Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH3:9])[C:3]([O:5][CH2:6][CH:7]=[CH2:8])=[O:4].C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C1(C)C=CC=CC=1>[CH3:17][S:18]([O:1][CH:2]([CH3:9])[C:3]([O:5][CH2:6][CH:7]=[CH2:8])=[O:4])(=[O:20])=[O:19]
Reactant: C=CCOC(=O)C(C)O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C=CCOC(=O)C(C)OS(C)(=O)=O
Reaction time: 0.33 h
Yield: 52.7 %

Procedure:
32.00 g (246 mmol) of 2-propenyl 2-hydroxypropionate and 31.3 g (310 mmol) of triethylamine were dissolved in 150 g of toluene (solvent), and 35.6 g (310 mmol) of methanesulfonyl chloride was dropwise added thereto at 10° C., taking 20 minutes. These were reacted at room temperature for 1 hour, the reaction liquid was washed twice with water, then the organic layer was separated and concentrated. The concentrate was purified through silica gel column chromatography, and from the fraction taken with hexane/ethyl acetate=5/1, 27 g (yield 53%) of 2-propenyl 2-(methanesulfonyloxy)propionate was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:12][CH2:11]2)[CH:7]=[CH:6][C:5]=1[NH:22]C(=O)C(F)(F)F)[CH3:2].[Li+].[OH-]>C1COCC1.O>[CH2:1]([O:3][C:4]1[CH:9]=[C:8]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:12][CH2:11]2)[CH:7]=[CH:6][C:5]=1[NH2:22])[CH3:2]
Reactant: CCOc1cc(C2CCN(CCS(C)(=O)=O)CC2)ccc1NC(=O)C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOc1cc(C2CCN(CCS(C)(=O)=O)CC2)ccc1N
Yield: 93.9 %

Procedure:
To N-(2-(ethyloxy)-4-{1-[2-(methylsulfonyl)ethyl]-4-piperidinyl}phenyl)-2,2,2-trifluoroacetamide (1.4 g, 3.3 mmol) in THF (25 mL) and H2O (25 mL) was added LiOH (0.21 g, 5.0 mmol). The mixture was stirred for two h and then more LiOH (0.21 g, 5.0 mmol) was added. After stirring for one h, the product was extracted with EtOAc. The organic layer was dried (MgSO4), filtered and rotovaped to provided the title compound of step G as a colorless oil (1.0 g, 3.1 mmol, 94%). 1H NMR (400 MHz, DMSO-d6) δ 6.66-6.56 (m, 3H), 4.02 (q, J=7.0 Hz, 2H), 3.15 (t, J=6.6 Hz, 2H), 3.03 (s, 3H), 2.99 (d, J=11.5 Hz, 2H), 2.88 (t, J=6.6 Hz, 2H), 2.42-2.32 (m, 1H), 2.13 (dd, J=11.9, 11.7 Hz, 2H), 1.82 (d, J=13.0 Hz, 2H), 1.70-1.58 (m, 2H), 1.39 (t, J=7.0 Hz, 3H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1.[O:17]1[CH2:21][C:20](=[O:22])[NH:19][C:18]1=[O:23].CN(C)C(N(C)C)=N.Cl>O1CCCC1.C(OCC)(=O)C>[C:7]1([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:19]2[C:20](=[O:22])[CH2:21][O:17][C:18]2=[O:23])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: BrCCCCOc1cccc2ccccc12
Reactant: O=C1COC(=O)N1
Agent: CN(C)C(=N)N(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1COC(=O)N1CCCCOc1cccc2ccccc12
Yield: 60.2 %

Procedure:
A solution of 3.1 g (11.1 mmol) of 1-[(4-bromobutyl)oxy]naphthalene (Eur. J. Med. Chem. 1997, 32, 175-179) and 1.35 g (13.3 mmol) of 1,3-oxazolidine-2,4-dione (J. Med. Chem. 1991, 34, 1542-1543) in 30 ml of tetrahydrofuran is admixed dropwise with a solution of 2.55 g (22.2 mmol) of 1,1,3,3-tetramethylguanidine in 15 ml of tetrahydrofuran. The mixture is heated at reflux for 8 hours. 0.28 g (2.7 mmol) of 1,3-oxazolidine-2,4-dione and 0.32 g (2.7 mmol) of 1,1,3,3-tetramethylguanidine are added and the mixture is heated at reflux for 4 more hours. The reaction mixture is cooled using an ice bath, and 100 ml of ethyl acetate and then 50 ml of 1M aqueous hydrochloric acid are added. The system is decanted and the aqueous phase is extracted with 2×80 ml of ethyl acetate. The organic phases are subsequently washed with 80 ml of water and then with 80 ml of saturated aqueous sodium chloride solution. They are dried over sodium sulfate and then evaporated to dryness. The product is purified by chromatography on silica gel, eluting with an 80/20 mixture of cyclohexane and ethyl acetate, to give 2.0 g of product, which is used as it is in the following step.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]([CH2:23][C:24]3([CH3:35])[O:28][C:27]4=[N:29][C:30]([N+:32]([O-:34])=[O:33])=[CH:31][N:26]4[CH2:25]3)[C:15]2=[O:36])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:35][C:24]1([CH2:23][N:16]2[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[C:15]2=[O:36])[O:28][C:27]2=[N:29][C:30]([N+:32]([O-:34])=[O:33])=[CH:31][N:26]2[CH2:25]1
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)n(CC3(C)Cn4cc([N+](=O)[O-])nc4O3)c3ccccc32)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(Cn2c(=O)n(C3CCNCC3)c3ccccc32)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.5 %

Procedure:
A mixture of 1-(1-tert-butoxycarbonyl-piperidin-4-yl)-3-(2-methyl-6-nitro-2,3-dihydroimidazo-[2,1-b]oxazol-2-ylmethyl)-1,3-dihydrobenzimidazol-2-one prepared in Example 567 (371 mg, 0.74 mmol), trifluoroacetic acid (1 ml) and methylene chloride (10 ml) was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. To the residue, a saturated sodium hydrogencarbonate solution, and the precipitates were filtered off. The precipitates were washed with water several times to afford 1-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)-(3-piperidin-4-yl)-1,3-dihydrobenzimidazol-2-one (255 mg, yield 86%) as a light yellow powder.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[Cl:13][C:14]1[C:15]([O:25][CH:26]([CH3:30])[C:27]([OH:29])=O)=[N:16][C:17]([CH3:24])=[N:18][C:19]=1[C:20]([F:23])([F:22])[F:21].[NH2:31][C:32]([CH3:39])([C:35]([CH3:38])([CH3:37])[CH3:36])[C:33]#[N:34].O>O1CCCC1>[Cl:13][C:14]1[C:15]([O:25][CH:26]([CH3:30])[C:27]([NH:31][C:32]([C:33]#[N:34])([CH3:39])[C:35]([CH3:38])([CH3:37])[CH3:36])=[O:29])=[N:16][C:17]([CH3:24])=[N:18][C:19]=1[C:20]([F:21])([F:22])[F:23]
Reactant: CC(C)(C)C(C)(N)C#N
Reactant: Cc1nc(OC(C)C(=O)O)c(Cl)c(C(F)(F)F)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(OC(C)C(=O)NC(C)(C#N)C(C)(C)C)c(Cl)c(C(F)(F)F)n1
Reaction time: 0.5 h

Procedure:
1-Ethyl-3-(3-dimethylaminopropyl)carbodimide hydrochloride (0.8 g) was added to a solution containing 2-(5-chloro-2-methyl-6-trifluoromethylpyrimidin-4-yloxy)propionic acid (1.0 g) dissolved in tetrahydrofuran (30 ml), at room temperature, and the mixture was stirred for 30 min. Subsequently, 2-amino-2,3,3-trimethylbutyronitrile (0.5 g) was added to the mixture, and the reaction mixture was stirred for 10 hours at room temperature. After completion of the reaction, water was added to the resulting mixture and the organic layer was extracted with ethyl acetate, and subsequently dried over anhydrous magnesium sulfate. The ethyl acetate was removed under reduced pressure. The residue was purified by column chromatography on silica gel to give 0.3 g of the A-configurational diastereomer having a melting point of 1 33° C. to 1 34° C. and 0.2 g of the B-configurational diastereomer having a melting point of 137° C. to 139° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=3)[N:20]=2)[N:10]=[N:9]1.[NH:32]1[CH2:37][CH2:36][O:35][CH:34]([CH2:38][OH:39])[CH2:33]1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:25]=[CH:26][C:27]([CH2:28][N:32]4[CH2:37][CH2:36][O:35][CH:34]([CH2:38][OH:39])[CH2:33]4)=[CH:30][CH:31]=3)[N:20]=2)[N:10]=[N:9]1
Reactant: O=Cc1ccc(-c2noc(-c3nnn(-c4ccccc4F)c3-c3ccncc3)n2)cc1
Reactant: OCC1CNCCO1
Product: OCC1CN(Cc2ccc(-c3noc(-c4nnn(-c5ccccc5F)c4-c4ccncc4)n3)cc2)CCO1

Procedure:
The title compound was prepared following the procedure described for Example 94, but starting from 4-(5-(1-(2-fluorophenyl)-5-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)-1,2,4-oxadiazol-3-yl)benzaldehyde, obtained as described in Example 113, Step 1, (100 mg; 0.24 mmol) and morpholin-2-ylmethanol (56.8 mg; 0.48 mmol) to give Example 143 as a white solid. 1H NMR: (DMSO-d6, 400 MHz) δ 8.75 (2H, dd, J=4.7, 1.6 Hz), 7.97 (2H, d, J=7.9 Hz), 7.94-7.87 (1H, m), 7.76-7.69 (1H, m), 7.61 (2H, dd, J=4.7, 1.6 Hz), 7.58-7.48 (4H, m), 4.65 (1H, t, J=5.6 Hz), 3.80 (1H, d, J=11.2 Hz), 3.62-3.50 (3H, m), 3.46-3.39 (2H, m), 3.34-3.28 (1H, m), 2.79 (1H, d, J=11.1 Hz), 2.66 (1H, d, J=11.4 Hz), 2.12 (1H, td, J=11.3, 3.3 Hz), 1.84 (1H, t, J=10.4 Hz). LC/MS (Method C): 514 (M+H)+. HPLC (Method E) Rt 2.12 min (Purity: 99.9%).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7]([C:14]([NH2:16])=[O:15])=[CH:8][NH:9]2.[CH2:17]([S:21][C:22]1[N:27]=[C:26](Cl)[CH:25]=[CH:24][N:23]=1)[CH2:18][CH2:19][CH3:20]>CN(C=O)C>[CH2:17]([S:21][C:22]1[N:23]=[C:24]([N:9]2[C:10]3[C:6](=[C:5]([O:4][CH3:3])[CH:13]=[CH:12][CH:11]=3)[C:7]([C:14]([NH2:16])=[O:15])=[CH:8]2)[CH:25]=[CH:26][N:27]=1)[CH2:18][CH2:19][CH3:20]
Reactant: COc1cccc2[nH]cc(C(N)=O)c12
Reactant: CCCCSc1nccc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCSc1nccc(-n2cc(C(N)=O)c3c(OC)cccc32)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 98.8 %

Procedure:
NaH (397 mg, 9.94 mmol, 60% dispersion) was added to a solution of 4-methoxy-1H-indole-3-carboxylic acid amide (1.575 g, 8.28 mmol) in dry DMF (5 mL) at 0° C., stirred for 20 min, and a solution of 2-butylsulfanyl-4-chloro-pyrimidine (1.846 g, 9.108 mmol) in DMF (4 mL) added at 0° C. The mixture was allowed to warm up to RT without stirring, whereupon a solid precipitated. Dry THF (20 mL) was added, and the mixture stirred overnight. Water was added to the mixture, and the resulting white solid was filtered off, washed with water (20 mL) and DCM (20 mL), and air-dried for 3 h to provide 1-(2-butylsulfanyl-pyrimidin-4-yl)-4-methoxy-1H-indole-3-carboxylic acid amide (2.916 g, 98.8% yield) as a crude solid.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH:9]=[C:10]2[CH2:18][CH2:17][CH2:16][C:15]3[N:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:13]=[CH:12][C:11]2=3)[CH2:4][CH2:3]1>CCO.[Pd]>[CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH:10]2[CH2:18][CH2:17][CH2:16][C:15]3[N:14]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:13]=[CH:12][C:11]2=3)[CH2:4][CH2:3]1
Reactant: CC1CCN(CC=C2CCCc3c2cnn3-c2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC1CCN(CCC2CCCc3c2cnn3-c2ccccc2)CC1
Reaction time: 18 h
Yield: 39.6 %

Procedure:
Pd—C (100 mg, 20%) is added to a solution of a mixture of E/Z isomers of 4,5,6,7-tetrahydro-4-(2-(4-methylpiperidin-1-yl)ethylidene)-1-phenyl-1H-indazole (324 mg, 1.01 mmol) in 75 mL of EtOH, and the resulting solution is stirred in a nitrogen atmosphere (45 psi) in a Parr hydrogenator for 18 hours. The reaction mixture is purged with nitrogen, filtered through Celite and the solvent is evaporated under reduced pressure. The resulting crude product is purified by means of silica gel chromatography giving 4,5,6,7-tetrahydro-4-(2-(4-methylpiperidin-1-yl)ethyl)-1-phenyl-1H-indazole (130 mg, 0.40 mmol, 40%, oil).
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[F:14].[Cl:15][S:16](O)(=[O:18])=[O:17]>C(Cl)Cl>[Cl:1][C:2]1[S:3][C:4]([S:16]([Cl:15])(=[O:18])=[O:17])=[CH:5][C:6]=1[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[F:14]
Reactant: Fc1ccc(F)c(-c2ccsc2Cl)c1
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: O=S(=O)(Cl)c1cc(-c2cc(F)ccc2F)c(Cl)s1
Yield: 82.6 %

Procedure:
To a solution of 2-chloro-3-(2,5-difluorophenyl)thiophene (0.73 g, 3.2 mmol) in CH2Cl2 (100 mL), cooled on ice, chlorosulfonic acid (0.37 g, 3.2 mmol) in CH2Cl2 (50 mL) was added dropwise over 1 h. The reaction was refluxed over night. The reaction mixture was cooled and washed with water (2×100 mL) and brine, dried over MgSO4, filtered and concentrated to a dark brown oil. The oil was dissolved in heptane (50 mL) and stored in the fridge over the weekend. A black tar precipitated. The solution was decanted and concentrated to give the title compound as a light brown oil (0.87 g, 21% over two steps). MS (ESI+) m/z 293 [M−Cl]+.
Reaction SMILES: [CH3:1][CH:2]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>CCOCC>[CH2:16]([C:2]([CH3:1])([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCCCCCBr
Reactant: CCOC(=O)C(C)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: CCCCCCCCCCCCC(C)(C(=O)OCC)C(=O)OCC
Temperature: 80 °C
Reaction time: 8 h
Yield: 86.7 %

Procedure:
A solution of 48.72 g (0.277 mol) of diethyl methylmalonate (available from Aldrich Chem. Co., Catalog No. 12,613-6) in 60 ml of N1N-dimethyl formamide (DMF) is added dropwise to a stirred solution of 6.86 g (0.277 mol) of sodium hydride (NaH) in DMF. The reaction mixture is heated during the dropwise addition of a solution of 72.17 g (0.284 mol) of 1-bromododecane (Aldrich Chem. Co., catalog no. B6,555-1) in 60 ml DMF. The reaction is heated to 80° C. and stirred overnight, after which the NaBr that precipitated is filtered and the DMF removed in vacuo. The oily residue obtained is dissolved in ether and filtered again to remove all NaBr. The ether solution is washed with water followed by saturated NaCl. The solution is dried over anhydrous sodium sulfate and the ether is removed under reduced pressure to yield a clear, yellow oil. Fractional distillation (130°-138° C., 0.007 mm Hg) gives 82.28 g (88% overall yield) of diethyl dodecyl-methylmalonate as a clear oil. The oil is dissolved in 175 ml of anhydrous ether, and the solution is added dropwise to a suspension of 19.21 g (0.480 mol) of lithium aluminum hydride. The reaction is stirred overnight, carefully quenched, and filtered. The solvent is removed in vacuo and the solid obtained is recrystallized and dried to give 51.00 g (81% overall yield) of 2-dodecyl-2-methylpropane-1,3-diol as a white solid (mp 67°-68° C.).
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:10])[CH2:8][NH2:9])([CH3:5])([CH3:4])[CH3:3].C1(N=C=NC2CCCCC2)CCCCC1.[Br:26][C:27]1[CH:32]=[C:31]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:30]=[CH:29][C:28]=1[S:38][C@@H:39]([CH2:43][CH2:44][CH2:45][C:46]1[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][CH:47]=1)[C:40](O)=[O:41].CN1CCOCC1>ClCCl.O>[Br:26][C:27]1[CH:32]=[C:31]([CH:30]=[CH:29][C:28]=1[S:38][C@H:39]([C:40]([NH:9][CH2:8][C:7]([O:6][C:2]([CH3:5])([CH3:4])[CH3:3])=[O:10])=[O:41])[CH2:43][CH2:44][CH2:45][C:46]1[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][CH:47]=1)[C:33]([O:35][CH2:36][CH3:37])=[O:34]
Reactant: CC(C)(C)OC(=O)CN
Reactant: CCOC(=O)c1ccc(S[C@@H](CCCc2ccc(OC)cc2)C(=O)O)c(Br)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1ccc(S[C@@H](CCCc2ccc(OC)cc2)C(=O)NCC(=O)OC(C)(C)C)c(Br)c1
Reaction time: 1.5 h

Procedure:
Glycine tert-butyl ester hydrochloride (2.03 g) and dicyclohexylcarbodiimide (DCC) (2.5 g) were added to a solution of (2S)-2-{[2-bromo-4-(ethoxycarbonyl)phenyl]thio}-5-(4-methoxyphenyl)pentanoic acid (the compound of Reference Example 8) (96% e.e.) in dichloromethane (56.4 ml) at −5° C., and N-methylmorpholine (1.26 ml) was added dropwise thereto. After stirring at the same temperature for 1.5 hours, water was added thereto and the resulting mixture was filtered through Celite. The filtrate was extracted with chloroform and the extract solution was washed with a saturated aqueous ammonium chloride solution and a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The drying agent was removed by filtration and the solvent was distilled off under reduced pressure. The residue was purified by a silica gel column chromatography (hexane/ethyl acetate=3/1) to obtain ethyl 3-bromo-4-({(1S)-4-(4-methoxyphenyl)-1-[(tert-butoxycarbonylmethylamino)carbonyl]butyl}thio)benzoate (4.83 g, 98% e.e.). The optical purity analysis conditions are as follows. [Optical purity analysis conditions: column=AD-H (Chiralcel, DAICEL Chemical Industries Ltd.); detecting wavelength (UV)=254 nm; flow rate: 1.0 ml/min; mobile phase=n-hexane/isopropyl alcohol/TFA (90/10/0.1)]
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]2[CH:9]=[CH:10][N:11]=[C:7]2[CH:6]=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:4]=1.[I:18]N1C(=O)CCC1=O>C(#N)C.C(OCC)(=O)C>[I:18][C:9]1[N:8]2[C:3]([O:2][CH3:1])=[CH:4][C:5]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:6][C:7]2=[N:11][CH:10]=1
Reactant: O=C1CCC(=O)N1I
Reactant: COc1cc(-c2ccccc2)cc2nccn12
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1cc(-c2ccccc2)cc2ncc(I)n12

Procedure:
To a solution of 5-methoxy-7-phenylimidazo[1,2-a]pyridine (397 mg, 1.77 mmol) in acetonitrile (30 ml) was added N-iodosuccinimide (478 mg, 2.12 mmol). After 1 h the reaction mixture was diluted with ethyl acetate, washed with 1N aqueous sodium hydroxide and water, then dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate/isohexane gradient) to give 3-iodo-5-methoxy-7-phenylimidazo[1,2-a]pyridine. 1H NMR (600 MHz, DMSO-d6) δ 7.86 (d, 1H); 7.83 (d, 1H); 7.52-7.53 (m, 1H); 7.48-7.45 (m, 2H); 7.38-7.40 (m, 1H); 7.33-7.35 (m, 1H); 6.61 (d, 1H); 4.10 (s, 3H). LRMS (ESI) calculated for C14H12IN2O [M+H]+, 351.0 found 350.9.
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[NH2:15][C:16]1[N:21]=[CH:20][N:19]=[C:18]2[N:22]([CH:26]([C:28]3[C:29]([O:47][CH2:48][CH3:49])=[C:30]([CH:37]4[CH2:40][N:39]([C:41]([CH3:46])([CH3:45])[C:42](O)=[O:43])[CH2:38]4)[C:31]([C:35]#[N:36])=[C:32]([Cl:34])[CH:33]=3)[CH3:27])[N:23]=[C:24]([CH3:25])[C:17]=12.CN1CCOCC1.ClC(OCC(C)C)=O.[BH4-].[Na+]>O1CCCC1.O>[NH2:15][C:16]1[N:21]=[CH:20][N:19]=[C:18]2[N:22]([CH:26]([C:28]3[CH:33]=[C:32]([Cl:34])[C:31]([C:35]#[N:36])=[C:30]([CH:37]4[CH2:40][N:39]([C:41]([CH3:45])([CH3:46])[CH2:42][OH:43])[CH2:38]4)[C:29]=3[O:47][CH2:48][CH3:49])[CH3:27])[N:23]=[C:24]([CH3:25])[C:17]=12
Reactant: CCOc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C#N)c1C1CN(C(C)(C)C(=O)O)C1
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CCOc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C#N)c1C1CN(C(C)(C)CO)C1
Temperature: -15 °C
Reaction time: 0.25 h
Yield: 4.5 %

Procedure:
A solution of 2-(3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-cyano-2-ethoxyphenyl}azetidin-1-yl)-2-methylpropanoic acid bis(trifluoroacetate) (0.10 g, 0.16 mmol) in tetrahydrofuran (0.9 mL) was cooled to −25° C., treated with 4-methylmorpholine (0.072 mL, 0.65 mmol) and isobutyl chloroformate (0.085 mL, 0.65 mmol), and stirred at −15° C. for 15 min. The reaction mixture was filtered though a disposable filter cartridge into a separate round bottom flask. This solution was then cooled to −20° C. and a solution of sodium tetrahydroborate (0.031 g, 0.82 mmol) in a minimum amount of water was added dropwise. The reaction mixture was stirred at −15° C. for 30 min, poured into water, and extracted with ethyl acetate. The organic layer was separated, concentrated, diluted with methanol, and purified by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (3.5 mg, 4%). The product was isolated as a single enantiomer. 1H NMR (300 MHz, DMSO-d6) δ 8.11 (s, 1H), 7.50 (s, 1H), 7.35 (br s, 2H), 6.23 (q, J=6.7 Hz, 1H), 4.44-4.35 (m, 1H), 4.04-3.88 (m, 1H), 3.86-3.73 (m, 1H), 3.72-3.57 (m, 3H), 3.12 (d, J=4.7 Hz, 2H), 2.54 (s, 3H), 1.71 (d, J=6.9 Hz, 3H), 1.31 (t, J=6.9 Hz, 3H), 0.80 (s, 6H). LCMS for C24H31ClN7O2 (M+H)+: m/z=484.2; Found: 484.2.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:38])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]3[S:29][C:30]([C:33]([O:35]CC)=[O:34])=[CH:31][N:32]=3)=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[CH:11]=1.[OH-].[Na+].Cl.C(OCC)(=O)C>C(O)C>[CH3:1][O:2][CH2:3][C@H:4]([CH3:38])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]3[S:29][C:30]([C:33]([OH:35])=[O:34])=[CH:31][N:32]=3)=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[CH:11]=1
Reactant: CCOC(=O)c1cnc(-c2ccc(-c3cc(Oc4ccc(S(C)(=O)=O)cc4)cc(O[C@@H](C)COC)c3)[nH]2)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(-c3ncc(C(=O)O)s3)[nH]2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 103.5 %

Procedure:
Ethyl 2-(5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-1,3-thiazole-5-carboxylate (53.5 mg, 0.096 mmol) synthesized in Example (5c) was dissolved in ethanol (4 mL). An aqueous sodium hydroxide solution (5M, 2 mL) was added, and stirring was carried out at 70° C. for 30 minutes. After cooling to room temperature, hydrochloric acid (2M, 5 mL) and ethyl acetate (10 mL) were added, and the solution was separated. The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, to afford the desired compound (52.5 mg, yield ˜100%) as a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH2:23][CH2:24][CH3:25])=[C:6]([CH:21]=1)[CH2:7][N:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([O:19]C)=[O:18])=[CH:13][N:12]=1)[CH2:9][CH3:10].[OH-].[Na+]>C1COCC1.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH2:23][CH2:24][CH3:25])=[C:6]([CH:21]=1)[CH2:7][N:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][N:12]=1)[CH2:9][CH3:10]
Reactant: CCCOc1ccc(Br)cc1CN(CC)c1ccc(C(=O)OC)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCOc1ccc(Br)cc1CN(CC)c1ccc(C(=O)O)cn1
Temperature: 40 °C
Yield: 87.7 %

Procedure:
A solution of methyl 2-[N-(5-bromo-2-propoxybenzyl)-N-ethylamino]pyridine-5-carboxylate (reference example 1) (0.12 g, 0.29 mmol) in THF (3 ml) and methanol (3 ml) was treated with aqueous sodium hydroxide (1N, 1.8 ml). The reaction was heated to 40° C. for 18 hours. The solvent was then evaporated off and the residue diluted with water (3 ml) and acidified with acetic acid (1N, 3 ml). The solid was filtered off to give the title compound (0.1 g, 88%) as a white solid.