Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2[CH:15]=[C:16](OS(C(F)(F)F)(=O)=O)[CH:17]=[CH:18][C:4]1=2)[CH3:2].[C:27]([O:31][CH2:32][CH3:33])(=[O:30])[CH:28]=[CH2:29].[Cl-].[Li+].C(N(CC)CC)C>CN(C=O)C>[CH2:32]([O:31][C:27](=[O:30])/[CH:28]=[CH:29]/[C:16]1[CH:17]=[CH:18][C:4]2[N:3]([CH2:1][CH3:2])[C:9](=[O:10])[C:8]([CH3:11])([CH3:12])[C:7](=[O:13])[N:6]([CH3:14])[C:5]=2[CH:15]=1)[CH3:33]
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OS(=O)(=O)C(F)(F)F)ccc21
Reactant: C=CC(=O)OCC
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1ccc2c(c1)N(C)C(=O)C(C)(C)C(=O)N2CC
Temperature: 180 °C
Yield: 103.1 %

Procedure:
Trifluoromethane sulfonic acid 1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yl ester(0.40 g), ethyl acrylate(0.13 g), dichlorobis(triphenylphosphine) Palladium (II) (35 mg),lithium chloride(64 mg), and triethylamine(0.19 ml) were added to DMF(4 ml). The mixture was heated at 180° C. (microwave reactor) for 20 minutes. The reaction liquid was cooled to room temperature, and subjected to celite filtration. The filtrate was condensed under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate=70:30→30:70). The purified product was condensed under reduced pressure to give the title compound(0.36 g) as a pale yellow solid.
Reaction SMILES: CO.[OH-].[K+].C[O:6][C:7]([C:9]1[C:10]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:11]=2[S:12][C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)=[O:8].Cl>O>[CH3:27][O:26][C:23]1[CH:24]=[CH:25][C:10]2[C:9]([C:7]([OH:8])=[O:6])=[C:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[S:12][C:11]=2[CH:22]=1
Reactant: COC(=O)c1c(-c2ccc(OC)cc2)sc2cc(OC)ccc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)O)cc1
Yield: 97.2 %

Procedure:
To methanol (25 ml) and water (10 ml) is added 2.5 N potassium hydroxide in methanol (7 ml, 18.5 mmol) and 6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene-3-carboxylic acid methyl ester (2.00 g, 6.09 mmol). The contents are heated to reflux for 16 hours, then cooled and poured into a solution of 1 N hydrochloric acid (50 ml). The resulting slurry is further diluted with water (75 ml), then filtered, and the filter cake rinsed with water, and dried in vacuo to afford 1.86 g (97%) of title compound. IR (KBr) 3100-2400 (br), 2935, 1673, 1608, 1527, 1433, 1250, 1178, 1030, 828 cm-1 ; 1H NMR (CDCl3 /DMSO-d6): δ8.27 (d, 1 H, J=9.0 Hz), 7.49 (d, 2 H, J=8.5 Hz), 7.26 (d, 1 H, J=1.7 Hz), 7.06 (dd, 1 H, J=9.0, 1.7 Hz), 6.93 (d, 2 H, J=8.5 Hz), 3.87 (s, 3 H), 3.84 (s, 3 H); 13C NMR (CDCl3 /DMSO-d6): d 166.0, 160.1, 157.6, 148.5, 139.8, 133.2, 131.0, 126.6, 125.7, 123.0, 115.1, 113.8, 104.3, 55.7, 55.5. Anal. Calcd. for C17H14O4S: C, 64.95; H, 4.49; S, 10.20. Found: C, 64.72; H, 4.49; S, 10.40.
Reaction SMILES: C([BH3-])#N.[Na+].[OH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH2:12][NH:11][CH2:10][CH2:9]2.[S:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[CH:21]=O.O.C1(C)C(S(O)(=O)=O)=CC=CC=1>C(O)C>[OH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH2:12][N:11]([CH2:21][C:17]1[S:16][CH:20]=[CH:19][CH:18]=1)[CH2:10][CH2:9]2
Reactant: Oc1ccc2c(c1)CCNC2
Reactant: O=Cc1cccs1
Agent: Cc1ccccc1S(=O)(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Oc1ccc2c(c1)CCN(Cc1cccs1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.6 g of sodium cyanoborohydride is added to a solution of 1.5 g of 6-hydroxy-1,2,3,4-tetrahydroisoquinoline, 1.2 g of thiophene-2-aldehyde and 1.8 g of toluenesulfonic acid monohydrate in 30 ml of ethanol. The mixture is stirred at room temperature for 8 hours, the solvent is removed in vacuo, and the residue is taken up with water/methylene chloride. The organic phase is again skaken with water, dried and evaporated in a rotary evaporator. The crude oily product is purified by chromatography on silica gel using a mixture of ethyl acetate/methylene chloride in the ratio 1:2. 1.7 g of a colorless oil, which crystallizes on standing (69% of theory), is obtained. Melting point: 110°-112° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:7][CH:6]=1)=[O:4].[C:19]([C:23]1[CH:46]=[CH:45][C:26]([C:27]([NH:29][C@H:30]([C:41]([O:43][CH3:44])=[O:42])[CH2:31][C:32]2[CH:40]=[CH:39][C:35]([C:36]([OH:38])=[O:37])=[CH:34][CH:33]=2)=[O:28])=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(#N)C>[C:19]([C:23]1[CH:46]=[CH:45][C:26]([C:27]([NH:29][C@H:30]([C:41]([O:43][CH3:44])=[O:42])[CH2:31][C:32]2[CH:33]=[CH:34][C:35]([C:36]([O:38][CH2:2][C:3]([C:5]3[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:7][CH:6]=3)=[O:4])=[O:37])=[CH:39][CH:40]=2)=[O:28])=[CH:25][CH:24]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CCCCCCCOc1ccc(C(=O)CBr)cc1
Reactant: COC(=O)[C@H](Cc1ccc(C(=O)O)cc1)NC(=O)c1ccc(C(C)(C)C)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CC#N
Product: CCCCCCCOc1ccc(C(=O)COC(=O)c2ccc(C[C@H](NC(=O)c3ccc(C(C)(C)C)cc3)C(=O)OC)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 49 %

Procedure:
A solution of 2-bromo-1-(4-(heptyloxy)phenyl)ethanone, INT-4 (166 mg, 0.45 mmol) in acetonitrile (1 mL) was added to a solution of (S)-4-(2-(4-(tert-butyl)benzamido)-3-methoxy-3-oxopropyl)benzoic acid INT-1 (190 mg, 0.50 mmol) and TEA (75.0 μl, 0.54 mmol) in acetonitrile (4 mL). The reaction mixture was stirred at RT for 18 h then poured onto 0.5 M citric acid (30 mL) and extracted with EA (3×25 mL). The combined organics were dried over MgSO4, filtered and concentrated. The residue was triturated with Et2O (10 mL) and the filtrate concentrated to afford 159 mg (49%) of (S)-2-(4-(heptyloxy)phenyl)-2-oxoethyl 4-(2-(4-(tert-butyl)benzamido)-3-methoxy-3-oxopropyl)benzoate as a white solid. LCMS-ESI (m/z) calculated for C37H45NO7: 615.8. found 616.0 [M+H]+, tR=2.76 min. (Method 4).
Reaction SMILES: [C:1]([NH:5][CH2:6][CH:7]([OH:17])[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:18](Cl)(Cl)=[O:19]>C(Cl)Cl.C1C=CC=CC=1>[C:1]([N:5]1[CH2:6][CH:7]([C:8]2[CH:9]=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=2)[O:17][C:18]1=[O:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NCC(O)c1ccc([N+](=O)[O-])cc1
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Solvent: c1ccccc1
Product: CC(C)(C)N1CC(c2ccc([N+](=O)[O-])cc2)OC1=O
Temperature: -5 °C
Reaction time: 3.5 h

Procedure:
In 270 ml of CH2Cl2, 12.97 g of α-[(tert-butylamino)methyl]-p-nitrobenzyl alcohol is dissolved. The solution is cooled to -5° C. and 54 ml of 12.5% phosgene in benzene is added slowly. After the addition is completed, the mixture is stirred for 3.5 hours and poured on ice. The organic phase is separated, and the aqueous layer is extracted with CH2Cl2 (2×100 ml). The combined organic layers are washed with saturated NaHCO3 solution (2×250 ml), 100 ml of H2O and dried over MgSO4. The solution is evaporated to dryness to give 16.3 g, which is recrystallized from MeOH twice to afford 12.58 g of 3-tert-butyl-5-(p-nitrophenyl)-2-oxazolidinone, mp 123°-125° C. This product (10 g) is dissolved in 200 ml of MeOH and hydrogenated over 6 g of Raney nicke at 51 p.s.i.g at 40° C. to give, after filtration and evaporation, 8.21 g of 5-(p-aminophenyl)-3-tert-butyl-2-oxazolidinone, mp 125°-129° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11](Cl)=[O:12].[C:14]12([OH:24])[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2.N1C=CC=CC=1>O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11]([O:24][C:14]12[CH2:21][CH:20]3[CH2:19][CH:18]([CH2:17][CH:16]([CH2:22]3)[CH2:15]1)[CH2:23]2)=[O:12]
Reactant: O=C(Cl)c1cnc2ccccc2n1
Reactant: OC12CC3CC(CC(C3)C1)C2
Solvent: O
Solvent: c1ccncc1
Product: O=C(OC12CC3CC(CC(C3)C1)C2)c1cnc2ccccc2n1
Yield: 16.6 %

Procedure:
Prepared from 2-quinoxaloyl chloride (0.84 g, 4.4 mmol), 1-adamantanol (0.60 g, 3.9 mmol), pyridine (10 mL), and water (100 mL) yielding 0.20 g (16%) of (92):
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]3[N:14]([CH3:27])[C:15](=[O:26])[C:16]([CH3:25])=[C:17]([NH:18]C4C=CC=CC=4)[C:12]=3[C:11](=[O:28])[N:10]([CH:29]3[CH2:31][CH2:30]3)[C:9]2=[O:32])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:13]2[N:14]([CH3:27])[C:15](=[O:26])[C:16]([CH3:25])=[C:17]3[C:12]=2[C:11](=[O:28])[N:10]([CH:29]2[CH2:31][CH2:30]2)[C:9](=[O:32])[N:18]3[NH:8][C:5]2[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=2)=[CH:6][CH:7]=1
Reactant: Cc1c(Nc2ccccc2)c2c(=O)n(C3CC3)c(=O)n(-c3ccc(Br)cc3)c2n(C)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1c(=O)n(C)c(Nc2ccc(Br)cc2)c2c(=O)n(C3CC3)c(=O)n(Nc3ccccc3)c12
Temperature: 25 °C
Reaction time: 10 h
Yield: 26 %

Procedure:
To 1-(4-bromo-phenyl)-3-cyclopropyl-6,8-dimethyl-5-phenylamino-1H,8H-pyrido[2,3-d]pyrimidine-2,4,7-trione 41 (78 mg) obtained in Step 7 was added chloroform-methanol [1:1 (volume ratio), 2.0 ml], potassium carbonate (22 mg) was added, and the mixture was stirred at room temperature for 10 hrs. The mixture was further stirred under reflux for 3 hrs, and allowed to cool to room temperature. The mixture was concentrated under reduced pressure and purified by column chromatography (chloroform:acetone=50:1) to give 5-(4-bromo-phenylamino)-3-cyclopropyl-6,8-dimethyl-1-phenylamino-1H,6H-pyrido[4,3-d]pyrimidine-2,4,7-trione 42 (23′ mg, yield 26%) as colorless crystals.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[N:17]1([C:23]2[N:24]=[CH:25][C:26]3[CH2:31][C:30](=[O:32])[N:29]([CH3:33])[C:27]=3[N:28]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>C(Cl)Cl>[C:8]([CH:18]1[CH2:19][NH:20][CH2:21][CH2:22][N:17]1[C:23]1[N:24]=[CH:25][C:26]2[CH2:31][C:30](=[O:32])[N:29]([CH3:33])[C:27]=2[N:28]=1)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CN1C(=O)Cc2cnc(N3CCNCC3)nc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1C(=O)Cc2cnc(N3CCNCC3C(=O)c3ccccc3)nc21
Yield: 75.8 %

Procedure:
One gram of triethylamine, 50 ml of methylene chloride and 0.6 g (4.3 mmoles) of benzoyl chloride were added to 1.0 g (4.3 mmoles) of 2-piperazino-5,6-dihydro-7-methyl-6-oxo(7H) pyrrolo[2,3-d]pyrimidine, and the mixture was reacted overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and after adding an aqueous solution of sodium hydrogen carbonate, extracted with chloroform. The chloroform layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give 1.1 g (yield 76%) of the desired compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11]C(=O)N(C)C)[CH:6]=1.[OH-].[K+].CO>O>[CH3:1][O:2][C:3](=[O:17])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([SH:11])[CH:6]=1
Reactant: COC(=O)Cc1cccc(SC(=O)N(C)C)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)Cc1cccc(S)c1

Procedure:
A mixture of (3-dimethylcarbamoylsulfanyl-phenyl)-acetic acid methyl ester (2.0 g., 7.9 mmol), potassium hydroxide (1.4 g, 24 mmol),methanol (50 mL), and water (5 mL) is stirred at reflux 3 hr. The mixture is concentrated, and product partitioned between 1M aqueous hydrochloric acid (50 mL) and ethyl acetate (3×75 mL). The combined extracts are dried over anhydrous magnesium sulfate, filtered and concentrated. The residue is taken up in methanol (50 mL), 2 mL concentrated sulfuric acid is added, and the mixture refluxed 3 hr. The mixture is concentrated, and the residue purified by silica chromatography eluting with 7:3 hexanes:ethyl acetate to afford the title compound as a pale yellow oil, 1.0 g, 69%. MS M++1 183. The structure is confirmed by 1H NMR spectroscopy.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][C:27]=1[C:28]1[NH:32][C:31](=[O:33])[O:30][N:29]=1)[O:6][CH2:7][C:8]1[S:12][C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)=[N:10][C:9]=1[CH:23]=O.C(N(CC)CC)C.Cl.[F:42][C:43]([F:48])([F:47])[CH2:44][CH2:45][NH2:46].[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:6][CH2:7][C:8]2[S:12][C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][CH:14]=3)=[N:10][C:9]=2[CH2:23][NH:46][CH2:45][CH2:44][C:43]([F:48])([F:47])[F:42])[CH:25]=[CH:26][C:27]=1[C:28]1[NH:32][C:31](=[O:33])[O:30][N:29]=1
Reactant: COc1cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C=O)ccc1-c1noc(=O)[nH]1
Reactant: NCCC(F)(F)F
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CNCCC(F)(F)F)ccc1-c1noc(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 18 %

Procedure:
To a suspension of 30 mg of 5-[3-methoxy-4-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-phenoxymethyl]-2-(4-trifluoromethyl-phenyl)-thiazole-4-carbaldehyde in 1.5 mL of methanol were added 0.018 mL of triethylamine, 10 mg of 3,3,3-trifluoro-propylamine hydrochloride and 0.5 g of 4 Å powdered molecular sieves. The resulting mixture was stirred at room temperature for 1 h then 2.4 mg of sodium borohydride was added. After stirring at room temperature for 45 minutes, the reaction mixture was concentrated under reduced pressure. The crude product was purified by preparative thin layer chromatography on silica gel (dichloromethane 90/methanol 10/water 1/acetic acid 1) followed by azeotropal removal of traces of acetic acid with cyclohexane to give 6.5 mg of 3-(2-methoxy-4-{2-(4-trifluoromethyl-phenyl)-4-[(3,3,3-trifluoro-propylamino)-methyl]-thiazol-5-ylmethoxy}-phenyl)-4H-[1,2,4]oxadiazol-5-one as a white solid.
Reaction SMILES: [F:1][CH:2]([F:37])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]3[CH2:25][CH2:24][N:23]([S:26]([CH:29]=[CH2:30])(=[O:28])=[O:27])[CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:5]=2[N:4]=1.[NH:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1>O1CCOCC1>[F:37][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([N:20]3[CH2:21][CH2:22][N:23]([S:26]([CH2:29][CH2:30][N:38]4[CH2:42][CH2:41][CH2:40][CH2:39]4)(=[O:28])=[O:27])[CH2:24][CH2:25]3)[N:9]=2)[C:6]2[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:5]=2[N:4]=1
Reactant: C1CCNC1
Reactant: C=CS(=O)(=O)N1CCN(c2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4c(OC)cccc43)n2)CC1
Solvent: C1COCCO1
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCN(S(=O)(=O)CCN3CCCC3)CC2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.5 %

Procedure:
A mixture of 2-(difluoromethyl)-4-methoxy-1-{4-(4-morpholinyl)-6-[4-(vinylsulfonyl)-1-piperazinyl]-1,3,5-triazin-2-yl}-1H-benzimidazole (Example 3) (150 mg, 0.280 mmol) and pyrrolidine (0.23 mL, 2.80 mmol) in 1,4-dioxane (20 mL) was stirred at room temperature for 16 hrs and then refluxed for 3 hrs. The solvent was removed under vacuum, the residue was diluted with water and the resulting precipitate was dissolved in CH2Cl2. The organic layer was separated and dried (Na2SO4), and solvent was removed under vacuum. Chromatography on silica eluting with CH2Cl2/MeOH (98:2), followed by recrystallization from CH2Cl2/hexanes gave 2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(4-{[2-(1-pyrrolidinyl)ethyl]sulfonyl}-1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (137 mg, 81%): mp 186-188° C.; 1H NMR (CDCl3) δ7.86 (dd, J=8.4, 0.6 Hz, 1H), 7.44 (t, JHF=53.5 Hz, 1H), 7.35 (t, J=8.2 Hz, 1H), 6.82 (d, J=7.6 Hz, 1H), 4.05 (s, 3H), 3.99 (br s, 4H), 3.88 (br s, 4H), 3.79 (m, 4H), 3.39 (t, J=5.0 Hz, 4H), 3.16 (m, 2H), 2.93 (m, 2H), 2.53 (m, 4H), 1.76 (m, 4H); Anal. Calcd. for C26H35F2N9O4S: C, 51.4; H, 5.8; N, 20.7. Found: C, 51.3; H, 5.9; N, 20.5%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([N:15]2[C:19]3[CH:20]=[CH:21][C:22]([C:24]4[N:25]=[N:26][N:27]([CH:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)[CH:28]=4)=[CH:23][C:18]=3[N:17]=[CH:16]2)[CH:12]=[C:11]([NH2:35])[CH:10]=1.N1C=CC=CC=1.[CH2:42]([S:44](Cl)(=[O:46])=[O:45])[CH3:43]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([N:15]2[C:19]3[CH:20]=[CH:21][C:22]([C:24]4[N:25]=[N:26][N:27]([CH:29]5[CH2:30][CH2:31][O:32][CH2:33][CH2:34]5)[CH:28]=4)=[CH:23][C:18]=3[N:17]=[CH:16]2)[CH:12]=[C:11]([NH:35][S:44]([CH2:42][CH3:43])(=[O:46])=[O:45])[CH:10]=1
Reactant: Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(-c4cn(C5CCOCC5)nn4)ccc32)c1
Reactant: CCS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCS(=O)(=O)Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(-c4cn(C5CCOCC5)nn4)ccc32)c1
Yield: 42 %

Procedure:
To a solution of 2′,4′-difluoro-5-(5-(1-(tetrahydro-2H-pyran-4-yl)-1H-1,2,3-triazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-amine (60 mg, 0.126 mmol) in DCM was added pyridine (19 mg, 2.52 mmol, 2.0 eq.) followed by ethanesulfonyl chloride (19 mg, 0.152 mmol, 1.2 eq). After completion of the reaction the solvent was distilled off and the crude product was purified by preparative HPLC to give the product in 42% yield (30 mg). 1H NMR (300 MHz, CD3OD): δ 8.92 (s, 1H), 8.3 (d, 1H), 8.06 (s, 1H), 8.0 (s, 1H), 7.95 (s, 1H), 7.88 (s, 1H), 7.77-7.69 (m, 5H), 7.45 (m, 1H), 6.56 (m, 1H), 3.92 (s, 3H), 3.28-3.27 (m, 4H), 1.6-1.49 (m, 6H); LC-MS (ESI): Calculated mass: 564.6; Observed mass: 565.4 [M+H]+ (rt: 1.46 min).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:25][CH2:26][OH:27])[S:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]([CH3:24])[C:16](=[O:23])[C:17](=[CH:21][CH:22]=2)[C:18]([OH:20])=[O:19])=[CH:10][CH:9]=1)(=[O:7])=[O:6].O[N:29]1[C:33](=[O:34])[CH2:32][CH2:31][C:30]1=[O:35].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[OH:1][CH2:2][CH2:3][N:4]([CH2:25][CH2:26][OH:27])[S:5]([C:8]1[CH:9]=[CH:10][C:11]([C:14]2[N:15]([CH3:24])[C:16](=[O:23])[C:17](=[CH:21][CH:22]=2)[C:18]([O:20][N:29]2[C:33](=[O:34])[CH2:32][CH2:31][C:30]2=[O:35])=[O:19])=[CH:12][CH:13]=1)(=[O:7])=[O:6]
Reactant: O=C1CCC(=O)N1O
Reactant: Cn1c(-c2ccc(S(=O)(=O)N(CCO)CCO)cc2)ccc(C(=O)O)c1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: Cn1c(-c2ccc(S(=O)(=O)N(CCO)CCO)cc2)ccc(C(=O)ON2C(=O)CCC2=O)c1=O
Temperature: 25 °C

Procedure:
A solution of 4.43 g. of 6-[4-[bis(2-hydroxyethyl)-aminosulfonyl]phenyl]-1,2-dihydro-1-methyl-2-oxonicotinic acid and 1.34 g. of N-hydroxysuccinimide in 60 ml. dimethylformamide was cooled in ice and treated dropwise with a solution of 2.56 g. of N,N'-dicyclohexylcarbodiimide in 5 ml. dimethylformamide. The solution was allowed to warm to room temperature over 16 hours. The mixture was cooled and the N,N'-dicyclohexylurea filtered off. Addition of 180 ml. of isopropanol to the filtrate precipitated the 6-[4-[bis(2-hydroxyethyl)aminosulfonyl]phenyl]-1,2-dihydro-1-methyl-2-oxonicotinic acid, 2,5-dioxo-1-pyrrolidinyl ester, which was collected by filtration.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[C:10](I)[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([C:18]1[CH:32]=[CH:31][C:21]([CH2:22][N:23]2[CH2:26][CH:25]([C:27]([O:29][CH3:30])=[O:28])[CH2:24]2)=[CH:20][C:19]=1[F:33])#[CH:17].C(N(C(C)C)C(C)C)C>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH2:1]([C:8]1[CH:9]=[C:10]2[C:11](=[CH:12][CH:13]=1)[NH:14][C:16]([C:18]1[CH:32]=[CH:31][C:21]([CH2:22][N:23]3[CH2:26][CH:25]([C:27]([O:29][CH3:30])=[O:28])[CH2:24]3)=[CH:20][C:19]=1[F:33])=[CH:17]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#Cc1ccc(CN2CC(C(=O)OC)C2)cc1F
Reactant: Nc1ccc(Cc2ccccc2)cc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CN(Cc2ccc(-c3cc4cc(Cc5ccccc5)ccc4[nH]3)c(F)c2)C1
Reaction time: 3 h

Procedure:
To a sealed flask was added 4-benzyl-2-iodobenzenamine (0.20 g, 0.65 mmol) and methyl 1-(4-ethynyl-3-fluorobenzyl)azetidine-3-carboxylate (0.32 g, 1.3 mmol) in THF (15 mL). To this solution was added PdCl2(PPh3)2 (0.045 g, 0.065 mmol), CuI (0.025 g, 0.13 mmol), and ethyldiisopropylamine (0.90 mL, 5.2 mmol). The flask was flushed with Ar, sealed and placed in a preheated oil bath at 100° C. for 3 h. The mixture was concentrated under reduced pressure to afford a dark oil which was adsorbed onto silica and purified (30% EtOAc/hexanes to 100% EtOAc) to afford title compound as a yellow oil. MS (ESI) m/z: Calculated: 428.1; Observed: 429.1 (M++1).
Reaction SMILES: Br[C:2]1[O:3][C:4]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:5]=2[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1CCC(C(O)=O)CC=1.[N:27]([O-:29])=[O:28].[Na+].[N+]([O-])(O)=O>C(O)(=O)C>[CH3:17][C:14]1[CH:15]=[CH:16][C:4]2[O:3][C:2]([N+:27]([O-:29])=[O:28])=[C:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:5]=2[CH:13]=1
Reactant: Cc1ccc2oc(Br)c(-c3ccccc3)c2c1
Reactant: O=N[O-]
Agent: O=C(O)C1CC=CCC1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O=[N+]([O-])O
Product: Cc1ccc2oc([N+](=O)[O-])c(-c3ccccc3)c2c1

Procedure:
To a solution of 25 g (0.0875 mole) of 2-bromo-5-methyl-3-phenylbenzofuran and 16.5 g of cyclohexene-4-carboxylic acid in 150 ml of acetic acid is added 17.5 g of sodium nitrite, then 17.5 ml of nitric acid is added dropwise with stirring. The mixture is stirred at about 25° C. for about three hours, then poured onto ice. The mixture is then extracted with diethyl ether. The ether solution is washed with 10% sodium bicarbonate solution, saturated sodium carbonate solution and dried. The dried solution is evaporated under vacuum to provide a yellow residue. The residue is recrystallized from carbon tetrachloride, then cyclohexane to provide yellow crystals of 5-methyl-2-nitro-3-phenylbenzofuran, m.p. 144.5°-146° C.
Reaction SMILES: [N:1]1[NH:2][N:3]=[N:4][C:5]=1[C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1)[N:10]=[C:9]2[Br:21].[C:22]1([C:28](Cl)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>CN(C)C=O>[Br:21][C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[C:6]([C:5]3[N:4]=[N:3][N:2]([C:28]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:1]=3)[CH:7]=2)[N:11]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[N:10]=1
Reactant: Brc1nn(C2CCCCO2)c2ccc(-c3nn[nH]n3)cc12
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Brc1nn(C2CCCCO2)c2ccc(-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc12
Temperature: 25 °C

Procedure:
To a solution of 2-(5-(2H-1,2,3,4-tetrazol-5-yl)-3-bromo-1H-indazolyl)perhydro-2H-pyran (0.554 g, 1.59 mmol) in dimethyl formamide (5 mL) was added triphenylmethyl chloride (0.662 g, 2.38 mmol), and triethyl amine (1.110 mL, 7.95 mmol). The reaction was heated to reflux temperature for 3.5 hours and maintained at room temperature overnight. The solvent was removed under reduced pressure. The resulting solid was dissolved in 20 mL of ethyl acetate and was washed with 10 ml-portions of water. The title compound was purified by column chromatography (SiO2, 20% ethyl acetate in hexanes) (0.754 g, 70%): ES-MS (m/z) mass not detected.