1[C:36]([Cl:37])=[CH:35][C:34]([O:8][C:6]2[CH:5]=[CH:4][C:3]([CH:9]([CH3:27])[C:10]([OH:15])([C:16]3[CH:17]=[CH:18][C:19]4[O:23][C:22](=[O:24])[N:21]([CH3:25])[C:20]=4[CH:26]=3)[C:11]([F:12])([F:13])[F:14])=[C:2]([Cl:1])[CH:7]=2)=[N:33][CH:32]=1
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc2oc(=O)n(C)c2c1)C(F)(F)F
Reactant: COC(=O)c1cnc(Cl)cc1Cl
Product: COC(=O)c1cnc(Oc2ccc(C(C)C(O)(c3ccc4oc(=O)n(C)c4c3)C(F)(F)F)c(Cl)c2)cc1Cl

Procedure:
The title compound was prepared in analogy to Example 182 from 5-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-3-methyl-3H-benzooxazol-2-one (obtained in Example 172) with methyl-4,6-dichloronicotinate [CAS Reg. No. 65973-52-6]. MS (m/e)=571.0 [M+H+].
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([O:11][C:12]2[C:17]([CH3:18])=[CH:16][C:15]([CH:19]3[CH2:21][CH2:20]3)=[CH:14][C:13]=2[CH3:22])[C:5]2[NH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[NH2:23][C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=1.C(O)(C(F)(F)F)=O>O>[CH:19]1([C:15]2[CH:16]=[C:17]([CH3:18])[C:12]([O:11][C:4]3[C:5]4[NH:10][CH:9]=[CH:8][C:6]=4[N:7]=[C:2]([NH:23][C:24]4[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=4)[N:3]=3)=[C:13]([CH3:22])[CH:14]=2)[CH2:21][CH2:20]1
Reactant: N#Cc1ccc(N)cc1
Reactant: Cc1cc(C2CC2)cc(C)c1Oc1nc(Cl)nc2cc[nH]c12
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C2CC2)cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)nc2cc[nH]c12
Temperature: 90 °C
Reaction time: 16 h
Yield: 41.5 %

Procedure:
In a sealed tube was placed 2-chloro-4-(4-cyclopropyl-2,6-dimethylphenoxy)-5H-pyrrolo[3,2-d]pyrimidine (20 mg, 0.064 mmol), 4-aminobenzonitrile (31 mg, 0.26 mmol), TFE (0.21 mL) and TFA (0.04 mL, 0.51 mmol). The reaction mixture was stirred at 90° C. for 16 h. Upon completion of the reaction, the resulting mixture was diluted with water and washed with EtOAc. The combined organic layers were washed with NaHCO3, brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by preparative TLC TLC, eluting with 5% Acetone/CH2Cl2 to give the product as a light yellow solid (10.5 mg, 45%).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].ClCCl.[CH3:10][O:11][C:12]1[C:17](B(O)O)=[CH:16][CH:15]=[CH:14][N:13]=1.[C:21]([O:24][C@@H:25]1[C@@H:38]([O:39][C:40](=[O:42])[CH3:41])[C@H:37]([O:43][C:44](=[O:46])[CH3:45])[CH2:36][S:35][C@H:26]1[O:27][C:28]1[CH:29]=[N:30][C:31](Br)=[CH:32][CH:33]=1)(=[O:23])[CH3:22]>O.COCCOC>[C:21]([O:24][C@@H:25]1[C@@H:38]([O:39][C:40](=[O:42])[CH3:41])[C@H:37]([O:43][C:44](=[O:46])[CH3:45])[CH2:36][S:35][C@H:26]1[O:27][C:28]1[CH:29]=[N:30][C:31]([C:17]2[C:12]([O:11][CH3:10])=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:32][CH:33]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(Br)nc1
Reactant: COc1ncccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: ClCCl
Product: COc1ncccc1-c1ccc(O[C@@H]2SC[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)cn1
Yield: 70 %

Procedure:
A solution of 0.354 g (3.34 mM) of sodium carbonate in 3 ml of water, 0.18 g (0.223 mM) of the [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane and 0.68 g (4.46 mM) of 2-methoxy-3-pyridineboronic acid are added to a solution of 1 g (2.23 mM) of 6-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation IV, in 10 ml of DME. The reaction mixture is heated using microwave radiation at 120° C. for 20 minutes and cooled, water is added and extraction is carried out with ethyl acetate. The organic phase is washed with a 1M sodium carbonate solution and then with water to neutral pH, dried over magnesium sulfate and concentrated under reduced pressure. The evaporation residue is purified by chromatography on a silica column (eluent: toluene/acctone 90/10; v/v) in order to obtain the expected product in the form of a white solid with a yield of 70%.
Reaction SMILES: [CH2:1]([Zn]CC)C.ClC1C=C(Cl)C=C(Cl)C=1O.ICI.[Br:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]=[CH2:27])[CH:21]=1.[Mn]([O-])(=O)(=O)=O.[K+].O>ClCCl.C1COCC1.C(OCC)C>[Br:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]2[CH2:1][CH2:27]2)[CH:21]=1
Reactant: CC[Zn]CC
Reactant: C=Cc1cccc(Br)c1
Agent: O=[Mn](=O)(=O)[O-]
Agent: Oc1c(Cl)cc(Cl)cc1Cl
Agent: [K+]
Solvent: ClCCl
Solvent: ICI
Solvent: C1CCOC1
Product: Brc1cccc(C2CC2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81 %

Procedure:
1.0 M Diethyl zinc in hexanes (27.3 ml, 27.3 mmol) was added to a solution of 2,4,6-trichlorophenol (5.4 g, 27.3 mmol) in dichloromethane (100 ml) at −40° C. After stirring for 15 minutes, diiodo-methane (2.2 mL, 27.3 mmol) was added at −40° C. and stirred for an additional 15 minutes. 1-Bromo-3-vinyl-benzene (2.5 g, 13.7 mmol) was then added to the reaction mixture, allowed to warm to room temperature, and left stirring overnight. The reaction mixture was diluted with dichloromethane, washed with 1N HCl (2×), saturated sodium bicarbonate (2×), saturated sodium sulfite, 1N sodium hydroxide, and saturated brine, dried over magnesium sulfate, filtered and concentrated. GC-MS revealed that the reaction mixture contained 1-Bromo-3-cyclopropyl-benzene and 1-bromo-3-vinyl-benzene. To remove the bromo-3-vinyl-benzene, the crude mixture was reacted with potassium permanganate. A solution of potassium permanganate/water (1.5 g/20 mL) was added drop-wise to a solution of the crude mixture (˜3.5 g) in THF (40 mL) at 0° C. and then allowed to warm to room temperature. After 1 hour, the reaction was diluted with diethyl ether, washed with water and saturated brine, dried over anhydrous sodium sulfate filtered and concentrated. Purication by flash column chromatography eluted with 100 hexanes afforded 1-bromo-3-cyclopropyl-benzene (2.20 g, 81%). 1.6 M n-Butyllithium in hexanes (3.2 mL, 5.1 mmol) was added drop-wise to a solution of 1-bromo-3-cyclopropyl-benzene at −78° C. and stirred for 1 hour. This reaction mixture was then transferred via canula to a 250 mL round bottom flask equipped with a stirrer bar approximately ¼ full of solid carbon dioxide and stirred and for 1 hour. The reaction mixture was concentrated and then the residue was diluted with water. The aqueous layer was washed with dichloromethane (3×), acidified with 1 N HCl to pH˜2, and extracted with ethyl acetate. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to afford 3-cyclopropyl-benzoic (356 mg, 43%, white solid). 1H NMR (DMSO), δ (ppm): 12.90 (bs, 1H), 7.71 (d, 1H), 7.64 (s, 1H), 7.34 (m, 2H), 2.01 (m, 1H), 0.99 (m, 2H), 0.70 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=2[CH2:20]O)[CH:7]=1)[CH3:2].P(Br)(Br)[Br:24]>O1CCOCC1>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=2[CH2:20][Br:24])[CH:7]=1)[CH3:2]
Reactant: BrP(Br)Br
Reactant: CCOC(=O)Cc1cccc(Oc2ccc(C)cc2CO)c1
Solvent: C1COCCO1
Product: CCOC(=O)Cc1cccc(Oc2ccc(C)cc2CBr)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.3 %

Procedure:
To [3-(2-hydroxymethyl-4-methyl-phenoxy)-phenyl]-acetic acid ethyl ester (0.17 g, 0.57 mmol) in 1,4-dioxane was added phosphorus tribromide (0.07 mL, 0.73 mmol), and the reaction was stirred for 1 hour at room temperature. After work-up, 0.1 g of the desired product was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[CH2:19][OH:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:28][C:29]1[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:28][C:29]2[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=2)[C@@H:12]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[CH2:19][OH:20])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: O=S(=O)(N[C@@H]1CCCCC[C@H]1CO)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(CN([C@@H]2CCCCC[C@H]2CO)S(=O)(=O)c2ccc(Cl)cc2)cc1
Yield: 90 %

Procedure:
A solution of 4-chloro-N-(trans-2-(hydroxymethyl)cycloheptyl)benzenesulfonamide (126 mg, 0.39 mmol), cesium carbonate (254 mg, 0.78 mmol), and 4-(bromomethyl)benzonitrile (92 mg, 0.47 mmol) was stirred in 2 mL dimethylformamide for 1.5 h. The reaction was partitioned between 25 mL diethyl ether and 25 mL 0.1 M HCl, concentrated and purified by flash chromatography on 40 g silica gel with 0 to 70% ethyl acetate in hexane to yield 4-chloro-N-(4-cyanobenzyl)-N-(trans-2-(hydroxymethyl)cycloheptyl)benzenesulfonamide (152 mg, 90%). 1H NMR (400 MHz, CDCl3) δ ppm 7.73 (2H, d, J=8.31 Hz), 7.60-7.65 (2H, m), 7.54 (2H, d, J=8.31 Hz), 7.50 (2H, d, J=8.56 Hz), 4.65 (1H, d, J=16.12 Hz), 4.01 (1H, d, J=16.12 Hz), 3.76-3.88 (1H, m), 3.61-3.72 (1H, m), 3.28-3.41 (1H, m), 2.18 (1H, br. s.), 1.44-1.63 (5H, m), 1.11-1.40 (6H, m). LC/MS R.T.=2.76 min; [M+H]+=433.14. HRMS [M+H]+ calc'd 433.1353, found 433.1352.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.[Cl:31][C:32]1[CH:33]=[C:34]([NH2:38])[CH:35]=[CH:36][CH:37]=1>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7]([NH:38][C:34]1[CH:35]=[CH:36][CH:37]=[C:32]([Cl:31])[CH:33]=1)=[O:9]
Reactant: Nc1cccc(Cl)c1
Reactant: O=C(O)c1cc(Br)ccc1OCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(Nc1cccc(Cl)c1)c1cc(Br)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Solid 5-bromo-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 5, method B; 200 mg, 0.65 mmol) was added to a stirred suspension of CDI (106 mg, 0.65 mmol) in THF (6 ml) under nitrogen at 20° C. The reaction mixture was stirred at room temperature for 10 min. 3-Chlorobenzenamine (83 mg, 0.65 mmol) was then added dropwise. After refluxing for 14 h, the reaction mixture was concentrated to obtain crude product. The crude product was purified by silica gel chromatography eluting with hexane:ethyl acetate (10:1) to yield the title compound. 110 mg.