Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH:22]=[C:21]([C:23]([O:25]CC)=[O:24])[CH:20]=[N:19]2)=[C:14]([F:28])[CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.[OH-].[Na+]>C(O)C.O>[CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH:22]=[C:21]([C:23]([OH:25])=[O:24])[CH:20]=[N:19]2)=[C:14]([F:28])[CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cnn(-c2ccc(NC(=O)OCc3ccccc3)cc2F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(Nc1ccc(-n2cc(C(=O)O)cn2)c(F)c1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 89.7 %

Procedure:
Ethyl 1-(4-{[benzyloxycarbonyl]amino}-2-fluorophenyl)-1H-pyrazole-4-carboxylate (J. Med. Chem, 2000, 43, 5, p 953) (1.33 g, 3.45 mmol) was taken up in ethanol/water (1/1, 80 ml), tetrahydrofuran (10 ml) was added, followed by aqueous sodium hydroxide solution (1M, 155 ml) and it was stirred at room temperature for 5 hours. The organic solvents were removed and the aqueous solution was acidified with 1M aqueous hydrochloric acid. The acidic solution was extracted with ethyl acetate, dried over magnesium sulfate and the solvent removed under reduced pressure to give the title product (1.1 g).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][CH:9]2[CH3:12])=[CH:4][CH:3]=1.B(O)O>>[CH3:12][CH:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([C:6]3[CH:7]=[N:8][CH:9]=[CH:10][CH:5]=3)[CH:11]=2)[CH2:6][CH2:7][NH:8]1
Reactant: CC1NCCc2ccc(Br)cc21
Agent: OBO
Product: CC1NCCc2ccc(-c3cccnc3)cc21

Procedure:
In close analogy to the procedure described above, 7-Bromo-1-methyl-1,2,3,4-tetrahydro-isoquinoline is reacted with the corresponding boronic acid to provide the title compound.
Reaction SMILES: [CH:1]([C:4]1[CH:8]=[C:7]([N:9]2[CH2:39][CH2:38][C:12]3[N:13]=[C:14]([C:18]4[CH:26]=[CH:25][CH:24]=[C:23]5[C:19]=4[C:20]([CH3:37])=[CH:21][N:22]5S(C4C=CC(C)=CC=4)(=O)=O)[N:15]=[C:16](O)[C:11]=3[CH2:10]2)[N:6]([CH3:40])[N:5]=1)([CH3:3])[CH3:2].[OH-].[K+].[OH-].[NH4+].Cl.C([O-])(O)=O.[Na+].P(Cl)(Cl)([Cl:53])=O>CO.CC(C)=O.O>[Cl:53][C:16]1[C:11]2[CH2:10][N:9]([C:7]3[N:6]([CH3:40])[N:5]=[C:4]([CH:1]([CH3:2])[CH3:3])[CH:8]=3)[CH2:39][CH2:38][C:12]=2[N:13]=[C:14]([C:18]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=2[C:20]([CH3:37])=[CH:21][NH:22]3)[N:15]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(C)c3c(-c4nc(O)c5c(n4)CCN(c4cc(C(C)C)nn4C)C5)cccc32)cc1
Reactant: O=P(Cl)(Cl)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC(C)=O
Solvent: CO
Solvent: O
Product: Cc1c[nH]c2cccc(-c3nc(Cl)c4c(n3)CCN(c3cc(C(C)C)nn3C)C4)c12
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6-(3-isopropyl-1-methyl-1H-pyrazol-5-yl)-2-(3-methyl-1-tosyl-1H-indol-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ol (550 mg, 0.988 mmol) in methanol (5 mL) in a microwave vial, was added potassium hydroxide (554 mg, 9.88 mmol) and then 28% ammonium hydroxide (1 mL, 0.988 mmol). The reaction was heated at 80° C. via microwave irradiation for 45 min. The reaction mixture was poured into iced water, then 4 N aq HCl was added to acidify the reaction mixture to pH=1, then NaHCO3 solid was added to neutralize reaction mixture to pH=7-8. The mixture was extracted twice with a solution of 5% trifluoroethanol in DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The resulting residue was dissolved in dichloroethane (3 mL), and the reaction flask was charged with phosphorus oxychloride (3.67 mL, 39.5 mmol). The reaction flask was capped and then heated to 80° C. for 1 h. The reaction mixture was cooled to r.t. and poured into ice water and diluted with acetone (10 mL). The reaction mixture was stirred for 30 min to provide a clear solution. At that point, NaHCO3 solid was added to neutralize the reaction, and the mixture was extracted twice with DCM. The resulting residue was purified via silica gel FCC (0-100% EtOAc/heptane) to provide 4-chloro-6-(3-isopropyl-1-methyl-1H-pyrazol-5-yl)-2-(3-methyl-1H-indol-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine. MS (ESI+) m/z 421.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1.C([Li])CCC.CCCCCC.CN([CH:27]=[O:28])C.C(=O)(O)[O-].[Na+]>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH:27]=[O:28]
Reactant: CN(C)C=O
Reactant: COCCOCCn1ccnc1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COCCOCCn1ccnc1C=O
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 54.3 %

Procedure:
1.30 g of (2) (0.008 mol) was dissolved in freshly distilled THF 35 mL under argon atmosphere, and the solution was cooled to −40° C. n-butyllithium 1.6M-hexane solution 5.6 mL (0.0088 mol) was added dropwise while the temperature was kept at −40° C. The mixture was then stirred at −40° C. for 30 min, after which dry DMF 1.28 mL (0.016 mol) was added. The contents were allowed to warm up to room temperature and stirred overnight. Sodium bicarbonate solution was added, then THF was dried (Rotavap), extracted by CHCl3, dried over Na2SO4, and dried (Rotavap) until a light yellow oil was left. The product was purified by silica gel flash column chromatography, CHCl3:CH3OH=50:1. 0.861 g product (3) (57% yield) was obtained as a light yellow oil. As an alternative to column chromatography, the product (3) is purified by vacuum distillation.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[N:3]=1.[CH3:19][N:20]([CH3:27])[CH2:21][C:22]([CH3:26])([CH3:25])[CH2:23][NH2:24].C(N(C(C)C)CC)(C)C.Cl>C1COCC1.CO.O1CCOCC1.CCOCC>[ClH:1].[CH3:19][N:20]([CH3:27])[CH2:21][C:22]([CH3:26])([CH3:25])[CH2:23][NH:24][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[N:3]=1
Reactant: FC(F)(F)c1cccc(Nc2nccc(Cl)n2)c1
Reactant: CN(C)CC(C)(C)CN
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CC(C)(C)CNc1ccnc(Nc2cccc(C(F)(F)F)c2)n1
Temperature: 25 °C

Procedure:
4-Chloro-N-(3-(trifluoro-methyl)phenyl)pyrimidin-2-amine, 6, (200 mg, 0.73 mmol), N1,N1,2,2-tetramethyl-propane-1,3-diamine (0.232 mL, 1.46 mmol), and diisopropylethylamine (0.254 mL, 1.46 mmol) are dissolved in THF (5 mL) and heated to reflux for 20 hours. The reaction is cooled to room temperature and partitioned between EtOAc and water. The organic layer is dried (MgSO4), concentrated in vacuo, and purified over silica (5% MeOH ramped to 6% MeOH in CH2Cl2 with 0.7% added triethylamine) to give an oil. The oil is dissolved in MeOH (0.5 mL) and Et2O (20 mL) and cooled to 0° C. To this solution is added a solution of 4M HCl in dioxane (0.25 mL) in one portion. The white precipitate which forms is collected by filtration and dried at reduced pressure to afford the desired compound as a white solid: 1H NMR (DMSO-d6, 300 MHz) δ 1.09 (s, 6H), 2.81 (s, 3H), 2.83 (s, 3H), 3.11 (d, J=4.2 Hz, 2H), 3.38-3.50 (m, 2H), 6.48 (d, J=7.2 Hz, 1H), 7.51 (d, J=7.5 Hz, 1H), 7.66 (t, J=7.5 Hz, 1H), 7.74 (d. J=6.6 Hz, 1H), 7.91 (d, J=7.2 Hz, 1H), 8.20 (s, 1H), 9.67 (bs, 1H), 10.80 (bs, 1H); HRMS calcd for C18H24F3N5, 368.2062 m/z (M+H)+; observed 368.2072 m/z.
Reaction SMILES: [C:1]([O:20][CH2:21][C@H:22]1[O:27][C@H:26]([O:28][CH2:29][C@H:30]([O:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61])[CH2:31][O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[C@H:25]([OH:62])[C@@H:24]([OH:63])[C@H:23]1[OH:64])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OC(=O)C)(=O)C.N1C=CC=CC=1>[C:1]([O:62][C@@H:25]1[C@@H:24]([O:63][C:26](=[O:27])[CH3:25])[C@@H:23]([O:64][C:29](=[O:28])[CH3:30])[C@@H:22]([CH2:21][O:20][C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:27][C@@H:26]1[O:28][CH2:29][C@H:30]([O:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61])[CH2:31][O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])(=[O:20])[CH3:2]
Reactant: CCCCCCCCCCCCCCOC[C@H](CO[C@H]1O[C@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@H](O)[C@H](O)[C@H]1O)OCCCCCCCCCCCCCC
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCOC[C@H](CO[C@H]1O[C@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O)OCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 24 h
Yield: 192.9 %

Procedure:
3-O-(6-O-trityl-α-D-galactopyranosyl)-1,2-di-O-tetra-decyl-Sn-glycerol (4) (672 mg) was dissolved in acetic anhydride (3 ml) and pyridine (3 ml). The solution was stirred at room temperature for 24 hours and concentrated in vacuo. The residue was subjected to column chromatography (Wakogel C-300, 70 g) and eluted with 0.5% methanol-containing chloroform to obtain 3-O-(2,3,4-tri-O-acetyl-6-O-trityl-α-D-galactopyranosyl)-1,2-di-O-tetradecyl-Sn-glycerol (5) (740 mg, 96.4%).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([C@@H:19]3[O:27][CH2:26][C@H:21]([S:22]C(=O)C)[CH2:20]3)=[O:18])[CH2:13][CH2:12]2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO>[C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([C@@H:19]3[O:27][CH2:26][C@H:21]([SH:22])[CH2:20]3)=[O:18])[CH2:13][CH2:12]2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)S[C@H]1CO[C@@H](C(=O)N2CCN(C(=O)OCc3ccccc3)CC2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(OCc1ccccc1)N1CCN(C(=O)[C@H]2C[C@@H](S)CO2)CC1
Reaction time: 1 h
Yield: 65 %

Procedure:
A 0° C. solution, under argon, of 0.20 g of product from Example 152 in 1.5 ml of dry methyl alcohol is treated with 0.25 ml of 4N sodium hydroxide. The reaction is monitored by thin layer chromatography. After 1 hour an additional 0.17 ml of 4N sodium hydroxide is added and the reaction stirred 1 hour. The reaction mixture is quenched with 1.86N hydrochloric acid/isopropyl alcohol, concentrated in vacuo and chromatographed (silica gel: 20-80% ethyl acetate/hexane) to give 0.116 g of the desired product.
Reaction SMILES: FC1C=CC(N2C(=O)C(OC)=C(Br)C=N2)=CC=1.FC1C=CC(N2C(=O)C(OC)=C(C3C=CC(SC)=CC=3)C=N2)=CC=1.[F:42][C:43]1[CH:48]=[CH:47][C:46]([N:49]2[C:54](=[O:55])[C:53]([OH:56])=[C:52]([C:57]3[CH:62]=[CH:61][C:60]([S:63]([CH3:66])(=[O:65])=[O:64])=[CH:59][CH:58]=3)[CH:51]=[N:50]2)=[CH:45][CH:44]=1.[OH-].[Na+].[C:69]1([CH3:79])[CH:74]=[CH:73][C:72]([S:75](Cl)(=[O:77])=[O:76])=[CH:71][CH:70]=1>>[F:42][C:43]1[CH:48]=[CH:47][C:46]([N:49]2[C:54](=[O:55])[C:53]([O:56][S:75]([C:72]3[CH:73]=[CH:74][C:69]([CH3:79])=[CH:70][CH:71]=3)(=[O:77])=[O:76])=[C:52]([C:57]3[CH:62]=[CH:61][C:60]([S:63]([CH3:66])(=[O:64])=[O:65])=[CH:59][CH:58]=3)[CH:51]=[N:50]2)=[CH:45][CH:44]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)cc3)c(=O)c2O)cc1
Agent: COc1c(-c2ccc(SC)cc2)cnn(-c2ccc(F)cc2)c1=O
Agent: COc1c(Br)cnn(-c2ccc(F)cc2)c1=O
Agent: [Na+]
Product: Cc1ccc(S(=O)(=O)Oc2c(-c3ccc(S(C)(=O)=O)cc3)cnn(-c3ccc(F)cc3)c2=O)cc1

Procedure:
2-(4-Fluorophenyl)-4-methoxy-5-bromo-3(2H)-pyridazinone (Example 194B) was converted into 2-(4-fluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone according to the method of Example 194C followed by the oxidation method in Example 10. The methoxy compound was converted to the 2-(4-fluorophenyl)-4-hydroxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone, by treatment with NaOH according to the procedure of Example 332. The hydroxy compound was treated with p-toluenesulfonyl chloride according to the procedure of Example 333, to furnish 2-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-4-tosyloxy-3(2H)-pyridazinone.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:35]=[CH:34][C:6]2[NH:7][C:8]([C:13]3[C:14](=[O:33])[C:15]([CH2:25][CH2:26][CH2:27][CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:24])[C:16]4[C:21]([C:22]=3[OH:23])=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:9][S:10](=[O:12])(=[O:11])[C:5]=2[CH:4]=1.[S:36](Cl)([CH3:39])(=[O:38])=[O:37].N1C=CC=CC=1>CC(C)=O>[CH3:32][C:29]([CH3:30])([CH3:31])[CH2:28][CH2:27][CH2:26][CH2:25][C:15]1([CH3:24])[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:22]([OH:23])=[C:13]([C:8]2[NH:7][C:6]3[CH:34]=[CH:35][C:3]([NH:2][S:36]([CH3:39])(=[O:38])=[O:37])=[CH:4][C:5]=3[S:10](=[O:12])(=[O:11])[N:9]=2)[C:14]1=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)CCCCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: CC(C)(C)CCCCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Yield: 74.7 %

Procedure:
A solution of Example 37B (0.374 g, 0.722 mmol), mesyl chloride (0.224 mL, 2.89 mmol), and pyridine (0.467 mL, 5.78 mmol) in acetone (15 mL) was stirred at 25° C. for 18 hours. The solution was partitioned between ethyl acetate and dilute citric acid and the layers were separated. The ethyl acetate layer was dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with methylene chloride and 2.5% methanol in methylene chloride to give the desired product (0.302 g, 75%).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)=[CH2:2].[C:10](OC(=O)C)(=[O:12])[CH3:11].[OH-].[Na+].[OH-].[K+]>>[C:10]([O:9][C:6]1[CH:7]=[CH:8][C:3]([CH:1]=[CH2:2])=[CH:4][CH:5]=1)(=[O:12])[CH3:11]
Reactant: C=Cc1ccc(O)cc1
Reactant: CC(=O)OC(C)=O
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Product: C=Cc1ccc(OC(C)=O)cc1

Procedure:
Pittet et al. in U.S. Pat. No. 4,316,995 describe a method for preparing p-vinylphenol. In that method, p-hydroxybenzaldehyde is first reacted with malonic acid using ethylenediamine as catalyst to give pHCA, which is decarboxylated in situ at a temperature of 115 to 120° C. to form impure p-vinylphenol. The p-vinylphenol is isolated from the reaction mixture and reacted with acetic anhydride in the presence of a base, such as sodium hydroxide or potassium hydroxide, to form 4-acetoxystyrene, which is separated from the reaction mixture and hydrolyzed in the presence of a strong base to give purified p-vinylphenol. The yield of 4-vinylphenol was about 31%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([F:15])[CH:13]=2)[N:8]([S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21](Br)[C:20]=2[CH3:26])(=[O:18])=[O:17])[CH:7]=1.[F:28][C:29]([F:41])([F:40])[O:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([F:15])[CH:13]=2)[N:8]([S:16]([C:19]2[C:20]([CH3:26])=[C:21]([C:34]3[CH:33]=[CH:32][C:31]([O:30][C:29]([F:28])([F:40])[F:41])=[CH:36][CH:35]=3)[CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:7]=1
Reactant: COC(=O)CCc1cn(S(=O)(=O)c2cccc(Br)c2C)c2ccc(F)cc12
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: COC(=O)CCc1cn(S(=O)(=O)c2cccc(-c3ccc(OC(F)(F)F)cc3)c2C)c2ccc(F)cc12
Temperature: 110 °C
Yield: 65.2 %

Procedure:
Into a 50 mL oven dried round bottom flask, 3-[1-(3-Bromo-2-methyl-benzenesulfonyl)-5-fluoro-1H-indol-3-yl]-propionic acid methyl ester (5, 52.062 mg, 1.1459E-4 mol), 4-trifluoromethoxy-phenyl boronic acid (6, 35.397 mg, 1.7189E-4 mol) and Tetrakis(triphenylphosphine)palladium(0) (13.24 mg, 1.146E-5 mol) were combined. A volume of 0.3 mL of 1N K2CO3 was added and the reaction was heated to 110° C. for 90 minutes. TLC analysis showed co-elution of product and starting material. Ethyl acetate was added and washed 5× with saturated sodium bicarbonate. The organic layer was dried over MgSO4, filtered and concentrated at reduced pressure. The crude material was purified using prep plate chromatography (7:3 hexane:ethyl acetate) to provide the desired compound (40 mg isolated, 65% yield). 1H NMR consistent with compound structure. MS(ESI) [M+H+]+=536.1 (calculated 535.51).
Reaction SMILES: [C:1]([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C@@H:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:15]([OH:18])[CH2:16][OH:17])[C:6]1=[O:25])([CH3:4])([CH3:3])[CH3:2].[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1.Cl>N1C=CC=CC=1>[C:1]([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C@@H:14]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C@H:15]([OH:18])[CH2:16][O:17][S:32]([C:29]2[CH:30]=[CH:31][C:26]([CH3:36])=[CH:27][CH:28]=2)(=[O:34])=[O:33])[C:6]1=[O:25])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)n1c(=O)n([C@@H](c2ccccc2)[C@H](O)CO)c2ccccc21
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@@H](O)[C@H](c2ccccc2)n2c(=O)n(C(C)(C)C)c3ccccc32)cc1

Procedure:
A solution of 1-tert-butyl-3-[(1S,2S)-2,3-dihydroxy-1-phenyl-propyl]-1,3-dihydro-2H-benzimidazol-2-one (0.55 g, 1.6 mmol) and para-toluenesulfonyl chloride (0.37 g, 1.9 mmol) in anhydrous pyridine (5 mL) was stirred at room temperature under nitrogen for 12 hours. The reaction was poured into a cold 1N aqueous solution of hydrochloric acid (50 mL) and extracted with ethyl acetate (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to give (2S,3S)-toluene-4-sulfonic acid 3-(3-tert-butyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-2-hydroxy-3-phenyl-propyl ester. To a solution of (2S,3S)-toluene-4-sulfonic acid 3-(3-tert-butyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-2-hydroxy-3-phenyl-propyl ester (0.8 g, 1.6 mmol) in methanol (10 mL) was added a 2N solution of methylamine in methanol (4 mL, 8 mmol) and the reaction mixture stirred for 12 hours at room temperature in a sealed tube. Upon completion, the reaction was partitioned between a saturated aqueous solution of sodium bicarbonate (50 mL) and ethyl acetate (50 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via flash column chromatography (silica, 20% MeOH in dichloromethane) to give 1-tert-butyl-3-[(1S,2R)-2-hydroxy-3-methylamino-1-phenylpropyl]-1,3-dihydro-2H-benzimidazol-2-one as a clear oil. The free base was dissolved in a minimum amount of ethanol and treated with a 2N ethereal solution of hydrochloric acid and stirred for 1 hour s. The ethanol was removed in vacuo and the clear oil was triturated with diethyl ether/dichloromethane to give 1-tert-butyl-3-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phenylpropyl]-1,3-dihydro-2H-benzimidazol-2-one hydrochloride as a white solid. HRMS: calcd for C21H27N3O2+H+, 354.21760. Found (ESI, [M+H]+), 354.2179.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[I-].C[S+](C)(C)=O.[O:13]1[CH2:18][CH2:17][CH2:16][O:15][CH:14]1[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[S:26][C:27]3[C:32]([N:33]=2)=[CH:31][CH:30]=[C:29]([C:34]([C:36]2[CH:41]=[CH:40][C:39]([O:42][CH2:43][C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)=[CH:38][CH:37]=2)=[CH2:35])[N:28]=3)=[C:21]([F:50])[CH:20]=1>CS(C)=O.C1COCC1>[O:15]1[CH2:16][CH2:17][CH2:18][O:13][CH:14]1[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[S:26][C:27]3[C:32]([N:33]=2)=[CH:31][CH:30]=[C:29]([C:34]2([C:36]4[CH:41]=[CH:40][C:39]([O:42][CH2:43][C:44]5[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=5)=[CH:38][CH:37]=4)[CH2:1][CH2:35]2)[N:28]=3)=[C:21]([F:50])[CH:20]=1
Reactant: C=C(c1ccc(OCc2ccccc2)cc1)c1ccc2nc(-c3ccc(C4OCCCO4)cc3F)sc2n1
Reactant: CC(C)(C)[O-]
Agent: C[S+](C)(C)=O
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: Fc1cc(C2OCCCO2)ccc1-c1nc2ccc(C3(c4ccc(OCc5ccccc5)cc4)CC3)nc2s1
Reaction time: 4 h

Procedure:
A solution of potassium tert-butoxide (0.206 g, 1.83 mmol) and trimethylsulfoxonium iodide (0.404 g, 1.83 mmol) in 5 mL DMSO under nitrogen was added 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-5-(1-(4-(benzyloxy)phenyl)vinyl)-thiazolo[5,4-b]pyridine (0.385 g, 0.734 mmol) as a solution in 6 mL THF (min volume to dissolve) slowly dropwise via addition funnel over 1 h. The cloudy reaction mixture was allowed to stir for 4 h and was quenched with ice. The reaction mixture was partitioned between water and EtOAc. The organic layer was washed with water, brine, dried, and concentrated in vacuo to give an oil/solid which was purified by silica gel chromatography 0-100% EA/hexanes to give 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-5-(1-(4-(benzyloxy)phenyl)cyclopropyl)thiazolo[5,4-b]pyridine as a yellow solid. The aqueous suspension from the extraction was further extracted with DCM, the combined org extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to give additional 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-5-(1-(4-(benzyloxy)phenyl)-cyclopropyl)thiazolo[5,4-b]pyridine. MS (ESI) m/z: calculated: 538.2; Observed: 539.1 (M++1).
Reaction SMILES: C(O)(=O)C.[F:5][C:6]1[CH:13]=[C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][N:17]=2)[CH:11]=[CH:10][C:7]=1[CH:8]=O.[N+:23]([CH3:26])([O-:25])=[O:24].C([O-])(=O)C.[NH4+]>C(OCC)(=O)C.O>[F:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][O:14][C:12]2[CH:11]=[CH:10][C:7](/[CH:8]=[CH:26]/[N+:23]([O-:25])=[O:24])=[C:6]([F:5])[CH:13]=2)=[N:17][CH:18]=1
Reactant: O=Cc1ccc(OCc2ccc(F)cn2)cc1F
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])/C=C/c1ccc(OCc2ccc(F)cn2)cc1F
Temperature: 110 °C
Reaction time: 2 h
Yield: 94.5 %

Procedure:
To an acetic acid (20.0 mL) solution of 2-fluoro-4-(5-fluoro-pyridin-2-ylmethoxy)-benzaldehyde (901 mg, 3.62 mmol) described in Manufacturing Example 96-1-1 were added nitromethane (1.10 g, 18.1 mmol) and ammonium acetate (558 mg, 7.24 mmol) under nitrogen atmosphere, which was stirred for 2 hours at 110° C. Water and ethyl acetate were added to the reaction mixture, and the organic layer was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (1.00 g) as a crude product.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][C:13]([OH:15])=O)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[CH:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:28]([O:30][C:31](=[O:43])[CH:32]([CH2:35][C:36]1[CH:41]=[CH:40][C:39]([NH2:42])=[CH:38][CH:37]=1)[CH2:33][CH3:34])[CH3:29]>C1COCC1>[CH2:28]([O:30][C:31](=[O:43])[CH:32]([CH2:35][C:36]1[CH:37]=[CH:38][C:39]([NH:42][C:13](=[O:15])[CH2:12][C:9]2[CH:8]=[CH:7][C:6]([N:1]3[CH:2]=[CH:3][CH:4]=[CH:5]3)=[CH:11][CH:10]=2)=[CH:40][CH:41]=1)[CH2:33][CH3:34])[CH3:29]
Reactant: CCOC(=O)C(CC)Cc1ccc(N)cc1
Reactant: O=C(O)Cc1ccc(-n2cccc2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCOC(=O)C(CC)Cc1ccc(NC(=O)Cc2ccc(-n3cccc3)cc2)cc1
Yield: 23.2 %

Procedure:
A solution of 4-(1-pyrryl)phenylacetic acid (3 g) in anhydrous THF (50 ml) is additioned with a solution of carbonyldiimidazole (2.9 g) in THF (80 ml). After 45 minutes a solution of ethyl-2-(p-aminobenzyl)-butyrate (3.3 g) in THF (30 ml). is added. It is reflux heated for an hour, then dried and the residue is dissolved in dichloromethane. The organic solution is washed, first with NaOH 1M, then with HCl 1M and lastly with water. After drying on anhydrous sodium sulfate it is filtered and dried. A yellow solid (1.4 g) is obtained which melts at 100°-102° C. Analysis: