Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[C:14](Cl)(=O)[C:15](Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl.CN(C=O)C.C1C=CC=CC=1>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([C:15]2[CH:14]=[CH:3][CH:2]=[CH:1][CH:5]=2)=[O:11])=[CH:12][CH:13]=1)[CH:2]([CH3:3])[CH3:4]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)Cc1ccc(C(=O)O)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)Cc1ccc(C(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
A solution of 4-isobutylbenzoic acid (5.00 g, 28.0 mmol) in CH2Cl2 was cooled in an ice bath and treated with oxalyl chloride (5 mL) and DMF (1 drop). The mixture was warmed to room temp and stirred 1 h. The volatiles were removed in vacuo to give the crude acid chloride which as dissolved in benzene (50 mL). Aluminum chloride (4.49 g, 33.3 mmol) was added and the mixture was heated to reflux for 3.5 h. The mixture was cooled to room temp and then poured onto ice (ca. 100 g). The mixture was extracted with EtOAc (3×100 mL) and the combined organic extracts were washed with ½ satd aqueous NaHCO3 (100 mL), dried (Na2SO4), filtered and evaporated in vacuo. The resulting residue was purified by silica gel chromatography (elute with 10:1 hexane/EtOAc) to give 4-isobutylbenzophenone (5.48 g, 81%). 1H NMR (CDCl3) 7.75 (m, 4H), 7.53 (d, 1H), 7.47 (t, 2H), 7.23 (d, 2H), 2.53 (d, 2H), 1.91 (m, 1H), 0.92 (d, 6H).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].[H-].[Na+].Cl.Cl[CH2:16][CH2:17][NH2:18]>O1CCCC1>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH2:16][CH2:17][NH2:18]
Reactant: Oc1ccccc1C(F)(F)F
Reactant: NCCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: NCCOc1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Add 5.0 g (30.9 mmol) of 2-trifluoromethylphenol to a 0° C. suspension of 2.72 g (67.9 mmol, 2.2 eq, 60% by wt. in mineral oil) of sodium hydride in 100 mL of dry tetrahydrofuran. Once the 2-trifluoromethylphenol is dissolved add 7.88 g (67.9 mmol, 2.2 eq) of 2-chloroethylamine hydrochloride and stir at room temperature for 18 hr. Concentrate the reaction mixture and partition between 200 mL of methylene chloride and 50 mL water. Dry the organic layer over Na2SO4 and concentrate in vacuo to obtain the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[CH:9][CH:10]=[CH:11][CH:12]=[C:5]2[CH2:4][C:3]1=[O:13].Br[CH2:15][CH2:16]Br.C([O-])([O-])=O.[K+].[K+].O>[N+](CCCC)(CCCC)(CCCC)CCCC.[O-]S(O)(=O)=O.CN(C)C=O>[CH3:1][N:2]1[C:3](=[O:13])[C:4]2([CH2:16][CH2:15]2)[C:5]2[C:6](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:8]
Reactant: CN1C(=O)Cc2ccccc2C1=O
Reactant: BrCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Solvent: O
Solvent: CN(C)C=O
Product: CN1C(=O)c2ccccc2C2(CC2)C1=O
Temperature: 70 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
To a solution of N-methylhomophthalimide (4.05 kg), 1,2-dibromoethane (2.39 L), and Bu4NHSO4 (785 g) in N,N-dimethylformamide (32 L) were added K2CO3 (6.39 kg) and N,N-dimethylformamide (8.5 L) at room temperature. Then the solution was heated to 70° C., and was stirred for 2 hours at 68˜70° C. After cooling the reaction mixture to 40° C., water (81 L) was added. After the slurry was stirred for 1 hour at 40° C., it was allowed to cool to room temperature and was stirred overnight. The suspension was filtered, and the obtained wet crystal was washed with the mixture of N,N-dimethylformamide and water (N,N-dimethylformamide:water=1:1, 20 L), twice, and water (20 L), sequentially. It was dried at room temperature under N2 flow for several hours and then under the reduced pressure overnight to afford the title compound as pale pink crystal (4.67 kg, 4.30 kg assay, 92% yield).
Reaction SMILES: I[CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:14].[N-:15]=[N+:16]=[N-:17].CN(C)C(=[NH2+])N(C)C.O>C(Cl)Cl>[N:15]([CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:14])=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1Nc2ccc(F)cc2CCC1I
Agent: CN(C)C(=[NH2+])N(C)C
Solvent: ClCCl
Solvent: O
Product: [N-]=[N+]=NC1CCc2cc(F)ccc2NC1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.9 %

Procedure:
101 mg (0.33 mmol) of 3-iodo-7-fluoro-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (Step B) dissolved in 8.3 mL of methylene chloride and 105 mg (0.66 mmol, 2 eq) of tetramethylguanidinium azide was added. The mixture was stirred at room temperature for 16 hours then water was added and the layers allowed to separate. The organic layer was removed, washed with water and brine, then dried over magnesium sulfate, filtered and solvents removed under vacuum to afford 66 mg (0.30 mmol, 90%) of the product. 1H NMR (200 MHz, CDCl3): 2.28 (m,1H), 2.45 (m,1H), 2.73 (m,1H), 2.93 (m,1H), 3.86 (dd;8,11 Hz;1H), 7.0 (m,3H), 8.15 (br s,1H). FAB-MS: calculated for C10H9FN4O 220; found 221 (M+H,100%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][C:15]=3[CH3:23])=[CH:7][C:6]=2[C:5]2[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:4]=2[N:3]=1.S(Cl)([Cl:31])=O>>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([Cl:31])=[O:19])=[CH:16][C:15]=3[CH3:23])=[CH:7][C:6]=2[C:5]2[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:4]=2[N:3]=1
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(C(=O)O)cc3C)cc12
Reactant: O=S(Cl)Cl
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(C(=O)Cl)cc3C)cc12
Temperature: 25 °C

Procedure:
A solution of 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylbenzoic acid (from the previous step) in thionyl chloride was stirred at 60° C. for 3 hour. After cooling to ambient temperature, the reaction mixture was concentrated en vaccuo. The crude material was used for next step without purification.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[C:15](Cl)[N:14]=[CH:13][N:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH:18][C:19]1[CH:28]=[C:27]2[C:22]([CH:23]=[CH:24][CH:25]=[N:26]2)=[CH:21][CH:20]=1.[H-].[Na+]>CN(C=O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[CH:13][N:14]=[C:15]([O:18][C:19]3[CH:28]=[C:27]4[C:22]([CH:23]=[CH:24][CH:25]=[N:26]4)=[CH:21][CH:20]=3)[CH:16]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(-c2cc(Cl)ncn2)cc1
Reactant: Oc1ccc2cccnc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(-c2cc(Oc3ccc4cccnc4c3)ncn2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a 100-mL, round-bottomed flask containing 4-(4-tert-butyl-phenyl)-6-chloro-pyrimidine, (Example 1(a)), (0.15 g, 0.61 mmol) and 7-hydroxyquinoline (0.12 g, 0.85 mmol, Acros) in DMF (4 mL), was added NaH (34 mg, 0.85 mmol, 60% in mineral oil, Aldrich) at room temperature. The solution was then stirred at room temperature for 4 h. After the solvent was removed in vacuum, the residue was taken up in EtOAc (10 mL), and the organic layers were washed with water (8 mL), dried over Na2SO4, filtered, and concentrated in vacuum. Silica gel chromatography (3:1 hexanes/EtOAc) gave the title compound as a white solid. Mp: 133-135° C. MS (ESI, pos. ion) m/z: 356 (M+1). Anal. Calcd for C23H21N3O: C, 77.72; H, 5.96; N, 11.82. Found: C, 77.43; H, 5.99; N, 11.74.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[Cl:23][C:24]1[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=1[N:31]=[C:32]=[O:33]>C1(C)C=CC=CC=1>[Cl:23][C:24]1[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=1[NH:31][C:32]([NH:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:21][CH:20]=1)=[O:33]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C=Nc1cccc(Cl)c1Cl
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4cccc(Cl)c4Cl)cc3)c2cc1OC
Yield: 100 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (52 mg) was dissolved in toluene (5 ml) with heat, 2,3-dichlorophenyl isocyanate (0.05 ml) was added, and the admixture was refluxed with heat for 20 minutes. The reaction solution was purified by column chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 84 mg of the title compound (yield: 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[O:5][C:6]1[CH:14]=[C:13]([F:15])[CH:12]=[C:11]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=2[F:24])[C:7]=1[C:8]([NH2:10])=[O:9].C(N(CC)CC)C.[CH2:35]([S:37](Cl)(=[O:39])=[O:38])[CH3:36]>C1COCC1.C(OCC)(=O)C>[CH2:35]([S:37]([NH:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[O:5][C:6]1[CH:14]=[C:13]([F:15])[CH:12]=[C:11]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=2[F:24])[C:7]=1[C:8]([NH2:10])=[O:9])(=[O:39])=[O:38])[CH3:36]
Reactant: CCS(=O)(=O)Cl
Reactant: NC(=O)c1c(Nc2ccc(I)cc2F)cc(F)cc1Oc1cccc(N)c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)Nc1cccc(Oc2cc(F)cc(Nc3ccc(I)cc3F)c2C(N)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
In analogy to GP 6a, 240 mg of 2-(3-amino-phenoxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide (Intermediate 1.4; 0.5 mmol, 1 eq.) were dissolved in 8 mL THF and treated with 0.1 mL triethylamine (0.75 mmol, 1.5 eq.) and 71 μL ethylsulfonyl chloride (0.75 mmol, 1.5 eq.). The reaction mixture was stirred at rt overnight, diluted with ethyl acetate, washed with saturated NaHCO3 solution, dried and concentrated in vacuo. HPLC purification of the residue provided 123 mg (0.22 mmol, 48% yield) of the desired compound.
Reaction SMILES: C([NH:4][C:5]1[S:6][C:7]([S:11]([NH:14][C:15]2[N:20]=[C:19]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH:18]=[C:17]([CH3:29])[CH:16]=2)(=[O:13])=[O:12])=[C:8]([CH3:10])[N:9]=1)(=O)C.[OH-].[Na+]>CO>[NH2:4][C:5]1[S:6][C:7]([S:11]([NH:14][C:15]2[N:20]=[C:19]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])[CH:18]=[C:17]([CH3:29])[CH:16]=2)(=[O:13])=[O:12])=[C:8]([CH3:10])[N:9]=1
Reactant: CC(=O)Nc1nc(C)c(S(=O)(=O)Nc2cc(C)cc(NC(=O)OC(C)(C)C)n2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(NC(=O)OC(C)(C)C)nc(NS(=O)(=O)c2sc(N)nc2C)c1
Temperature: 24 °C

Procedure:
A solution of tert-butyl [6-({[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]sulfonyl}amino)-4-methylpyridin-2-yl]carbamate (2.1 g, 4.8 mmol, 1 equiv) and 1 N aqueous sodium hydroxide (7.2 mL) in methanol (30 mL) was heated to 50° C. for 48 h. Upon cooling to 24° C., the reaction mixture was concentrated in vacuo (˜25 mm Hg). The resulting solid was dissolved in water (20 mL). The solution was neutralized with concentrated hydrochloric acid until pH=7. The resulting solid was collected by filtration, washed with water (30 mL) and diethyl ether (2×30 mL) (1.59 g, 83%). 1H NMR (400 MHz, CDCl3), δ: 8.29 (br s, 1H), 7.48 (s, 1H), 6.91 (s, 1H), 2.40 (s, 3H), 2.33 (s, 3H), 1.52 (s, 9H); LCMS (ESI) m/z: 400.2.
Reaction SMILES: O.Cl.Cl.[NH2:4][C:5]1[CH:6]=[C:7]([CH:26]=[CH:27][CH:28]=1)[O:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:13][CH:14]1[O:19][C:18]2[C:20]([O:24]C)=[CH:21][CH:22]=[CH:23][C:17]=2[O:16][CH2:15]1.C(=O)([O-])[O-].[Na+].[Na+]>Br.O>[NH2:4][C:5]1[CH:6]=[C:7]([CH:26]=[CH:27][CH:28]=1)[O:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:13][CH:14]1[O:19][C:18]2[C:20]([OH:24])=[CH:21][CH:22]=[CH:23][C:17]=2[O:16][CH2:15]1
Reactant: COc1cccc2c1OC(CNCCCOc1cccc(N)c1)CO2
Agent: Br
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Product: Nc1cccc(OCCCNCC2COc3cccc(O)c3O2)c1
Yield: 40.7 %

Procedure:
N-[3-(3-Aminophenoxy)propyl]-2,3-dihydro-8-methoxy-1,4-benzodioxin-2-methanamine dihydrochloride hydrate (1.2 g, 2.75 mmole), prepared in Example 11 above, was dissolved in 25 ml of 48% HBr and refluxed overnight under nitrogen. The mixture was diluted with water to 300 ml, carefully neutralized with solid sodium carbonate, and twice extracted with 200 ml of 3:1 dichloromethane/isopropanol. The combined extracts were washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated in vacuum. The residue was crystallized from 50 ml of isopropanol with the addition of 2 ml of 4N HCl/isopropanol to give 0.37 g of the title compound as a tan solid, dihydrochloride, quarter hydrate, m.p. 249°-255° C.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[C:8]([N+:9]([O-])=O)=[CH:7][N:6]=[C:5]([N:12]2[CH2:17][CH2:16][CH2:15][C@@H:14]([C:18]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:19])[CH2:13]2)[N:4]=1>CO.[Pd]>[ClH:1].[ClH:1].[NH2:2][C:3]1[C:8]([NH2:9])=[CH:7][N:6]=[C:5]([N:12]2[CH2:17][CH2:16][CH2:15][C@@H:14]([C:18]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:19])[CH2:13]2)[N:4]=1
Reactant: Nc1nc(N2CCC[C@@H](C(=O)N3CCCC3)C2)ncc1[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Nc1cnc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N

Procedure:
Concentrated hydrochloric acid (470 μL, 37 wt % aq) was added to a solution of (R)-(1-(4-amino-5-nitropyrimidin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone (380 mg, 1.13 mmol) in methanol (30 mL). The solution was hydrogenated using the H-Cube (10% Pd/C, full H2, 18° C., 1 mL/min). A second cycle was run using the same conditions. The solvent was removed under reduced pressure and the residue was co-evaporated with toluene several times to afford the title compound as a yellow solid (405 mg). The material was used without further purification. 1H NMR (CD3OD) δ 1.68 (d, 1H), 1.81 (d, 1H), 1.91 (quin, 3H), 1.96-2.09 (m, 3H), 2.84 (t, 1H), 3.34-3.47 (m, 4H), 3.52-3.59 (m, 1H), 3.61-3.70 (m, 1H), 4.32 (d, 1H), 4.17 (d, 1H), 7.70 (s, 1H); MS (ES+) (M+H) 291.2.
Reaction SMILES: [CH3:1][O:2]/[C:3](/[C:9]1[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=1[CH2:11]P(=O)(OC)OC)=[CH:4]/[C:5]([O:7][CH3:8])=[O:6].[CH2:22]([O:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[H-].[Na+].[NH4+].[Cl-]>CN(C)C=O>[CH2:22]([O:29][C:30]1[CH:31]=[CH:32][C:33]([CH:34]=[CH:11][C:10]2[CH:18]=[CH:19][CH:20]=[CH:21][C:9]=2/[C:3](/[O:2][CH3:1])=[CH:4]\[C:5]([O:7][CH3:8])=[O:6])=[CH:36][CH:37]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)/C=C(/OC)c1ccccc1CP(=O)(OC)OC
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Agent: COC(=O)/C=C(/OC)c1ccccc1/C=C/c1ccc(OCc2ccccc2)cc1
Agent: [Cl-]
Agent: [H-]
Solvent: CN(C)C=O
Product: COC(=O)/C=C(/OC)c1ccccc1C=Cc1ccc(OCc2ccccc2)cc1
Reaction time: 3 h

Procedure:
A solution of 3.0 g (10 mmol) of dimethyl (E)-2-(1-methoxy-2-methoxycarbonylethenyl)benzylphosphonate and 2.1 g (10 mmol) of 4-benzyloxybenzaldehyde in 50 ml of dimethylformamide is added dropwise at room temperature to 0.26 g (11 mmol) of NaH in 20 ml of dimethylformamide. The mixture is stirred for 3 h, and then NH4Cl solution is added. After extraction with ethyl acetate, the organic phase is washed with water, dried over Na2SO4 and concentrated. Recrystallization from diisopropyl ether/n-hexane results in 1.9 g (48%) of pale yellow crystals of methyl 2-[2-(4-benzyloxyphenyl)-(E)-ethenyl]-(E)-β-methoxycinnamate of melting point 118°-120° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5]([OH:7])=[O:6].O=S(Cl)Cl.[CH3:18]O>>[CH3:18][O:6][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=[C:2]([I:1])[CH:3]=1
Reactant: CO
Reactant: O=C(O)c1cc(I)cc([N+](=O)[O-])c1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(I)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a solution of 3-iodo-5-nitrobenzoic acid (20.00 g, 0.068 mol) in methanol (50 mL) was added SOCl2 (5.45 mL, 0.075 mol) at 0° C. The reaction mixture was allowed to warm to room temperature and was then heated to breflux for 2 hours. The reaction was cooled and solvent was removed in vacuo to afford 3-Iodo-5-nitro-benzoic acid methyl ester as light yellow solid (20.67 g, 99%). MS (M+H)=309.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:21])=[C:6]([CH:8]([C:10]2[S:11][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[CH:13][CH:14]=2)O)[CH:7]=1.[BH4-].[Na+]>FC(F)(F)C(O)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:21])=[C:6]([CH2:8][C:10]2[S:11][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[CH:13][CH:14]=2)[CH:7]=1
Reactant: OC(c1ccc(-c2ccccn2)s1)c1cc(Br)ccc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(Br)cc1Cc1ccc(-c2ccccn2)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.8 %

Procedure:
2-(2-Pyridyl)thiophene and 5-bromo-2-chlorobenzaldehyde obtained in Reference Example 16-(1) were treated in a manner similar to Reference Example 7-(1) to give 5-bromo-2-chlorophenyl-5-(2-pyridyl)-2-thienylmethanol as colorless powder. APCI-Mass m/Z 380/382 (M+H). (2) A solution of the above 5-bromo-2-chlorophenyl-5-(2-pyridyl)-2-thienylmethanol (3.52 g) in trifluoroacetic acid (45 ml) was added to a solution of sodium borohydride (1.75 g) in trifluoroacetic acid (45 ml), and the mixture was stirred at room temperature for 4 hours. Trifluoroacetic acid was evaporated under reduced pressure. The residue was basified with an aqueous potassium hydroxide solution, and extracted with diethyl ether. The extract was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1-4:1) to give 5-bromo-2-chloro-1-(5-(2-pyridyl)-2-thienylmethyl)benzene (2.42 g) as a colorless solid. APCI-Mass m/Z 364/366 (M+H).
Reaction SMILES: [F:1][C:2]1[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:3]=1[CH2:4][S:5][C:6]1[N:11]=[C:10]([O:12][C@H:13]([CH3:19])[C:14](OCC)=[O:15])[CH:9]=[C:8]([NH:20][S:21]([N:24]2[CH2:31][CH2:30][CH:29]3[N:32]([CH3:33])[CH:26]([CH2:27][CH2:28]3)[CH2:25]2)(=[O:23])=[O:22])[N:7]=1.[Li+].[BH4-].[NH4+].[Cl-]>C1COCC1>[F:1][C:2]1[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:3]=1[CH2:4][S:5][C:6]1[N:7]=[C:8]([NH:20][S:21]([N:24]2[CH2:31][CH2:30][CH:29]3[N:32]([CH3:33])[CH:26]([CH2:27][CH2:28]3)[CH2:25]2)(=[O:22])=[O:23])[CH:9]=[C:10]([O:12][C@H:13]([CH3:19])[CH2:14][OH:15])[N:11]=1
Reactant: CCOC(=O)[C@@H](C)Oc1cc(NS(=O)(=O)N2CCC3CCC(C2)N3C)nc(SCc2cccc(F)c2F)n1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@H](CO)Oc1cc(NS(=O)(=O)N2CCC3CCC(C2)N3C)nc(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of ethyl (2R)-2-[(2-[(2,3-difluorobenzyl)thio]-6-{[(9-methyl-3,9-diazabicyclo[4.2.1]non-3-yl)sulfonyl]amino}pyrimidin-4-yl)oxy]propanoate (the product from step i), 0.35 g) in THF (10 ml) was added 2M LiBH4 in THF (0.6 ml). The reaction was then stirred for 18 h at room temperature. Saturated NH4Cl (150 ml) was then added to the reaction mixture which was extracted with DCM (3×150 ml). Organics were combined, dried (MgSO4) and reduced in vacuo and the resulting residue was purified by prep HPLC to give the title compound as a white solid. Yield 20 mg
Reaction SMILES: C([Li])CCC.CC(NC(C)C)C.[C:13]1([CH2:19][CH2:20][N:21]2[CH:25]=[N:24][CH:23]=[N:22]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CN(C)[CH:28]=[O:29]>CCCCCC.O1CCCC1>[C:13]1([CH2:19][CH2:20][N:21]2[C:25]([CH:28]=[O:29])=[N:24][CH:23]=[N:22]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CN(C)C=O
Reactant: c1ccc(CCn2cncn2)cc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=Cc1ncnn1CCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of butyllithium in hexane (119 ml) was added dropwise at -70° C. under nitrogen to a solution of N-(1-methylethyl)-2-propanamine (26.7 ml) in tetrahydrofuran (280 ml) and the mixture was stirred for 30 minutes. 1-(2-phenylethyl)-1,2,4-triazole (0.173 mol) in tetrahydrofuran (20 ml) was added and the mixture was stirred at -70° C. for 1 hour. N,N-dimethylformamide (17.4 ml) was added dropwise and the mixture was stirred at -70° C. for 1 hour and then at room temperarure for 2 hours. The mixture was poured into ice water and extracted with 1,1'-oxybisethane. The organic layer was dried (MgSO4), filtered off and evaporated. The residue (11.7 g) was purified by column chromatography over silica gel (eluent: CH2Cl2 /CH3OH/NH4OH 99/1/0.1) (35-70 μm). The pure fractions were collected and evaporated, yielding 7g (40%) of 2-(2-phenylethyl)-2H-1,2,4-triazole-3-carboxaldehyde (interm. 1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([F:13])=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1)[CH3:2].C(O)(=[O:16])C.OO>O1CCCC1>[CH2:1]([O:3][C:4]1[C:5]([F:13])=[C:6]([OH:16])[CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CC(=O)O
Reactant: CCOc1cccc(B(O)O)c1F
Agent: OO
Solvent: C1CCOC1
Product: CCOc1cccc(O)c1F
Reaction time: 23 h
Yield: 71 %

Procedure:
To a solution of 3-ethoxy-2-fluoro-phenylboronic acid (10.0 g, 0.054 mol) in tetrahydrofuran (150 mL) was added glacial acetic acid (60 mL). The resulting mixture was cooled to 0° C. before hydrogen peroxide (50% aqueous solution, 8 mL) was added. The resulting mixture was allowed to come to room temperature and stirred for 23 h. The mixture was evaporated and the residue was dissolved in ethyl acetate, washed with hydrochloric acid (0.5N), water and brine. The organic phase was dried, filtered and evaporated to give 3-ethoxy-2-fluoro-phenol (6.00 g, 71%) as a brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[C:13]([O:17][C:18](Cl)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(N(CC)CC)C>C(Cl)Cl>[C:13]([O:17][C:18]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Br:1])[CH:10]=2)[C:6]([CH:11]=[O:12])=[CH:7]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: O=Cc1c[nH]c2cc(Br)ccc12
Reactant: CC(C)(C)OC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1cc(C=O)c2ccc(Br)cc21
Temperature: 0 °C

Procedure:
6-Bromoindole-3-carboxaldehyde, 23 (5.0 g, 22.3 mmol) is dissolved in methylene chloride (40 mL), then cooled to 0° C. and tert-butylchloroformate (3.40 g, 25.0 mmol) and triethyl amine (2.50 g, 25.0 mmol) are added over 5 minutes. The reaction is maintained at reflux, under inert atmosphere for 3 hours. The reaction is cooled, filtered and the solvent removed in vacuo. The residue composed primarily of compound 24 is used in the Example 18 without purification. (See, e.g., G. Wille and W. Steglich, Synthesis, 2001, 759-762 for a related procedure.)
Reaction SMILES: [ClH:1].C(OC([N:9]1[C@H:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@H:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:11]=[C:10]1[NH:26][C:27](=[O:35])[C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1)=O)(C)(C)C>CCOC(C)=O>[ClH:1].[C:14]1([C@H:13]2[C@@H:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[NH:11][C:10]([NH:26][C:27](=[O:35])[C:28]3[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)=[N:9]2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1C(NC(=O)c2ccc(F)cc2)=N[C@@H](c2ccccc2)[C@H]1c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(NC1=N[C@@H](c2ccccc2)[C@@H](c2ccccc2)N1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Hydrogen chloride is bubbled into a solution of 125 (123 mg, 0.267 mmol) in EtOAc (20 mL) for 1 min, and the solution is stirred at RT overnight. The solvent is removed by rotary evaporation, and the residue is triturated with Et2O to give 50 mg of the product 126. 1H NMR (DMSO-d6) δ 12.9 (s, 1H), 9.70 (s, 2H), 8.35-8.15 (m, 2H), 7.60-7.40 (m, 2H), 7.20-6.90 (m, 10), 5.70 (s, 2H); LC/MS: 3.20 m/z 360 (M++1).