Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH:16]2[CH2:21][CH2:20][N:19]([S:22]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[NH2:32])(=[O:24])=[O:23])[CH2:18][CH2:17]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:33])[CH:11]=2)[CH:6]=1.O.[OH-].[Li+]>C1COCC1.O>[NH2:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][S:22]([N:19]1[CH2:20][CH2:21][CH:16]([C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([F:33])[CH:11]=3)[CH:6]=[C:5]([CH2:4][C:3]([OH:34])=[O:2])[C:14]=2[CH3:15])[CH2:17][CH2:18]1)(=[O:24])=[O:23]
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(C2CCN(S(=O)(=O)Cc3ccccc3N)CC2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(CC(=O)O)cc2ccc(F)cc2c1C1CCN(S(=O)(=O)Cc2ccccc2N)CC1
Reaction time: 15 h
Yield: 92.1 %

Procedure:
To a solution of {4-[1-(2-amino-phenylmethanesulfonyl)-piperidin-4-yl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (178 mg, 0.367 mmol) in THF 8.0 mL) was added a solution of lithium hydroxide monohydrate (176 mg, 7.35 mmol) in water (2.0 mL) at room temperature. The resulting solution was stirred for 15 hours under nitrogen. The solvent was removed under vacuum and the aqueous solution was diluted with water and slowly neutralized with 1.0 N HCl until the pH was between 5 and 6. The resulting precipitated solids were collected by filtration and washed with water and hexanes. After drying in the air, {4-[1-(2-amino-phenylmethane-sulfonyl)-piperidin-4-yl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid (159 mg, 92%) was isolated as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 12.44 (br. s, 1H), 7.86 (dd, J=8.85, 6.59 Hz, 1H), 7.61 (s, 1H), 7.31 (t, J=7.91 Hz, 1H), 7.18 (d, J=7.35 Hz, 1H), 6.99-7.12 (m, 2H), 6.68-6.78 (m, 1H), 6.53-6.67 (m, 1H), 5.14 (br. s, 2H), 4.28-4.51 (m, 4H), 3.76 (d, J=10.93 Hz, 2H), 3.61 (br. s, 5H), 2.41 (br. s, 3H), 1.66 (d, J=11.49 Hz, 2H). MS cald. for C25H26FN2O4S [(M−H)−] 469, obsd. 469.1.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:11][CH2:10]2)=[C:5]([NH:19][C:20]([C:22]2[CH:26]=[C:25]([CH3:27])[O:24][N:23]=2)=[O:21])[CH:4]=1)=O.C(O)(=O)C.[C:32]1([C@H:38]([NH2:40])[CH3:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.CCOC(C)=O>[CH3:27][C:25]1[O:24][N:23]=[C:22]([C:20]([NH:19][C:5]2[CH:4]=[C:3]([CH2:1][NH:40][C@@H:38]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH3:39])[CH:8]=[CH:7][C:6]=2[N:9]2[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:11][CH2:10]2)=[O:21])[CH:26]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: COC(=O)C1CCN(c2ccc(C=O)cc2NC(=O)c2cc(C)on2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: COC(=O)C1CCN(c2ccc(CN[C@H](C)c3ccccc3)cc2NC(=O)c2cc(C)on2)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 67 %

Procedure:
To a solution of methyl 1-(4-formyl-2-(5-methylisoxazole-3-carboxamido)phenyl)piperidine-4-carboxylate 60 (0.268 g, 0.72 mmol) in DCE (10 mL) was added acetic acid (0.045 mL, 0.78 mmol), (R)-1-phenylethanamine (0.11 mL, 0.88 mmol), and NaBH(OAc)3 (0.186 g, 0.88 mmol). The reaction mixture was stirred at room temperature for 15 h and diluted with EtOAc. The organic phase was washed with saturated NaHCO3 (1×), brine (1×), dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash column chromatography on silica gel (eluted with 70% to 100% EtOAc in hexanes) gave (R)-methyl 1-(2-(5-methylisoxazole-3-carboxamido)-4-((1-phenylethylamino)methyl)phenyl)piperidine-4-carboxylate 61 (0.230 g, 67% yield) as a white solid. Mass spectrum: calculated for C27H32N4O4 476.2. found 477.3 (M++1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]3[N:15]=[C:16]([NH:18][C:19]4[CH:39]=[CH:38][C:22]([O:23][CH2:24][CH2:25][CH2:26][N:27]5C(=O)C6C(=CC=CC=6)C5=O)=[CH:21][CH:20]=4)[N:17]=[C:13]3[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.O.NN>C(O)C>[NH2:27][CH2:26][CH2:25][CH2:24][O:23][C:22]1[CH:21]=[CH:20][C:19]([NH:18][C:16]2[N:17]=[C:13]3[CH:12]=[CH:11][CH:10]=[C:9]([C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)[N:14]3[N:15]=2)=[CH:39][CH:38]=1
Reactant: COc1ccc(-c2cccc3nc(Nc4ccc(OCCCN5C(=O)c6ccccc6C5=O)cc4)nn23)cc1
Agent: NN
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2cccc3nc(Nc4ccc(OCCCN)cc4)nn23)cc1

Procedure:
To a solution of 2-(3-{4-[5-(4-methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-phenoxy}-propyl)-isoindole-1,3-dione (XX-039) (0.1 g, 0.192 mmol) in ethanol (2 mL), hydrazine hydrate (0.05 mL, 0.192 mmol) was added and the solution was refluxed overnight. After removal of the volatiles under reduced pressure, the crude product was purified by preparatory HPLC. LCMS Method: 2: RT: 2.62 min, MI: 390 [M+1].
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=1[NH:18][CH:19]=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pt].CCO>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:10]([NH:18][CH:19]=[O:20])[CH:11]=1
Reactant: O=CNc1cc([N+](=O)[O-])ccc1OCc1ccccc1
Agent: [Pt]
Solvent: CCO
Product: Nc1ccc(OCc2ccccc2)c(NC=O)c1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A mixture of N-(2-benzyloxy-5-nitrophenyl)-formamide (9.0 g, 33 mmol), 5% Pt/C (3.1 g) and EtOH at 65° C. is stirred under an atmosphere of H2 for 19 h at ambient temperature. The mixture is filtered through Celite, washed with EtOH and the filtrate is concentrated at reduced pressure. The resulting solid is washed with MTBE several times to afford N-(5-amino-2-benzyloxyphenyl)-formamide as a white solid: (M−H)−=241.1.
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([N:15]=[C:16]=[O:17])[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:18][C:19]1[CH:39]=[CH:38][C:22]([O:23][C:24]2[C:29]([C:30]3[CH:35]=[CH:34][N:33]=[C:32]([NH:36][CH3:37])[N:31]=3)=[CH:28][CH:27]=[CH:26][N:25]=2)=[C:21]([CH3:40])[CH:20]=1>C1(C)C=CC=CC=1>[CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([NH:15][C:16]([NH:18][C:19]3[CH:39]=[CH:38][C:22]([O:23][C:24]4[C:29]([C:30]5[CH:35]=[CH:34][N:33]=[C:32]([NH:36][CH3:37])[N:31]=5)=[CH:28][CH:27]=[CH:26][N:25]=4)=[C:21]([CH3:40])[CH:20]=3)=[O:17])[CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CNc1nccc(-c2cccnc2Oc2ccc(N)cc2C)n1
Reactant: COc1ccc(C2CCCCC2)cc1N=C=O
Solvent: Cc1ccccc1
Product: CNc1nccc(-c2cccnc2Oc2ccc(NC(=O)Nc3cc(C4CCCCC4)ccc3OC)cc2C)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 4-cyclohexyl-2-isocyanato-1-methoxy-benzene (56 mg, 0.24 mmol) in toluene (3.0 mL) was added {4-[2-(4-amino-2-methyl-phenoxy)-pyridin-3-yl]-pyrimidin-2-yl}-methyl-amine (46 mg, 0.15 mmol). The mixture was stirred overnight at RT, concentrated and purified by preparative TLC (50% EtOAc/CH2Cl2) to yield N-(5-cyclohexyl-2-(methyloxy)phenyl)-N′-(3-methyl-4-((3-(2-(methylamino)-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)urea. MS m/z=539 [M+1]+. Calc'd for C31H34N6O3: 538.66.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[C:6]([N:8]1[CH2:24][CH2:23][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][NH:13][C:12]2=[O:22])[CH2:10][CH2:9]1)=[O:7].C(=O)([O-])[O-].[K+].[K+].COCCOCCN(CCOCCOC)CCOCCOC.[Cl:62][C:63]1[CH:68]=[C:67](Cl)[N:66]=[CH:65][N:64]=1>C1(C)C(C)=CC=CC=1.Cl[Cu]>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:14][N:13]([C:67]3[CH:68]=[C:63]([Cl:62])[N:64]=[CH:65][N:66]=3)[C:12]2=[O:22])[CH2:23][CH2:24]1)=[O:7]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)NCN2c1ccccc1
Reactant: Clc1cc(Cl)ncn1
Agent: Cl[Cu]
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1C
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)N(c1cc(Cl)ncn1)CN2c1ccccc1
Reaction time: 18 h
Yield: 23.6 %

Procedure:
A mixture of 8-(3,5-bis-trifluoromethyl-benzoyl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one (0.1 g, 0.21 mmol), potassium carbonate (59 mg, 0.42 mmol), CuCl (2 mg, 0.021 mmol), tris[2-(2-methoxyethoxy)-ethyl]-amine (1.5 μL) and 4,6-dichloropyrimidine (32 mg, 0.21 mmol) in xylene (5 mL) was stirred and boiled for 18 h. The mixture was cooled, washed with water, ammonia in water (10%) and water again. Evaporation of the solvent yielded a residue which was purified by chromatography on silica gel (ethyl acetate/n-hexane 1:2) to yield the desired product (29 mg, 24%), m.p. 212-214° C. and MS: m/e=584.1 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2C2CCCCO2)=[C:4]([C:17]2[C:18]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([NH:30][C:31]([CH:33]4[CH2:35][CH2:34]4)=[O:32])=[CH:26][CH:25]=3)=[N:19][CH:20]=[CH:21][CH:22]=2)[N:3]=1.FC(F)(F)C(O)=O.CO>C(Cl)Cl>[CH3:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([C:17]2[C:18]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([NH:30][C:31]([CH:33]4[CH2:35][CH2:34]4)=[O:32])=[CH:26][CH:25]=3)=[N:19][CH:20]=[CH:21][CH:22]=2)[N:3]=1
Reactant: Cc1nc(-c2cccnc2Nc2ccc(NC(=O)C3CC3)cc2)c2ncn(C3CCCCO3)c2n1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc(-c2cccnc2Nc2ccc(NC(=O)C3CC3)cc2)c2nc[nH]c2n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 30.6 %

Procedure:
A suspension of N-(4-(3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)cyclopropanecarboxamide (80 mg, 0.170 mmol) in DCM (3 mL) was cooled to 0° C. and treated with trifluoroacetic acid (3 mL, 40.4 mmol). The yellow solution was stirred at 0° C. for 1 h. The mixture was concentrated in vacuo, the residue was neutralized with 2 M NH3 in MeOH and then concentrated in vacuo.The crude product was purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g) eluting with a gradient of 2% to 10% 2 M NH3.MeOH in DCM to give N-(4-(3-(2-methyl-9H-purin-6-yl)pyridin-2-ylamino)phenyl)cyclopropanecarboxamide (20 mg, 0.052 mmol, 30.5% yield) as a yellow solid. 1H NMR (400 MHz, d6-DMSO) δ 13.47-13.72 (m, 1H); 12.82 (s, 1H); 10.10 (s, 1H); 9.78 (s, 1H); 8.59 (s, 1H); 8.33 (d, J=3.20 Hz, 1H); 7.75 (d, J=76.46 Hz, 2H); 7.58 (d, J=8.53 Hz, 2H); 6.94-7.03 (m, 1H); 2.87 (s, 3H); 1.72-1.82 (m, 1H); 0.72-0.84 (m, 4H). m/z (ESI, +ve ion) 386 (M+H)+.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].[CH2:11]([OH:13])C>>[O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:13])[OH:10])[OH:8])[OH:6])[OH:4]
Reactant: CCO
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)CO
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
All strains used glucose efficiently; however, strains 22-1-12 and 14-2-6 achieved the highest ethanol levels, productivities, and fermentation efficiencies, while having the lowest residual sugar levels (Table 2, top). When cellobiose was provided as the carbon source, all strains performed poorly, but in these trials strains WT-2-1 and 22-1-1 performed slightly better than the other strains (Table 2, middle). The results using xylose as the carbon source showed that the strains performing best were 14-2-6 and 22-1-12 (Table 2, bottom). However, compared to the results with glucose (about 18 g/L ethanol), these strains produced only about 3 g/L on xylose, which is about 12% of the theoretical yield (25.6 g/L for xylose). Yet the fermentation efficiency was about 30%, indicating that less than half the consumed xylose was converted to ethanol. The fermentation efficiency of the mutagenized strain on the individual sugar substrates is compared graphically in FIG. 1B. Initial concentrations of all sugar carbon sources were 50 g/L. Theoretical ethanol yield for glucose is 50 g/L [(2×46)/180]=25.6 g/L; for cellobiose is 50 g/L [(4×46)/342]=26.9 g/L; and for xylose is 50 g/L [(10×46)/(6×150)]=25.6 g/L. Fermentation efficiency was calculated by (50 g/L−residual sugar g/L)×100/50 g/L.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:33])[NH:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)=[CH:17][C:16]=2[NH:34][C:35]2[C:36]3[CH:44]=[CH:43][C:42]([CH:45]([CH3:47])[CH3:46])=[N:41][C:37]=3[N:38]=[CH:39][N:40]=2)=[CH:10][CH:9]=1)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:31])([F:32])[F:30])=[CH:25][CH:24]=3)=[O:33])=[CH:17][C:16]=2[NH:34][C:35]2[C:36]3[CH:44]=[CH:43][C:42]([CH:45]([CH3:47])[CH3:46])=[N:41][C:37]=3[N:38]=[CH:39][N:40]=2)=[CH:10][CH:9]=1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4ccc(C(F)(F)F)cc4)ccc3Oc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4ccc(C(F)(F)F)cc4)ccc3Oc3ccc(N)cc3)ncnc2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The product from Example 172e was dissolved in a 1:1 mixture of TFA in DCM and stirred at room temperature for 2 hrs. The solvent was removed under vacuum and the crude oil was purified by HPLC with TFA providing the product as a trifluoroacetic acid salt (85 mg, 36%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 1.75 (d, J=6.99 Hz, 6 H), 7.21 (d, J=8.09 Hz, 2 H), 7.29-7.35 (m, 2 H), 7.38 (d, J=8.82 Hz, 1 H), 8.14 (d, J=8.82 Hz, 2 H), 8.25 (d, J=8.46 Hz, 1 H), 8.40 (d, J=8.46 Hz, 3 H), 8.56 (d, J=1.84 Hz, 1 H), 9.26 (s, 1 H), 9.37 (d, J=8.82 Hz, 1 H), 10.98 (s, 1 H); MS (ESI+) m/z 559 (M+TFA+H)+; (ESI−) m/z 557 (M+TFA−H)−.
Reaction SMILES: [CH2:1]([C:8]1[C:9]([NH:22][C:23](=[S:33])[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31]C)=[CH:27][CH:26]=2)=[N:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br.C(=O)(O)[O-].[Na+].CCCCCC>ClCCl.C(OCC)(=O)C>[CH2:1]([C:8]1[C:9]([NH:22][C:23](=[S:33])[CH2:24][C:25]2[CH:26]=[CH:27][C:28]([OH:31])=[CH:29][CH:30]=2)=[N:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[N:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CC(=S)Nc2ncc(-c3ccc(OC)cc3)nc2Cc2ccccc2)cc1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Oc1ccc(CC(=S)Nc2ncc(-c3ccc(O)cc3)nc2Cc2ccccc2)cc1
Temperature: 25 °C
Yield: 66.4 %

Procedure:
Under an argon atmosphere, 3-benzyl-5-(4-methoxyphenyl)-2-[(4-methoxyphenyl)thioacetylamino]pyrazine (c-44) (823 mg, 1.81 mmol) was dissolved in anhydrous dichloromethane (30 mL) and to this was added 1.0 M solution of boron tribromide in dichloromethane (6.80 mL, 6.80 mmol) at room temperature and heated to reflux for 21 h. After cooling to room temperature, to this was added saturated aqueous solution of sodium bicarbonate and concentrated under reduced pressure with a rotary evaporator to remove dichloromethane. The resulting suspension was filtrated and the residue was dried to give the crude product (591 mg) as a red solid. The crude product was dissolved in ethyl acetate and to this was added n-hexane to form a precipitate. The solid was collected by filtration and dried in vacuo to give 3-benzyl-5-(4-hydroxyphenyl)-2-[(4-hydroxyphenyl)thioacetylamino]pyrazine (coelenterathioamide) (c-45) as an orange solid (514 mg, 66.6%). Rf=0.23 (n-hexane/ethyl acetate=1/1). Mp. 101-103° C. 1H NMR (400 MHz, DMSO-d6) δ 3.90 (s, 2H), 4.00 (s, 2H), 6.71-6.77 (AABB′, 2H), 6.85-6.91 (AA′BB′, 2H), 6.97-7.03 (AA′BB′, 2H), 7.12-7.25 (m, 3H), 7.27-7.34 (m, 2H), 7.94-8.00 (AA′BB′, 2H), 8.91 (s, 1H), 9.34 (s, 1H), 9.94 (s, 1H), 12.05 (s, 1H). 13C NMR (67.8 MHz, DMSO-d6) δ 50.9, 115.1 (2C), 115.8 (2C), 126.0, 126.2, 127.0, 128.18 (2C), 128.24 (2C), 128.9 (2C), 129.9 (2C), 137.4, 138.0, 144.6, 149.9, 152.0, 156.4, 159.3, 205.3 (one carbon at benzyl position was unobservable due to over lapping with septet peak of DMSO). IR (KBr, cm−1) 515, 561, 706, 731, 837, 908, 935, 1063, 1130, 1171, 1238, 1315, 1371, 1443, 1514, 1609, 2808, 3026, 3159. HRMS (ESI+) m/z 428.1434 ((M+H)+, C25H22N3O2S+ requires 428.1427).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4]Br.[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[OH-].[K+].C(OCC)(=O)C>CN(C=O)C.O>[Br:1][CH2:2][CH2:3][CH2:4][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: c1ccc2[nH]ncc2c1
Reactant: BrCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: BrCCCn1ncc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.8 %

Procedure:
1,3-Dibromopropane (508 μl, 5.0 mmol)) was dissolved in 10 mL DMF and placed in a 100 mL flask. Indazole (592 mg, 5.0 mmol) and KOH (282 mg, 5.0 mmol) were added and the suspension was stirred overnight at room temperature. Ethyl acetate (50 mL) and water (50 mL) were added. Phases were separated and the aqueous phase was re-extracted with ethyl acetate (50 mL). The combined organic phases were washed with brine, dried over magnesium sulphate and evaporated to dryness to produce 751 mg of a yellow oil. Crude product was further purified by column chromatography (0-10% methanol:dichloromethane) to produce pure 22 (169 mg, 14%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:13][C@H:14]([C:18]([NH:20][C@H:21]([C:32]#[N:33])[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][C:24]=2[F:31])=[O:19])[CH:15]([CH3:17])[CH3:16])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[F:34][CH:35]([F:53])[C@@H:36]([C:38]1[CH:43]=[CH:42][C:41](B2OC(C)(C)C(C)(C)O2)=[CH:40][CH:39]=1)[OH:37]>>[C:32]([C@H:21]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][C:24]=1[F:31])[NH:20][C:18](=[O:19])[C@@H:14]([NH:13][C@@H:8]([C:5]1[CH:6]=[CH:7][C:2]([C:41]2[CH:40]=[CH:39][C:38]([C@@H:36]([OH:37])[CH:35]([F:53])[F:34])=[CH:43][CH:42]=2)=[CH:3][CH:4]=1)[C:9]([F:12])([F:11])[F:10])[CH:15]([CH3:17])[CH3:16])#[N:33]
Reactant: CC(C)[C@H](N[C@@H](c1ccc(Br)cc1)C(F)(F)F)C(=O)N[C@H](C#N)Cc1ccc(C#N)cc1F
Reactant: CC1(C)OB(c2ccc([C@@H](O)C(F)F)cc2)OC1(C)C
Product: CC(C)[C@H](N[C@@H](c1ccc(-c2ccc([C@@H](O)C(F)F)cc2)cc1)C(F)(F)F)C(=O)N[C@H](C#N)Cc1ccc(C#N)cc1F

Procedure:
(S)—N—[(S)-Cyano-(4-cyano-2-fluoro-benzyl)-methyl]-2-{(S)-1-[4′-((R)-2,2-difluoro-1-hydroxy-ethyl)-biphenyl-4-yl]-2,2,2-trifluoro-ethylamino}-3-methyl-butyramide was prepared from N2-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N-[(1S)-1-cyano-2-(4-cyano-2-fluorophenyl)ethyl]-L-valinamide and (1R)-2,2-difluoro-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethanol (described in U.S. Pat. No. 7,407,959, hereby incorporated by reference in its entirety.) using procedure described in step 2 of Example 10.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:11]=[C:12]([C:17](=[O:21])[CH:18]([CH3:20])[CH3:19])[CH:13]=[C:14]([OH:16])[CH:15]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:28]([O:30][C:31](=[O:56])[CH2:32][CH2:33][CH2:34][O:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47]Br)[C:37]=1[CH2:49][CH2:50][C:51]([O:53][CH2:54][CH3:55])=[O:52])[CH3:29]>CC(C)=O.CN(C=O)C>[CH2:28]([O:30][C:31](=[O:56])[CH2:32][CH2:33][CH2:34][O:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][O:16][C:14]2[CH:13]=[C:12]([C:17](=[O:21])[CH:18]([CH3:19])[CH3:20])[CH:11]=[C:10]([C:8]3[CH:7]=[CH:6][C:5]4[O:1][CH2:2][O:3][C:4]=4[CH:9]=3)[CH:15]=2)[C:37]=1[CH2:49][CH2:50][C:51]([O:53][CH2:54][CH3:55])=[O:52])[CH3:29]
Reactant: CC(C)C(=O)c1cc(O)cc(-c2ccc3c(c2)OCO3)c1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCBr)c1CCC(=O)OCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)C(C)C)cc(-c3ccc4c(c3)OCO4)c2)c1CCC(=O)OCC
Temperature: 75 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
To a solution of 1-(3-benzo[1,3]dioxol-5-yl-5-hydroxy-phenyl)-2-methyl-propan-1-one (109 mg) in a mixture of acetone and DMF (2:1, 3 mL) were added cesium carbonate (624 mg) and 4-[3-(6-bromo-hexyl)-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (190 mg). The resulting mixture was stirred at 75° C. overnight. Then the insoluble material was filtered out and the filtrate was diluted with ethyl acetate and washed with water and brine. The organic extract was dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column using ethyl acetate and hexanes to yield 194 mg of the title compound (75% yield). HRMS calcd for C40H50O9 [M+Na]+ 697.3347, observed 697.3344.
Reaction SMILES: N1C2C(=CC(B(O)O)=CC=2)C=C1.Br[C:14]1[CH:15]=[C:16]2C(I)=C[N:20](S(C3C=CC(C)=CC=3)(=O)=O)[C:17]2=[N:18][CH:19]=1.NC1N=CC(B(O)O)=CC=1.COC1C=C(B(O)O)C=C(OC)C=1OC.Br[C:60]1[CH:61]=[C:62]2[C:68]([C:69]3[CH:70]=[C:71]4[C:75](=[CH:76][CH:77]=3)[NH:74]C=C4)=[CH:67][N:66](S(C3C=CC(C)=CC=3)(=O)=O)[C:63]2=[N:64][CH:65]=1>>[NH2:74][C:75]1[CH:76]=[CH:77][C:69]([C:68]2[C:62]3[C:63](=[N:64][CH:65]=[C:60]([C:14]4[CH:15]=[CH:16][C:17]([NH2:20])=[N:18][CH:19]=4)[CH:61]=3)[NH:66][CH:67]=2)=[CH:70][CH:71]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(Br)cnc32)cc1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccc4[nH]ccc4c3)c3cc(Br)cnc32)cc1
Agent: COc1cc(B(O)O)cc(OC)c1OC
Agent: Nc1ccc(B(O)O)cn1
Agent: OB(O)c1ccc2[nH]ccc2c1
Product: Nc1ccc(-c2c[nH]c3ncc(-c4ccc(N)nc4)cc23)cc1

Procedure:
Compound Z was prepared by a method analogous to that described in Example 1 by substituting 4-aminophenylboronic acid for 1H-indol-5-ylboronic acid in the reaction with Intermediate A and 6-aminopyridin-3-ylboronic acid for 3,4,5-trimethoxyphenylboronic acid in the reaction with Intermediate B. HPLC retention time: 0.68 minutes. MS ESI (m/z): 302.4 (M+H)+, calc. 301.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:66])[NH:4][CH:5]([C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[C:6]([N:8]1[CH2:12][C:11](F)(F)[CH2:10][CH:9]1[C:15]1[NH:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[C:31]([C:36]5[NH:37][C:38]([CH:41]6[CH2:45][CH2:44][CH2:43][N:42]6[C:46](=[O:59])[CH:47]([NH:54][C:55]([O:57][CH3:58])=[O:56])[CH:48]6[CH2:53][CH2:52][O:51][CH2:50][CH2:49]6)=[N:39][CH:40]=5)[CH:32]=4)[CH:27]=3)=[CH:22][CH:21]=2)=[CH:18][N:19]=1)=[O:7].[C:67](OC(N1CC(F)(F)CC1C1NC(C2C=CC(C3C=CC4C(=CC=C(C5NC(C6CCCN6C(OCC6C=CC=CC=6)=O)=NC=5)C=4)C=3)=CC=2)=CN=1)=O)(C)(C)[CH3:68]>>[CH3:1][O:2][C:3](=[O:66])[NH:4][CH:5]([C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[C:6]([N:8]1[CH:9]([C:15]2[NH:16][C:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:35]=[CH:34][C:33]5[C:28](=[CH:29][CH:30]=[C:31]([C:36]6[NH:37][C:38]([CH:41]7[CH2:45][CH2:44][CH2:43][N:42]7[C:46](=[O:59])[CH:47]([NH:54][C:55]([O:57][CH3:58])=[O:56])[CH:48]7[CH2:53][CH2:52][O:51][CH2:50][CH2:49]7)=[N:39][CH:40]=6)[CH:32]=5)[CH:27]=4)=[CH:22][CH:21]=3)=[CH:18][N:19]=2)[CH2:10][C:11]2([CH2:68][CH2:67]2)[CH2:12]1)=[O:7]
Reactant: COC(=O)NC(C(=O)N1CC(F)(F)CC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC)C6CCOCC6)[nH]5)ccc4c3)cc2)[nH]1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC(F)(F)CC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)OCc6ccccc6)[nH]5)ccc4c3)cc2)[nH]1
Product: COC(=O)NC(C(=O)N1CC2(CC2)CC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC)C6CCOCC6)[nH]5)ccc4c3)cc2)[nH]1)c1ccccc1
Yield: 33 %

Procedure:
{2-[6-(5-{4-[6-(2-{-[2-Methoxycarbonylamino-2-(tetrahydro-pyran-4-yl)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-naphthalen-2-yl]-phenyl}-1H-imidazol-2-yl)-5-aza-spiro[2.4]hept-5-yl]-2-oxo-1-phenyl-ethyl}-carbamic acid methyl ester (0.09 g, 33%) was prepared following the procedure for {2-[4,4-Difluoro-2-(5-{4-[6-(2-{1-[2-methoxycarbonylamino-2-(tetrahydro-pyran-4-yl)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-naphthalen-2-yl]-phenyl}-1H-imidazol-2-yl)-pyrrolidin-1-yl]-2-oxo-1-phenyl-ethyl}-carbamic acid methyl ester, substituting 6-[5-(4-{6-[2-(1-Benzyloxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]-naphthalen-2-yl}-phenyl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carboxylic acid tert-butyl ester for 2-[5-(4-{6-[2-(1-Benzyloxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]-naphthalen-2-yl}-phenyl)-1H-imidazol-2-yl]-4,4-difluoro-pyrrolidine-1-carboxylic acid tert-butyl ester. LCMS-ESI+: calc'd for C51H54N8O7: 890.41 (M+); Found: 891.96 (M+H+).