Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[S:11][C:10]=1[C:20]([OH:22])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+].C([N:27](CC)CC)C.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(=O)([O-])O.[Na+]>O.CN(C=O)C>[CH2:1]([NH:8][C:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[S:11][C:10]=1[C:20]([NH2:27])=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1sc(-c2ccncc2)cc1NCc1ccccc1
Reactant: CCN(CC)CC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1sc(-c2ccncc2)cc1NCc1ccccc1
Reaction time: 0.17 h
Yield: 59.7 %

Procedure:
A mixture of 3-(benzylamino)-5-(pyridin-4-yl)thiophene-2-carboxylic acid (1.16 g, 3.73 mmol), ammonium chloride (2.00 g, 37.3 mmol), triethylamine (5.23 mL, 3.80 g, 37.3 mmol) and DMF (19 mL) was stirred for 10 min. Then, 1-hydroxybenzotri-azole (1.51 g, 11.2 mmol) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (2.15 g, 11.2 mmol) were added and stirring was continued for 3 days. The mixture was then poured into sat. aqueous sodium hydrogen carbonate (100 mL) and water (100 mL). The mixture was extracted with ethyl acetate (2×100 mL), and the organic layer was washed with sat. aqueous sodium hydrogen carbonate and brine, dried over magnesium sulfate and filtrated. The filtrate was concentrated at reduced pressure to give a yellow solid. This solid was triturated with dichloromethane (20 mL), and the precipitate was collected by filtration to afford the title compound (0.689 g, 59%) as a yellow solid. The filtrate was purified by column chromatography (Combiflash, 12 g silica gel, dichloromethane to ethyl acetate) to afford the additional title compound (0.103 g, 8.9%) as an yellow solid:
Reaction SMILES: [C:1]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]1[C:16](=[O:17])[C:15](=[O:18])[CH2:14][C:13]1=[O:19])([O:3][CH2:4][CH3:5])=[O:2].[N+](=[CH2:22])=[N-]>CCOCC>[C:1]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[C:13](=[O:19])[CH2:14][C:15](=[O:18])[C:16]=1[O:17][CH3:22])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: C=[N+]=[N-]
Reactant: CCOC(=O)CCCCCCC1C(=O)CC(=O)C1=O
Solvent: CCOCC
Product: CCOC(=O)CCCCCCC1=C(OC)C(=O)CC1=O

Procedure:
Five grams (5 g) of 2-(6'-carboethoxyhexyl)-cyclopentan-1,3,4-trione was reacted with diazomethane in ether according to conventional procedures to give 3.8 g of 2-(6'-carbethoxyhexyl)-3-methoxy-4-oxo-2-cyclopenten-1-one, b.p. 165°-170°C/0.4-0.6 mmHg.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:7]=[C:8]([N:14]2[CH:18]=[N:17]N=N2)[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].Cl.CC(C)=O.C(=O)(O)[O-].[Na+]>O1CCCC1.CCCCCC.ClCCl>[CH:2]([C:6]1[CH:7]=[C:8]([NH:14][C:18]#[N:17])[CH:9]=[CH:10][C:11]=1[O:12][CH3:13])=[O:1]
Reactant: COc1ccc(-n2cnnn2)cc1C1OCCO1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc(NC#N)cc1C=O
Yield: 95 %

Procedure:
To a solution of 1-(3-[1,3]-dioxolan-2-yl4-methoxy-phenyl)-1H-tetrazole (0.46 g) in tetrahydrofuran (10 ml) at 0° under nitrogen n-butyl lithium (1.7 ml; a 1.6M solution in hexane) was added. After stirring for 5 min dilute aqueous hydrogen chloride solution (5 ml) and acetone (2ml) were added. The mixture was stirred for 1 h before addition of dichloromethane (30 ml) and 8% aqueous sodium bicarbonate solution (20 ml). The layers were separated and the aqueous layer extracted with dichloromethane (3×30 ml). The organic layers were combined, dried (Na2SO4), and evaporated to leave an orange solid. The material was washed with a small amount of ether and cyclohexane and dried in vacuo to yield the title compound as an orange solid (0.31 g).
Reaction SMILES: [CH3:1][O:2][P:3]([CH2:7][CH2:8]O)(=[O:6])[O:4][CH3:5].N1C(C)=CC=CC=1C.[F:18][C:19]([F:32])([F:31])[S:20]([O:23]S(C(F)(F)F)(=O)=O)(=[O:22])=[O:21]>ClCCl>[CH3:1][O:2][P:3]([CH:7]([O:23][S:20]([C:19]([F:32])([F:31])[F:18])(=[O:22])=[O:21])[CH3:8])([O:4][CH3:5])=[O:6]
Reactant: COP(=O)(CCO)OC
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: COP(=O)(OC)C(C)OS(=O)(=O)C(F)(F)F
Temperature: -40 °C
Reaction time: 2 h

Procedure:
To a solution of (2-hydroxy-ethyl)-phosphonic acid dimethyl ester (0.250 g, 1.62 mmol) in dichloromethane (4 mL) was added 2,6-lutidine (0.284 mL, 2.44 mmol). The reaction mixture was cooled to −40° C. and trifluoromethanesulfonic anhydride (0.355 mL, 2.11 mmol) was added. The mixture stirred in the cold bath under an inert atmosphere for 2 hours at which point the reaction was completed as shown by 31P NMR (CDCl3) δ 25.7. The mixture was partitioned between dichloromethane and water both cooled by an ice-water bath. The organic phase was washed with brine, dried (MgSO4), and concentrated in vacuo to afford trifluoromethanesulfonic acid dimethoxy-phosphoryl-2-ethyl ester 185 as an oil which was immediately carried forward with no further purification or characterization.
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10](=[O:20])[CH2:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13].C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH3:9][O:8][C:6]1[CH:5]=[C:4]2[C:3]([C:10](=[O:20])[CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:13]2)=[CH:2][CH:7]=1
Reactant: COc1ccc(C(=O)CC(=O)c2ccccc2)c(O)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc2c(=O)cc(-c3ccccc3)oc2c1
Yield: 70 %

Procedure:
240 mg (0.89 mmol) of 1-(2-hydroxy-4-methoxy-phenyl)-3-phenyl-propan-1,3-dione was dissolved in acetic acid, and 0.73 g (8.9 mmol) of sodium acetate was added thereto. The mixture was refluxed overnight. Acetic acid was removed by distillation under reduced pressure, and then the residue was purified by silica gel column chromatography (eluent: n-hexane/ethylacetate=5/1, v/v) to give the title compound in a yield of 70%.
Reaction SMILES: [CH2:1]1[CH:12]2[CH:4]([NH:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=32)[CH2:3][CH2:2]1.[H-].[Na+].Cl[CH2:16][C:17]#[N:18]>CS(C)=O>[CH2:1]1[CH:12]2[CH:4]([N:5]([CH2:16][C:17]#[N:18])[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=32)[CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)NC1CCCC21
Reactant: N#CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCN1c2ccccc2C2CCCC21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 1,2,3,3a,4,8b-hexahydrocyclopenta[b]indole (22 mmol, 3.5 g) in DMSO (44 mL) was added 60% sodium hydride (24 mmol, 0.97 g) portionwise, followed by 2-chloroacetonitrile (33 mmol, 2.1 mL). The reaction mixture stirred at ambient temperature for 18 h and then additional 60% sodium hydride (22 mmol, 0.88 g) and 2-chloroacetonitrile (24 mmol, 1.5 mL) was added. The reaction was heated to 60° C. for 18 h. The reaction was concentrated and the diluted with ethyl acetate and water. The phases were separated and the organic phase was washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by flash column chromatography through silica gel (elution with 60% ethyl acetate-hexanes) to afford the desired material.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6](F)[CH:5]=1.[CH2:14]([OH:17])[CH2:15][OH:16]>CN1CCCC1=O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6]([CH:5]=1)[O:16][CH2:15][CH2:14][OH:17]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Reactant: OCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1ccc(Cl)cc1OCCO
Temperature: 80 °C
Reaction time: 18 h

Procedure:
Sodium hydride (125 mg, 60% dispersion in mineral oil, 3.13 mmol) was added to a mixture of 4-chloro-2-fluoronitrobenzene (500 mg, 2.85 mmol) and ethylene glycol (0.18 ml, 3.13 mmol) in 1-methyl-2-pyrrolidinone (5 ml) and the reaction stirred at 80° C. for 18 hours. TLC analysis showed starting material remaining, so additional sodium hydride (114 mg, 60% dispersion in mineral oil, 2.85 mmol) and ethylene glycol (0.82 ml, 14.25 mmol) were added and the reaction stirred at 110° C. for a further 18 hours. The cooled mixture was partitioned between water and dichloromethane, and the layers separated. The organic phase was dried over magnesium sulphate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using ethyl acetate:pentane (50:50) as eluant to afford the title compound as a solid, 290 mg.
Reaction SMILES: [C:1]([C:5]1[C:10]([OH:11])=[CH:9][C:8]([C:12]([CH3:21])([CH3:20])[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[C:7]([OH:22])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:23](O)[CH2:24][CH2:25][CH2:26][CH2:27]C.C[O-].[Na+]>CCOCC>[C:1]([C:5]1[C:10]([OH:11])=[CH:9][C:8]([C:12]([CH3:21])([CH3:20])[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:17])=[C:7]([OH:22])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCCCO
Reactant: COC(=O)CCCC(C)(C)c1cc(O)c(C(C)(C)C)cc1O
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Product: CCCCCCOC(=O)CCCC(C)(C)c1cc(O)c(C(C)(C)C)cc1O

Procedure:
5 Parts of methyl 5-(4-t-butyl-2,5-dihydroxyphenyl)-5-methylhexanoate is converted to the corresponding n-hexyl ester after reaction with 20 parts n-hexanol and 0.25 part of sodium methoxide in a sealed glass tube for 7 days. The reaction mixture is diluted with ether, washed with dilute hydrochloric acid, then water, and stripped of ether and excess hexanol under reduced pressure to give a residue. Short-path distillation of the residue at 0.4 mb yields n-hexyl 5-(4-t-butyl-2,5-dihydroxyphenyl)-5-methyl-hexanoate [formula (125)] as an amber oil with the following percentage composition by weight:
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C@:9]12[C:15]([CH3:17])([CH3:16])[C@H:12]([CH2:13][CH2:14]1)[CH:11]([C:18](Cl)=[O:19])[C:10]2=[O:21].[C:22]([O:26][C:27]([NH:29][NH:30][C:31]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:32]=1[Cl:38])=[O:28])([CH3:25])([CH3:24])[CH3:23]>ClCCl>[C:22]([O:26][C:27]([NH:29][N:30]([C:31]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:32]=1[Cl:38])[C:18]([CH:11]1[C:10](=[O:21])[C@@:9]2([CH3:8])[C:15]([CH3:17])([CH3:16])[C@@H:12]1[CH2:13][CH2:14]2)=[O:19])=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)C(=O)C2C(=O)Cl
Reactant: CC(C)(C)OC(=O)NNc1cc(Cl)ccc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NN(C(=O)C1C(=O)[C@]2(C)CC[C@H]1C2(C)C)c1cc(Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 0.05 h

Procedure:
Triethylamine (26 mL, 186.5 mmol) was added dropwise to a cooled (0° C.) solution of (1R,4R)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl chloride (Intermediate 20; 13.33 g, 62.1 mmol) in dichloromethane (150 mL), yielding a thick suspension. This was stirred for 3 min and then N′-(2,5-dichloro-phenyl)-hydrazinecarboxylic acid tert-butyl ester (Intermediate 34; 13.00 g, 46.9 mmol) was added in one portion. The cooling bath was removed and the reaction mixture was stirred at room temperature for 10 min, then in an oil-bath at 50° C. for 4 h. The reaction mixture was cooled to room temperature, then added to water (200 mL) and extracted with dichloromethane (3×150 mL). The combined organic layers were washed with brine (200 mL), dried (magnesium sulfate), filtered, and evaporated to give N′-(2,5-dichloro-phenyl)-N′-((1R,4R)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl)-hydrazinecarboxylic acid tert-butyl ester (29.55 g, 138% of the expected amount) as a brown oil. This was used directly in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]([CH3:23])([CH3:22])[CH2:3][C:4]([NH:6][C:7]1[C:15]([C:16]2C=N[CH:19]=[CH:20][CH:21]=2)=[C:10]2[N:11]=[CH:12][CH:13]=[CH:14][N:9]2[N:8]=1)=[O:5].[Cl:24][C:25]1[CH:30]=CC(/C=C/B(O)O)=[CH:27][CH:26]=1>>[Cl:24][C:25]1[CH:30]=[CH:19][C:20](/[CH:21]=[CH:16]/[C:15]2[C:7]([NH:6][C:4](=[O:5])[CH2:3][C:2]([CH3:1])([CH3:22])[CH3:23])=[N:8][N:9]3[CH:14]=[CH:13][CH:12]=[N:11][C:10]=23)=[CH:27][CH:26]=1
Reactant: OB(O)/C=C/c1ccc(Cl)cc1
Reactant: CC(C)(C)CC(=O)Nc1nn2cccnc2c1-c1cccnc1
Product: CC(C)(C)CC(=O)Nc1nn2cccnc2c1/C=C/c1ccc(Cl)cc1

Procedure:
The product from Example 110B and trans-2-(4-chlorophenyl)vinylboronic acid were processed using the method analogous to that described in Example 110C to afford the title compound. H NMR (400 MHz, CD3OD) δ ppm 8.80 (dd, J=7.0, 1.7 Hz, 1H), 8.60 (dd, J=4.1, 1.6 Hz, 1H), 7.65 (d, J=16.3 Hz, 1H), 7.47-7.50 (m, 2H), 7.31-7.34 (m, 2H), 7.19 (d, J=16.5 Hz, 1H), 7.03 (dd, J=7.0, 4.1 Hz, 1H), 2.41-2.41 (bs, 2H), 1.17 (s, 9H); MS (ESI) m/z 369 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([CH:12]2[CH2:17][CH2:16][N:15]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:25])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].ClC1C=[C:35]([S:40](C2CCN(C3CCNCC3)CC2)(=[O:42])=[O:41])C=CC=1Cl.C(O)(=O)C1C=CC=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([CH:12]2[CH2:17][CH2:16][N:15]([CH:18]3[CH2:19][CH2:20][N:21]([C:24]([C:26]4[CH:27]=[CH:28][C:29]([S:40]([CH3:35])(=[O:42])=[O:41])=[CH:30][CH:31]=4)=[O:25])[CH2:22][CH2:23]3)[CH2:14][CH2:13]2)(=[O:10])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(c1ccccc1)N1CCC(N2CCC(S(=O)(=O)c3ccc(Cl)c(Cl)c3)CC2)CC1
Reactant: O=S(=O)(c1ccc(Cl)c(Cl)c1)C1CCN(C2CCNCC2)CC1
Agent: O=C(O)c1ccccc1
Product: CS(=O)(=O)c1ccc(C(=O)N2CCC(N3CCC(S(=O)(=O)c4ccc(Cl)c(Cl)c4)CC3)CC2)cc1

Procedure:
1H NMR (299.946 MHz, DMSO-D6) δ 1.34–1.62 (5H, m), 1.70–1.85 (4H, m), 2.13 (3H, t), 2.72–3.04 (4H, m), 3.27 (3H, s), 3.37–3.48 (1H, m), 4.44–4.52 (1H, m), 7.63 (2H, d), 7.81 (1H, dd), 7.95–8.00 (3H, m), 8.06 (1H, d). [4-(3,4-Dichloro-benzenesulfonyl)-[1,4′]bipiperidinyl-1′-yl]-phenyl-methanone (Compound 5 of Table V). The product of step 5 was coupled to benzoic acid following the procedure of Example 2 step c. 1H NMR (299.946 MHz, DMSO-D6) δ 1.31–1.69 (5H, m), 1.82 (3H, d), 2.15 (2H, d), 2.69–2.75 (1H, m), 2.90–2.97 (4H, m), 3.33–3.43 (1H, m), 3.48–3.63 (1H, m), 4.42–4.53 (1H, m), 7.39 (5H, dt), 7.81 (1H, dd), 7.96 (1H, d), 8.06 (1H, d).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([S:18]([C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH2:13][CH2:12]3)=[CH:5][CH:4]=1.Cl.[NH2:32][OH:33].C(N(CC)CC)C>O1CCCC1.CO>[OH:33][NH:32][C:25](=[NH:26])[C:24]1[CH:27]=[CH:28][C:21]([S:18]([N:14]2[C:15]3[C:11](=[CH:10][C:9]([C:6]4[CH:7]=[N:8][C:3]([C:2]([F:30])([F:29])[F:1])=[CH:4][CH:5]=4)=[CH:17][CH:16]=3)[CH2:12][CH2:13]2)(=[O:20])=[O:19])=[CH:22][CH:23]=1
Reactant: N#Cc1ccc(S(=O)(=O)N2CCc3cc(-c4ccc(C(F)(F)F)nc4)ccc32)cc1
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N=C(NO)c1ccc(S(=O)(=O)N2CCc3cc(-c4ccc(C(F)(F)F)nc4)ccc32)cc1
Temperature: 90 °C
Reaction time: 4 h
Yield: 229 %

Procedure:
223 mg 4-[5-(6-Trifluoromethyl-pyridin-3-yl)-2,3-dihydro-indole-1-sulfonyl]-benzonitrile were dissolved in a mixture of 8 ml tetrahydrofuran and 8 ml methanol. 902 mg hydroxylamine hydrochloride were added followed by the addition of 1.82 ml triethylamine. The reaction mixture was stirred at 90° C. for four hours. The solvents were removed in vacuo and the resulting residue poured into 50 ml water and extracted five times with portions of 50 ml ethylacetate. The combined organic extracts were washed with 100 ml brine, dried over MgSO4 and the solvent was evaporated in vacuo to obtain 550 mg crude N-Hydroxy-4-[5-(6-trifluoromethyl-pyridin-3-yl)-2,3-dihydro-indole-1-sulfonyl]-benzamidine. This material was used without further purification.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([CH3:12])=[CH:6][C:5]=1[OH:13])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>CC(C)=O>[CH2:25]([O:24][C:22](=[O:23])[CH2:21][O:13][C:5]1[CH:6]=[C:7]([CH3:12])[C:8]([O:10][CH3:11])=[CH:9][C:4]=1[CH:1]([CH3:3])[CH3:2])[CH3:26]
Reactant: CCOC(=O)CBr
Reactant: COc1cc(C(C)C)c(O)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1cc(C)c(OC)cc1C(C)C
Yield: 82.3 %

Procedure:
To a solution of 2-isopropyl-4-methoxy-5-methyl-phenol (3.933 g, 21.8 mmol) in acetone (100 ml) was added potassium carbonate (20 g, 145 mmol) and ethyl bromoacetate (5 ml, 45.1 mmol). The mixture refluxed over night and was filtered through celite. The filtrate was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic phase was washed with brine and dried over anhydrous sodium sulfate. After removal of drying agent, the organic solution was concentrated under reduced pressure. The residue was purified with silica gel chromatography (10% to 15% methylene chloride in hexane) to yield (2-isopropyl-4-methoxy-5-methyl-phenoxy)-acetic acid ethyl ester as white solid (4.78 g, 82%).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[NH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>CN(C=O)C.O>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[N:4]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:3]=1
Reactant: O=[N+]([O-])c1cccc2[nH]nc(Br)c12
Reactant: CCOC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1nc(Br)c2c([N+](=O)[O-])cccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89.3 %

Procedure:
A solution of 3-bromo-4-nitro-1H-indazole (Preparation B; 1.00 g, 4.13 mmol) in anhydrous DMF (20 mL) was treated at ambient temperature with potassium carbonate (2.28 g, 16.5 mmol). The reaction mixture was stirred at ambient temperature for 10 minutes and ethyl 2-chloroacetate (0.53 g, 4.34 mmol) was added dropwise. Stirring was continued under nitrogen for 16 hours. The reaction mixture was diluted with excess water and extracted multiple times with DCM and EtOAc. The combined extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the product (1.21 g) as a brown solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][NH:9][C:10]2[N:11]=[C:12]([NH:21][C@@H:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)C)[C:13]3[S:18][CH:17]=[C:16]([CH:19]=[CH2:20])[C:14]=3[N:15]=2)[CH2:3][CH2:2]1.[H][H]>CO.[Ni]>[CH2:22]([NH:21][C:12]1[C:13]2[S:18][CH:17]=[C:16]([CH2:19][CH3:20])[C:14]=2[N:15]=[C:10]([NH:9][CH2:8][CH2:7][N:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[N:11]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: C=Cc1csc2c(N[C@H](C)c3ccccc3)nc(NCCN3CCOCC3)nc12
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: CCc1csc2c(NCc3ccccc3)nc(NCCN3CCOCC3)nc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 90.6 %

Procedure:
Raney Ni was added to (R)—N2-(2-Morpholinoethyl)-N4-(1-phenylethyl)-7-vinylthieno[3,2-d]pyrimidin-2,4-diamine (10 mg, 0.025 mmol) in methanol (1 mL), and the mixture was stirred at room temperature for 24 hours under a pressure of a balloon filled with hydrogen gas. Filtration of the reaction mixture with celite followed by washing with methanol and concentration yielded the target compound (9 mg, 89% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([C@@H:27]3[CH2:31][CH2:30][CH2:29][C@H:28]3[C:32]([O:34]C)=[O:33])=[O:26])=[CH:21][CH:20]=2)[CH:5]=[CH:6][C:7]=1[NH:8][C:9]1[O:10][C:11]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:12]=2[N:13]=1.[OH-].[Na+]>O1CCOCC1.C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([C@@H:27]3[CH2:31][CH2:30][CH2:29][C@H:28]3[C:32]([OH:34])=[O:33])=[O:26])=[CH:21][CH:20]=2)[CH:5]=[CH:6][C:7]=1[NH:8][C:9]1[O:10][C:11]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: COC(=O)[C@@H]1CCC[C@H]1C(=O)c1ccc(-c2ccc(Nc3nc4ccc(C)cc4o3)c(F)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: Cc1ccc2nc(Nc3ccc(-c4ccc(C(=O)[C@@H]5CCC[C@H]5C(=O)O)cc4)cc3F)oc2c1
Temperature: 50 °C
Yield: 15 %

Procedure:
To a solution of methyl (1R,2R)-2-[(4′-amino-3′-fluoro-1,1′-biphenyl-4-yl)carbonyl]-cyclopentanecarboxylate (800 mg, 2.34 mmol, 78% ee) in dichloroethane (15 mL), 6-methyl-2-(methylsulfonyl)-1,3-benzoxazole (891 mg, 4.22 mmol) was added, and the mixture was heated at 85° C. overnight. The solvent was removed by rotary evaporation, and the residue was purified by using a Biotage QuadUV flash chromatography system (eluant: 80:20 hexane/EtOAc) to give methyl (1R,2R)-2-({3′-fluoro-4′-[(6-methyl-1,3-benzoxazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)-cyclopentanecarboxylate (472 mg). This ester intermediate was redissolved in 1:1 dioxane/THF (20 mL), a solution of 1 N aqueous NaOH (7.02 mL, 7.02 mol) was added, and the mixture was heated at 50° C. overnight. The solvent was removed by rotary evaporation, and water (20 mL) and EtOAc (40 mL) were added to the residue. The aqueous layer was separated, acidified to pH 5 by the addition of 1 N aqueous HCl, and then extracted with EtOAc (2×60 mL). The combined organic phases were washed with saturated NaCl and dried (Na2SO4). The solvent was removed by rotary evaporation and the residue was redissolved in DMF (10 mL) and methanol (20 mL). The crude product was purified by preparative reverse-phase HPLC (water/acetonitrile gradient, containing 0.1% TFA) to afford (1R,2R)-2-({3′-fluoro-4′-[(6-methyl-1,3-benzoxazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentanecarboxylic acid as an off-white solid (161 mg, 15% yield, 80% ee). 1H NMR (300 MHz, DMSO-d6) δ 8.40 (m, 1H), 8.00-7.60 (m, 6H), 7.30 (d, 2H), 7.00 (d, 1H), 4.05 (m, 1H), 3.20 (m, 1H), 2.40 (s, 3H), 2.20 (m, 1H), 1.95 (m, 1H), 1.80-1.60 (m, 4H); LC-MS ret. time 3.57 min, m/z 459.3 (MH+).
Reaction SMILES: S(=O)(=O)(O)O.Br.N[C:8]1[C:16]([F:17])=[CH:15][C:14]([Br:18])=[CH:13][C:9]=1[C:10]([OH:12])=[O:11].Cl.N([O-])=O.[Na+].[I-:24].[K+]>O>[Br:18][C:14]1[CH:15]=[C:16]([F:17])[C:8]([I:24])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11]
Reactant: [I-]
Reactant: Nc1c(F)cc(Br)cc1C(=O)O
Agent: Br
Agent: Cl
Agent: O=N[O-]
Solvent: O
Product: O=C(O)c1cc(Br)cc(F)c1I
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Sulfuric acid (47.0 mL, 882 mmol) was added to a mixture of 2-amino-5-bromo-3-fluorobenzoic acid hydrobromide (16.34 g, 51.9 mmol) and HCl (12.45 mL, 156 mmol) at 0° C. The resulting slurry was stirred at 0° C. and sodium nitrite (3.58 g, 51.9 mmol) in water (20 mL) was added dropwise over 10 minutes. The reaction was stirred 40 minutes at 0° C. before a solution of potassium iodide (17.23 g, 104 mmol) in water (20.00 mL) was added dropwise. The solution was stirred allowed to warm to RT, leading to the formation of a viscous mixture. After 1 hour at ambient temperature, the reaction was poured into ice water (500 mL) and the resulting precipitate was filtered. The black solid was washed with well water to give a dark brown solid which was dried in a vacuum oven at 50° C. for 12 hours to afford 5-bromo-3-fluoro-2-iodobenzoic acid as an orange/tan solid. MS m/z=344.8 [M+H].
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:9]([CH3:13])=[C:10]([CH3:12])[N:11]=2)[CH:5]=[C:6]([Br:8])[CH:7]=1.[CH3:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:16]=1[CH2:17]Cl.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+].CC1C(C)=CC=CC=1CCl>CC(C)=O>[Br:8][C:6]1[CH:7]=[C:2]([NH:1][CH2:17][C:16]2[C:19]([CH3:23])=[CH:20][CH:21]=[CH:22][C:15]=2[CH3:14])[C:3]2[N:4]([C:9]([CH3:13])=[C:10]([CH3:12])[N:11]=2)[CH:5]=1
Reactant: Cc1nc2c(N)cc(Br)cn2c1C
Reactant: Cc1cccc(C)c1CCl
Agent: Cc1cccc(CCl)c1C
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(C)=O
Product: Cc1cccc(C)c1CNc1cc(Br)cn2c(C)c(C)nc12
Reaction time: 8 h
Yield: 80.9 %

Procedure:
A mixture of 8-amino-6-bromo-2,3-dimethylimidazo[1,2-a]pyridine (1.2 g, 5.0 mmol), 2,6-dimethylbenzylchloride (0.772 g, 5.0 mmol), sodium carbonate (0.8 g), sodium iodide (0.2 g) and acetone (45 ml) was stirred overnight. More 2,3-dimethylbenzylchloride (0.285 g) was added and the reaction mixture was refluxed for 5 h. After addition of acetone the reaction mixture was filtered. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2, washed with NaHCO3, dried over Na2SO4 and evaporated. The crude product dissolved in ethyl acetate and petroleum ether was added. Filtration and evaporation of the solvent gave a residue which was recrystallized from ethyl acetate to give 1.45 g of the title compound.