Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:5]2[CH2:6][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[CH2:20]([NH:22][CH2:23][CH3:24])[CH3:21].CC(C)([O-])C.[Na+].O>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>[CH2:20]([N:22]([CH2:23][CH3:24])[C:2]1[CH:19]=[CH:18][C:5]2[CH2:6][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1)[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCOc2cc(Br)ccc2C1
Reactant: CCNCC
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Solvent: O
Product: CCN(CC)c1ccc2c(c1)OCCN(C(=O)OC(C)(C)C)C2
Yield: 85.3 %

Procedure:
A solution of tert-butyl 8-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (300 mg, 0.915 mmol), diethylamine (0.310 ml, 3.00 mmol), X-phos (26.1 mg, 0.0546 mmol), tris(dibenzylideneacetone)dipalladium(0) (16.6 mg, 0.00187 mmol) and sodium tert-butoxide (131 mg, 1.37 mmol) in dioxane (6 ml) was stirred under an argon atmosphere for 1 hr at 80° C. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=2:1) to give the desired product (250 mg, 85.3%) as an oil.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH:5]1([CH2:15]O)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][O:6]1.N1C=CC=CC=1>C1C=CC=CC=1>[CH:5]1([CH2:15][Cl:3])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][O:6]1
Reactant: O=S(Cl)Cl
Reactant: OCC1OCCc2ccccc21
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: ClCC1OCCc2ccccc21
Yield: 97.8 %

Procedure:
8.4 g (70.6 mmol) of thionyl chloride was dropwise added to a solution of 10 g (61 mmol) of (isochroman-1-yl)methanol [J. Med. Chem., 28, 1026 (1985)] and 5 g (63 mmol) of anhydrous pyridine in dried benzene, and the resulting mixture was heated under reflux for 2 hours. Excessive amounts of thionyl chloride and benzene were evaporated, and the residue was dissolved in ether. The ethereal solution was washed with water and dried, and the solvent was then evaporated. The residue was distilled under reduced pressure (140° C./20 mmHg) to give 10.9 g (98%) of the desired compound as an oily.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:10]([C:23]1([C:26]([F:29])([F:28])[F:27])CO1)[CH2:11][NH:12][C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH:15]=[CH:16]C=[N:18]2.[C:30](=[O:33])([O-])[O-].[Cs+].[Cs+].C(S)C>CN(C=O)C>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:10]([C:11]1[CH:16]=[CH:15][C:14]2[C:19]([NH2:18])=[CH:20][CH:21]=[CH:22][C:13]=2[N:12]=1)[C:23]1([C:26]([F:29])([F:28])[F:27])[CH2:30][O:33]1
Reactant: COc1cccc(C(CNc2cccc3ncccc23)C2(C(F)(F)F)CO2)c1F
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCS
Solvent: CN(C)C=O
Product: COc1cccc(C(c2ccc3c(N)cccc3n2)C2(C(F)(F)F)CO2)c1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 61.2 %

Procedure:
[(2-Fluoro-3-methoxyphenyl)-2-(2-trifluoromethyl-oxiranyl)ethyl]quinolin-5-yl-amine (97 mg, 0.25 mmol) was dissolved in DMF (0.5 mL). Caesium carbonate (161 mg, 0.5 mmol) was added followed by ethanethiol (75 μL, 1 mmol). The mixture was vigorously stirred at ambient temperature for 90 minutes. The reaction mixture was partitioned between diethylether and water. The organic phase was washed trice with water and then with brine and evaporated. The residue was dissolved in methylene chloride, filtered through a plug of glass wool to remove residual NaCl and again evaporated. The crude product was dissolved in methylene chloride and flash-chromatographed on a column of silica using a gradient of heptane-ethyl acetate (10→90% ethyl acetate) to yield the title product (60 mg, 53%) as an amorphous solid.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([NH:8][CH2:9][C:10]2[S:11][C:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=3)=[CH:13][CH:14]=2)=[O:7])=[CH:4][N:3]=1.CC[C@@H]([C@H](NCN[C:36]([O:38][CH2:39]C)=O)C(O)=O)C.C=O.C(OCC)(=O)C>CO>[Cl:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[CH2:15][C:12]1[S:11][C:10]([CH2:9][NH:8][C:6](=[O:7])[C:5]2[CH:23]=[CH:24][C:2]([NH:1][CH2:36][O:38][CH3:39])=[N:3][CH:4]=2)=[CH:14][CH:13]=1
Reactant: CCOC(=O)NCN[C@H](C(=O)O)[C@@H](C)CC
Reactant: Nc1ccc(C(=O)NCc2ccc(Cc3cccc(Cl)c3)s2)cn1
Agent: C=O
Solvent: CO
Solvent: CCOC(C)=O
Product: COCNc1ccc(C(=O)NCc2ccc(Cc3cccc(Cl)c3)s2)cn1
Yield: 54 %

Procedure:
To a solution of 6-amino-N-(5-(3-chloro-benzyl)-thiophen-2-ylmethyl)-nicotinamide described in Example A-145 (110 mg, 0.3 mmol) in methanol (10 mL) were added 5,5-dimethylimidazo phospho-2,4-dione (43 mg, 0.33 mmol) and an aqueous solution of 37% formaldehyde (0.5 mL), and the solution was stirred under reflux for 2 hours. NH silica gel was added to the reaction solution, the solvent was evaporated in vacuo for adsorption, purification was carried out by NH silica gel column chromatography (hexane:ethyl acetate=1:1, then ethyl acetate), and the title compound (65 mg, 0.16 mmol, 54%) was obtained as a slightly yellow solid.
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:15]3[S:16][CH:17]=[CH:18][N:19]=3)=[N:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:28])C=1.S(OS([O-])=O)([O-])=O.[Na+].[Na+]>ClCCl>[C:1]1([S:7]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:15]3[S:16][CH:17]=[CH:18][N:19]=3)=[N:12][CH:13]=2)=[O:28])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(Sc2ccc(Nc3nccs3)nc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])OS(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=S(c1ccccc1)c1ccc(Nc2nccs2)nc1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 44 %

Procedure:
(5-Phenylsulfanyl-pyridine-2-yl)-thiazole-2-yl-amine (0.13 mmol) is dissolved in dichloromethane, cooled to 0° C. and m-chloro-perbenzoic acid (1 eq.) is added. The reaction is stirred 30 min at 0° C. and 2.5 hours at RT. Sodium disulfite (50 ml) is added and extracted with dichloromethane. The combined organic layers are washed with saturated NaHCO3, dried over MgSO4 and the solvent is removed in vacuo. “A13” is obtained after reversed phase column chromatography (water/acetonitrile) as a yellow powder in a yield of 44% HPLC (method C): 1.41 min; LC-MS (method A): 1.223 min, 301.95 (M+H+); 1H-NMR (DMSO-d6, 500 MHz): δ [ppm] 11.657 (s, 1H), 8.634-8.628 (m, 1H), 7.853 (dd, 1H, J=2.4 Hz, J=8.9 Hz), 7.722-7.703 (m, 2H), 7.583-7.507 (m, 3H), 7.425 (d, 1H, J=3.6 Hz), 7.152 (d, 1H, J=8.9 Hz), 7.100 (d, 1H, J=3.6 Hz).
Reaction SMILES: [C:1]1([S:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:9]=[C:10](Cl)[CH2:11][CH2:12][C:13](=[O:16])[O:14][CH3:15].[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClC(Cl)C.ClCCl>[CH3:8][S:7][C:1]1[CH:6]=[CH:5][C:4]([C:10](=[O:9])[CH2:11][CH2:12][C:13]([O:14][CH3:15])=[O:16])=[CH:3][CH:2]=1
Reactant: CSc1ccccc1
Reactant: COC(=O)CCC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: COC(=O)CCC(=O)c1ccc(SC)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Thioanisole (12.4 g) and 1,4-dioxo-4-methoxybutyl chloride (16.5 g) in dichloroethane (100 ml) were cooled to 0° C. and aluminum chloride (16 g) was added, followed by another equivalent (16 g) and the reaction mixture was stirred at 0° C. for 2 hours. Ice was added, followed by 1N HCl. Dichloromethane (100 ml) was then added and the organic layer was separated, washed with water and then brine and dried with Na2SO4. Removal of the solvents yielded the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14](O)[CH2:15][CH2:16][C:12]=3[N:11]=[C:10]2[C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:4][CH:3]=1.[CH2:22]([O:24][C:25]([CH:27]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:26])[CH3:23].CP(C)C.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1.CC1CCCO1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:13]3[CH:14]([C:27]([C:33]([O:35][CH2:36][CH3:37])=[O:34])([C:25]([O:24][CH2:22][CH3:23])=[O:26])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:15][CH2:16][C:12]=3[N:11]=[C:10]2[C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)OCC
Reactant: CC(C)(C)c1nc2c(n1Cc1ccc(Cl)cc1)C(O)CC2
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: CP(C)C
Solvent: Cc1ccccc1
Solvent: CC1CCCO1
Product: CCOC(=O)C(C(=O)OCC)(C(=O)OCC)C1CCc2nc(C(C)(C)C)n(Cc3ccc(Cl)cc3)c21
Temperature: 25 °C

Procedure:
To a suspension of Intermediate 34 (300 mg) and triethylmethanetricarboxylate (0.417 ml) in toluene (3.5 ml) and methyltetrahydrofuran (3.50 ml), stirred at RT under an inert atmosphere of nitrogen, was added trimethylphosphine, 1M in toluene (1.97 ml). The resulting solution was cooled to −78° C. and diisopropyl azodicarboxylate (0.39 ml) was added dropwise via syringe and the reaction was stirred at −78° C. for 45 mins. The reaction mixture was removed from the cold bath and allowed to warm to RT and stirred under N2 atmosphere overnight. Reaction mixture concentrated in vacuo. The residue was taken up in DCM (20 ml) and washed with water (20 mL). The 2 phases were separated, the organic extract was dried (hydrophobic frit) and concentrated under vacuum. The residue was purified on silica using a cyclohexane:ethyl acetate 0-100% gradient. The desired fractions were combined and concentrated under vacuum to give the title compound (496 mg). LC/MS MH+ 519, Rt 3.53 min (5 minute run)
Reaction SMILES: [OH:1][N:2]1[C:6]([CH3:7])=[CH:5][S:4][C:3]1=[S:8].C(=O)(O)[O-].[Na+].[C:14](OC(=O)C)(=[O:16])[CH3:15]>O>[C:14]([O:1][N:2]1[C:6]([CH3:7])=[CH:5][S:4][C:3]1=[S:8])(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1csc(=S)n1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(=O)On1c(C)csc1=S

Procedure:
0.74 parts of 3-hydroxy-4-methylthiazol-2(3H)-thione, 0.84 parts of sodium bicarbonate and 30 parts of water were stirred at 0°-5° C. while 0.52 parts of acetic anhydride were added dropwise and the reaction mixture was stirred at 0°-5° C. for a further hour. A precipitate was formed which was separated by filtration and recrystallised from aqueous methanol. 0.33 parts of 3-acetoxy-4-methylthiazol-2(3H)-thione, of melting point 100°-101° C., was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[F:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:24]=1[CH:23]([C:25]([F:28])([F:27])[F:26])[NH:22][CH2:21][CH2:20]2>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:22]3[CH2:21][CH2:20][C:19]4[C:24](=[C:15]([F:14])[CH:16]=[CH:17][CH:18]=4)[CH:23]3[C:25]([F:26])([F:28])[F:27])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: Fc1cccc2c1C(C(F)(F)F)NCC2
Product: O=C(c1cc2ncc(Br)cn2n1)N1CCc2cccc(F)c2C1C(F)(F)F

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 8-fluoro-1-trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[C:11]([C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:36]3[CH:41]=[CH:40][C:39]([C:42](=[O:44])[CH3:43])=[CH:38][CH:37]=3)[C:19]3[C:24]([C:25]=2[CH:26]=1)=[CH:23][C:22]([C:27](=[O:35])[C:28]1[CH:33]=[CH:32][C:31](F)=[CH:30][CH:29]=1)=[CH:21][CH:20]=3)(=[O:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+]>>[C:42]([C:39]1[CH:38]=[CH:37][C:36]([N:18]2[C:17]3[CH:16]=[CH:15][C:14]([C:11](=[O:13])[CH3:12])=[CH:26][C:25]=3[C:24]3[C:19]2=[CH:20][CH:21]=[C:22]([C:27](=[O:35])[C:28]2[CH:33]=[CH:32][C:31]([S:1][C:2]4[S:3][C:4]5[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=5[N:6]=4)=[CH:30][CH:29]=2)[CH:23]=3)=[CH:41][CH:40]=1)(=[O:44])[CH3:43]
Reactant: CC(=O)c1ccc(-n2c3ccc(C(C)=O)cc3c3cc(C(=O)c4ccc(F)cc4)ccc32)cc1
Reactant: Sc1nc2ccccc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(=O)c1ccc(-n2c3ccc(C(C)=O)cc3c3cc(C(=O)c4ccc(Sc5nc6ccccc6s5)cc4)ccc32)cc1

Procedure:
An analogous reaction as described in example 5.a by using 2-mercaptobenzothiazole and 1-{4-[3-acetyl-6-(4-fluoro-benzoyl)-carbazol-9-yl]-phenyl}-ethanone in the presence of potassium carbonate gives the product. The structure is confirmed by the 1H-NMR spectrum (CDCl3). δ [ppm]: 2.74 (s, 3H), 2.75 (s, 3H), 7.35 (t, 1H), 7.47 (t, 2H), 7.52 (d, 1H), 7.72 (d, 2H), 7.77 (d, 1H), 7.86 (d, 2H), 7.92 (d, 2H), 7.96 (d, 1H), 8.03 (d, 1H), 8.15 (d, 1H), 8.28 (d, 2H), 8.71 (s, 1H), 8.81 (s, 1H).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:20][C@H:19]([CH3:21])[C@@H:18]([OH:22])[CH2:17][C:15](=[O:16])[O:14][C@H:13]([C@H:23]2[C@H:27]([C:28]([OH:30])=[O:29])[CH2:26][CH2:25][CH2:24]2)[CH2:12][CH:11]=[CH:10][CH:9]=[C:8]([C:31]#[N:32])[C@H:7]([OH:33])[C@@H:6]([CH3:34])[CH2:5][C@H:4]([CH3:35])[CH2:3]1.[N:36]1[CH:41]=[CH:40][CH:39]=[C:38]([CH2:42][NH2:43])[CH:37]=1>C(Cl)(Cl)Cl.CO>[CH3:1][C@@H:2]1[CH2:20][C@H:19]([CH3:21])[C@@H:18]([OH:22])[CH2:17][C:15](=[O:16])[O:14][C@H:13]([C@H:23]2[C@H:27]([C:28]([OH:30])=[O:29])[CH2:26][CH2:25][CH2:24]2)[CH2:12][CH:11]=[CH:10][CH:9]=[C:8]([C:31]#[N:32])[C@H:7]([OH:33])[C@@H:6]([CH3:34])[CH2:5][C@H:4]([CH3:35])[CH2:3]1.[N:36]1[CH:41]=[CH:40][CH:39]=[C:38]([CH2:42][NH-:43])[CH:37]=1
Reactant: NCc1cccnc1
Agent: C[C@@H]1C[C@H](C)C[C@H](C)[C@@H](O)CC(=O)O[C@H]([C@@H]2CCC[C@H]2C(=O)O)C/C=C/C=C(/C#N)[C@H](O)[C@@H](C)C1
Agent: C[C@@H]1C[C@H](C)C[C@H](C)[C@@H](O)CC(=O)O[C@H]([C@@H]2CCC[C@H]2C(=O)O)CC=CC=C(C#N)[C@H](O)[C@@H](C)C1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: [NH-]Cc1cccnc1
Reaction time: 3 h

Procedure:
To a mixed anhydride solution prepared from 4.0 g (8.2 mmol) of borrelidin according to Example 34.2 ml (41.2 mmol, 4.46 g) of 3-picolylamine were added. After stirring for 3 hours, the starting borrelidin (Rf=0.43) disappeared and the product (Rf=0.24) appeared, which was proved by thin-layer chromatography (silica gel plate, eluent system: chloroform/methanol 95:5). The reaction mixture was evaporated to dryness. The dry residue was dissolved in 500 ml of chloroform, washed with 3×1500 ml of water, dried over sodium sulfate and evaporated to dryness. The dry residue was chromatographed on a silica gel column with mixtures of chloroform and ethyl acetate of increasing ethyl acetate content. The fractions containing the product eluting with a 2:8 eluting mixture were combined and evaporated to dryness. To the thus-obtained solidifying oily substance (3.62 g) 4 ml of ethyl acetate and 20 ml of n-hexane were added, the solid material was triturated and then filtered. In this way 3.04 g product were obtained. Mp.: 99-105° C.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH3:10])=[CH:5][C:6]=1[C:7](Cl)=[O:8].[BH4-].[Na+].Cl.O>O1CCCC1>[CH3:1][C:2]1[O:3][C:4]([CH3:10])=[CH:5][C:6]=1[CH2:7][OH:8]
Reactant: Cc1cc(C(=O)Cl)c(C)o1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(CO)c(C)o1
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.5 %

Procedure:
A solution of 2,5-dimethylfuran-3-carbonyl chloride (5.0 g) in tetrahydrofuran (20 mL) was added dropwise to a suspension of sodium borohydride (3.4 g) in tetrahydrofuran (50 mL) at 0° C. and, after the completion of the dropwise addition, the mixture was stirred at 0° C. for 1 hr. The reaction mixture was treated with 1N hydrochloric acid, poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (3.8 g, 100%) as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([Br:27])[CH:21]=1)[C:9]([NH2:18])=[N:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:35][CH2:36][CH2:37][OH:38]>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:35][CH2:36][CH2:37][OH:38])=[C:22]([Br:27])[CH:21]=1)[C:9]([NH2:18])=[N:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N=C(N)N(Cc1ccc(O)c(Br)c1)C(=O)OC(C)(C)C
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N=C(N)N(Cc1ccc(OCCCO)c(Br)c1)C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
To a solution of 1,2-bis(tert-butoxycarbonyl)-1-[3-bromo-4-hydroxybenzyl]-guanidine (for synthesis, see, for example, Purohit et al., International PCT Patent Publication No. WO2008/083056, incorporated herein by reference) (2.0 g, 4.51 mmol) dissolved in anhydrous DMF (45 mL) was added K2CO3 (1.12 g, 8.13 mmol), and 3-bromopropanol (816 mg, 5.87 mmol) and the reaction mixture warmed to 50° C. using an oil bath. After 2 h, the reaction mixture was diluted with water (30 mL), and the aqueous layer separated then extracted with EtOAc (3×100 mL). The combined organic layers were dried over MgSO4, filtered and concentrated to a solid. The crude material was purified using silica gel chromatography (4:1 to 3:2 hexanes:EtOAc) to yield a white solid product (2.00 g, 88% yield). 1H NMR (CDCl3, 600 MHz): δ 9.42 (brs, 1H), 9.27 (brs, 1H), 7.54 (d, J=1.8 Hz, 1H), 7.26 (m, 1H), 6.85 (d, J=2.4 Hz, 1H), 5.08 (brs, 2H), 4.19 (t, J=5.4 Hz, 2H), 3.92 (m, 2H), 2.16 (m, 1H), 2.18 (m, 2H), 1.51 (s, 9H), 1.43 (s, 9H); 13C NMR (CDCl3, 150 MHz): δ 163.8, 160.8, 155.0, 154.3, 144.8, 133.1, 132.6, 127.9, 113.0, 111.7, 84.7, 79.2, 67.8, 60.6, 46.7, 31.9, 28.5, 28.3.
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]2[NH:15][CH:16]=[N:17][C:12]2=[CH:11][CH:10]=1)C1C=CC=CC=1.[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1B(O)O>>[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[N:15]1[C:13]2=[N:14][C:9]([OH:8])=[CH:10][CH:11]=[C:12]2[N:17]=[CH:16]1
Reactant: c1ccc(COc2ccc3nc[nH]c3n2)cc1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Product: Oc1ccc2ncn(-c3ccc(Cl)cc3Cl)c2n1

Procedure:
From 5-(benzyloxy)-3H-imidazo[4,5-b]pyridine and 2,4-dichlorophenylboronic acid, prepared in a similar manner as the one described in Example 1.26, the title compound was obtained. LCMS m/z=279.9 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 6.72 (d, J=8.7 Hz, 1H), 7.57 (dd, J1=8.5 Hz, J2=2.2 Hz, 1H), 7.63 (d, J=8.5 Hz, 1H), 7.79 (d, J=2.2 Hz, 1H), 7.99 (d, J=8.7 Hz, 1H), 8.34 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]1[NH:18][C:17]2[C:19]3[C:24]([CH2:25][CH2:26][C:16]=2[N:15]=1)=[CH:23][C:22]([C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[CH:33]=[C:32]([C:37]1[NH:41][C:40]([C@@H:42]4[CH2:46][CH2:45][CH2:44][N:43]4[C:47](=[O:57])[C@@H:48]([NH:52][C:53](=[O:56])[O:54][CH3:55])[CH:49]([CH3:51])[CH3:50])=[N:39][CH:38]=1)[CH:31]=[CH:30]2)=[CH:21][CH:20]=3)=[O:8])=[O:4].BrC1C=C2C(=CC=1)C=C(C1NC([C@@H]3CCCN3C(=O)[C@@H](N[C:91](=O)[O:92][CH3:93])C(C)C)=NC=1)C=C2>>[CH3:1][O:2][C:3]([NH:5][C@H:6]([C:58]1[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=1)[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]1[NH:18][C:17]2[C:19]3[C:24]([CH2:25][CH2:26][C:16]=2[N:15]=1)=[CH:23][C:22]([C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[CH:33]=[C:32]([C:37]1[NH:41][C:40]([C@@H:42]4[CH2:46][CH2:45][CH2:44][N:43]4[C:47](=[O:57])[C@@H:48]([NH:52][C:53](=[O:56])[O:54][CH3:55])[CH:49]4[CH2:51][CH2:93][O:92][CH2:91][CH2:50]4)=[N:39][CH:38]=1)[CH:31]=[CH:30]2)=[CH:21][CH:20]=3)=[O:8])=[O:4]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3cc(Br)ccc3c2)[nH]1)C(C)C
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3cc(-c4ccc5c(c4)CCc4nc([C@@H]6CCCN6C(=O)[C@H](NC(=O)OC)c6ccccc6)[nH]c4-5)ccc3c2)[nH]1)C(C)C
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3cc(-c4ccc5c(c4)CCc4nc([C@@H]6CCCN6C(=O)[C@H](NC(=O)OC)c6ccccc6)[nH]c4-5)ccc3c2)[nH]1)C1CCOCC1

Procedure:
Title compound was synthesized using methods analogous to the preparation of methyl (S)-1-((S)-2-(5-(6-(2-((S)-1-((R)-2-methoxycarbonylamino-2-phenylacetyl)pyrrolidin-2-yl)-4,5-dihydro-1H-naphtho[1,2-d]imidazol-7-yl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate, substituting methyl (S)-2-((S)-2-(5-(6-bromonaphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethylcarbamate for methyl (S)-1-((S)-2-(5-(6-bromonaphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate. MS (ESI) m/z 891 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14](=O)[CH2:13][CH:12]1[C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC(C2N(S(C3C=CC(Cl)=CC=3)(=O)=O)CC3[CH:48]=[N:49][NH:50]C=3C2)=CC=1.O.NN.N1CCC(=O)CC1>>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([CH:12]2[N:11]([C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])[CH2:16][C:15]3[CH:48]=[N:49][NH:50][C:14]=3[CH2:13]2)=[CH:19][CH:20]=1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)C(c2ccc(Cl)cc2)C1
Reactant: O=S(=O)(c1ccc(Cl)cc1)N1Cc2cn[nH]c2CC1c1ccc(Cl)cc1
Agent: NN
Agent: O=C1CCNCC1
Solvent: O
Product: O=C(OCc1ccccc1)N1Cc2cn[nH]c2CC1c1ccc(Cl)cc1

Procedure:
6-(4-Chlorophenyl)-5-(4-chlorophenylsulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine Benzyl 2-(4-chlorophenyl)-4-oxopiperidine-1-carboxylate, 67, was formylated and treated with hydrazine hydrate as described for compounds 50 and 51 in Example 1 to give benzyl 6-(4-chlorophenyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate which was then deprotected and sulfonylated as described for compound 84 in Example 7.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([OH:15])=O.[OH:16][C:17]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>ClCCl>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[C:13]([N:20]1[CH2:19][CH2:18][C:17]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([OH:16])[CH2:22][CH2:21]1)=[O:15]
Reactant: Cc1onc(-c2ccccc2)c1C(=O)O
Reactant: OC1(c2ccccc2)CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1onc(-c2ccccc2)c1C(=O)N1CCC(O)(c2ccccc2)CC1
Temperature: 25 °C

Procedure:
5-Methyl-3-phenylisooxazole-4-carboxylic acid (40 mg, 0.197 mmol), 4-hydroxy-4-phenylpiperidine (28.8 mg, 0.151 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (37.7 mg, 0.197 mmol) and triethylamine (59.8 mg, 0.591 mmol) were mixed in dichloromethane (2 mL) and stirred at room temperature over night. Solvent was evaporated in vacuo, and the residue was taken up in methanol (1 mL), filtered and purified by preparative chromatography. The combined fractions were partitioned between NaHCO3 (sat) and ethylacetate. The organic layer was washed with water and concentrated in vacuo to afford the title compound. HRMS (ESI, pos. ion) m/z calcd for C22H22N2O3: 362.1630, found 362.1627.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[S:10][C:9]([C:12]3[CH:13]=[C:14]([N:18]([CH3:22])[C:19](=[O:21])[CH3:20])[CH:15]=[CH:16][CH:17]=3)(I)[CH2:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:37]2[CH:45]=[CH:44][CH:43]=[C:42]3[C:38]=2[CH:39]=[N:40][NH:41]3)O1>>[NH:41]1[C:42]2[C:38](=[C:37]([C:2]3[N:3]=[C:4]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[C:5]4[S:10][C:9]([C:12]5[CH:13]=[C:14]([N:18]([CH3:22])[C:19](=[O:21])[CH3:20])[CH:15]=[CH:16][CH:17]=5)=[CH:8][C:6]=4[N:7]=3)[CH:45]=[CH:44][CH:43]=2)[CH:39]=[N:40]1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Reactant: CC(=O)N(C)c1cccc(C2(I)Cc3nc(Cl)nc(N4CCOCC4)c3S2)c1
Product: CC(=O)N(C)c1cccc(-c2cc3nc(-c4cccc5[nH]ncc45)nc(N4CCOCC4)c3s2)c1

Procedure:
N-(3-(2-Chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine-6-yl)phenyl)-N-methylacetamide (62 mg) was coupled to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 via General Procedure A to yield 352. MS (Q1) 485.2 (M)+