Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH:23]1([C:29]2[C:30]3[CH:31]=[CH:32][C:33]([C:50]([O:52][CH3:53])=[O:51])=[CH:34][C:35]=3[N:36]3[CH2:42][C:41]([C:43](O)=[O:44])=[CH:40][C:39]4[CH:46]=[CH:47][CH:48]=[CH:49][C:38]=4[C:37]=23)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.CCN(C(C)C)C(C)C.Cl.Cl.[CH3:65][N:66]1[CH2:72][CH:71]2[NH:73][CH:68]([CH2:69][CH2:70]2)[CH2:67]1>CN(C=O)C>[CH:23]1([C:29]2[C:30]3[CH:31]=[CH:32][C:33]([C:50]([O:52][CH3:53])=[O:51])=[CH:34][C:35]=3[N:36]3[CH2:42][C:41]([C:43]([N:73]4[CH:68]5[CH2:69][CH2:70][CH:71]4[CH2:72][N:66]([CH3:65])[CH2:67]5)=[O:44])=[CH:40][C:39]4[CH:46]=[CH:47][CH:48]=[CH:49][C:38]=4[C:37]=23)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C(=O)O)=Cc1ccccc1-3
Reactant: CN1CC2CCC(C1)N2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C(=O)N1C2CCC1CN(C)C2)=Cc1ccccc1-3

Procedure:
TBTU (115 mg, 0.361 mmol) was added at rt, in one portion, to a solution containing 13-cyclohexyl-10-(methoxycarbonyl)-7H-indolo[2,1-a][2]benzazepine-6-carboxylic acid (100 mg, 0.241 mmol), DIEA (0.17 mL, 0.964 mmol), 3-Methyl-3,8-diaza-bicyclo[3.2.1]octane dihydrochloride (115 mg, 0.289 mmol), and DMF (2.4 mL). The solution was maintained for 18 h and concentrated. The resultant residue was charged with dichloromethane (30 mL), washed with water (4×15 mL), washed with brine (15 mL), dried (magnesium sulfate), filtered and concentrated to afford a yellow solid which was used without further purification in the next step. LCMS: retention time: 2.272 min LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where solvent A was 5% CH3CN/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% CH3CN/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode: m/z 524 (MH+). Crude 1H NMR (300 MHz, CDCl3) δ ppm: 8.19 (s, 1H), 7.92 (d, J=8.4 Hz, 1H), 7.77 (dd, J=8.78 Hz, J=1.46 Hz, 1H), 7.61 (m, 1H), 7.49 (m, 3H), 6.96 (s, 1H), 5.2 (s, 1H), 4.41 (s, 1H), 2.81 (m, 4H), 2.51 (s, 1H), 1.95 (m, 15H), 1.29 (m, 11H), 0.76 (m, 2H).
Reaction SMILES: [C:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCN(CC)CC.[C:23]1([S:33](Cl)(=[O:35])=[O:34])[C:24]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:26]=[CH:27][CH:28]=1>C(Cl)Cl>[O:34]=[S:33]1(=[O:35])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[S:29](=[O:30])(=[O:31])[N:15]1[C:12]1[CH:11]=[CH:10][C:9]([NH:8][C:1](=[O:2])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[CH:14][CH:13]=1
Reactant: O=S(=O)(Cl)c1ccccc1S(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ccc(N2S(=O)(=O)c3ccccc3S2(=O)=O)cc1

Procedure:
A solution of N-Boc-p-phenylenediamine (0.68 g, 3.26 mmol) and Et3N (0.51 mL, 7.19 mmol) in dry DCM (29 mL) was added to a refluxing solution of 1,2-benzenedisulfonyl dichloride (0.90 g, 3.27 mmol) in DCM (135 mL). After the addition was complete, the reaction solution was maintained at reflux for an additional 2 h. The heat was removed and after 16 h at rt, the solvent was removed under reduced pressure. The residue of the crude reaction mixture was dissolved in DCM and washed with saturated NaHCO3, brine, and dried. After filtration and concentration under reduced pressure yielding tert-butyl (4-(1,1,3,3-tetraoxidobenzo[d][1,3,2]dithiazol-2-yl)phenyl)carbamate, 1.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6]([NH2:10])=[CH:7][CH:8]=[CH:9][C:2]1=2.N1C=CC=CC=1.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C(Cl)Cl>[S:1]1[CH:5]=[CH:4][C:3]2[C:6]([NH:10][S:18]([CH3:17])(=[O:20])=[O:19])=[CH:7][CH:8]=[CH:9][C:2]1=2
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cccc2sccc12
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cccc2sccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.8 %

Procedure:
To a stirred solution of benzo[b]thiophen-4-amine (1 g, 6.70 mmol) and pyridine (1.355 mL, 16.75 mmol) in CH2Cl2 (15 mL) was added dropwise methanesulfonyl chloride (0.574 mL, 7.37 mmol) at 0° C. under nitrogen atmosphere. The reaction mixture was then allowed to warm to room temperature while stirring overnight. The reaction mixture was washed with saturated sodium bicarbonate solution, water, brine and dried over sodium sulfate. Evaporation of the solvent furnished a crude residue, which was subjected to BIOTAGE® (100% methylene chloride) to give the title compound as a white solid (1.2 g, 79%). LC/MS: Example 105A @ 2.88 min (RT) (Condition H). MS (ES): m/z=226.0, [M+H]+. 1H NMR (400 MHz, MeOD) δ ppm 7.77 (1 hr, d, J=7.81 Hz), 7.59 (2 hr, d, J=1.26 Hz), 7.25-7.42 (2 hr, m), 2.94 (3 hr, s).
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([CH3:7])[CH2:5][OH:6].Cl[C:9]1[N:14]=[CH:13][N:12]=[C:11]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[C:25]([F:30])[CH:24]=3)=[O:22])[CH2:17][CH2:16]2)[CH:10]=1>CN(C=O)C>[F:30][C:25]1[CH:24]=[C:23]([C:21]([N:18]2[CH2:19][CH2:20][N:15]([C:11]3[CH:10]=[C:9]([O:6][CH2:5][CH:4]([CH3:7])[CH3:3])[N:14]=[CH:13][N:12]=3)[CH2:16][CH2:17]2)=[O:22])[CH:28]=[CH:27][C:26]=1[CH3:29]
Reactant: Cc1ccc(C(=O)N2CCN(c3cc(Cl)ncn3)CC2)cc1F
Reactant: CC(C)CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)N2CCN(c3cc(OCC(C)C)ncn3)CC2)cc1F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a suspension of sodium hydride (60% in mineral oil, 20 mg, 0.52 mmol) in DMF was added 2-methylpropan-1-ol (39 mg, 0.52 mmol) at rt. After stirring at rt for 15 min, (4-(6-chloropyrimidin-4-yl)piperazin-1-yl)(3-fluoro-4-methylphenyl)methanone (35 mg, 0.11 mmol) was added to the mixture. After stirring at rt for 12 h, the mixture was poured onto water (5 mL), and the aqueous phase was extracted with dichloromethane (three times). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative LC-MS to give 14.4 mg (37% yields) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:19])[C:10]=2[O:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[N:5]=[CH:4][N:3]=1.O[CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:19][CH2:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]3)[C:10]=2[O:12][CH:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)[N:5]=[CH:4][N:3]=1
Reactant: CN1CCN(CCCO)CC1
Reactant: Oc1ccc2ncnc(Cl)c2c1OC1CCOCC1
Product: CN1CCN(CCCOc2ccc3ncnc(Cl)c3c2OC2CCOCC2)CC1

Procedure:
Using an analogous procedure to that described in the last paragraph of the portion of Note [10] immediately above that is concerned with the preparation of starting materials, 4-chloro-6-hydroxy-5-tetrahydropyran-4-yloxyquinazoline (1.12 g) was reacted with 1-(3-hydroxypropyl)-4-methylpiperazine to give 4-chloro-6-[3-(4-methylpiperazin-1-yl)propoxy]-5-tetrahydropyran-4-yloxyquinazoline (0.56 g); NMR Spectrum: (CDCl3) 1.85–2.2 (m, 6H), 2.32 (s, 3H), 2.35–2.7 (m, 10H), 3.42 (m, 2H), 4.05 (m, 2H), 4.25 (m, 2H), 4.65 (m, 1H), 7.75 (d, 1H), 7.85 (d, 1H), 8.9 (s, 1H); Mass Spectrum: M+H+ 421 and 423.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1Br)(=[O:3])[CH3:2].[N:27]1[CH:32]=[CH:31][CH:30]=[C:29](B(O)O)[CH:28]=1>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:29]1[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccccc1Br
Reactant: OB(O)c1cccnc1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccccc1-c1cccnc1

Procedure:
By carrying out the operation analogously to example 1, starting from 2-bromophenyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation IV, and 3-pyridineboronic acid, the expected compound is obtained. The latter was not isolated and is used directly in the following stage.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>>[F:32][C:33]1[CH:38]=[CH:37][C:36]([C:12]2[N:13]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:14]=[C:15]3[C:11]=2[CH2:10][CH2:9][NH:8][CH2:17][CH2:16]3)=[CH:35][CH:34]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(-c3ccccc3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Product: Fc1ccc(-c2c3c(nn2-c2ccccc2)CCNCC3)cc1
Yield: 50.8 %

Procedure:
The title compound (70.0 mg) was prepared from 207.0 mg of 2-phenyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 176, Step B) and 98.5 mg of 4-fluorophenylboronic acid as in Example 199. MS (ESI): exact mass calculated for C19H18FN3, 307.15. found, m/z 308.2 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.28-7.24 (m, 2H), 7.22-7.16 (m, 3H), 7.13-7.10 (m, 2H), 7.05-7.01 (m, 2H), 3.12-3.08 (m, 2H), 3.05-3.02 (m, 2H), 3.01-2.98 (m, 2H), 2.68-2.64 (m, 2H).
Reaction SMILES: Br.[N:2]1([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH2:11]3)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[C:30](Cl)=[O:31].O>CN(C)C=O>[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[C:30]([N:5]1[CH2:6][CH2:7][N:2]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH2:11]3)[CH2:3][CH2:4]1)=[O:31]
Reactant: O=C1Cc2cc(N3CCNCC3)ccc2N1
Reactant: COc1ccc(C(=O)Cl)cc1OC
Agent: Br
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)N2CCN(c3ccc4c(c3)CC(=O)N4)CC2)cc1OC
Yield: 58.6 %

Procedure:
5-(1-Piperazinyl)oxindol.hydrobromide (2.0 g) was suspended in 30 ml of N,N-dimethylformamide (DMF), and 2.3 ml of triethylamine was added thereto subsequently. The mixture was cooled to 0° to 5° C. To the mixture was added dropwise 5 ml of DMF solution containing 1.5 g of 3,4-dimethoxybenzoyl chloride at the same temperature as above with stirring. After completion of addition, the mixture was stirred at room temperature for one hour. The reaction mixture was poured into a large amount of water and extracted with chloroform. After washing with water, the extract was dried over anhydrous sodium sulfate and chloroform was removed by distillation. The residue was purified by silica-gel column chromatography (eluent: chloroform:methanol=100:1) and recrystallized from methanol to give 1.5 g of 5-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]oxindol.
Reaction SMILES: B(F)(F)F.CCOCC.[BH4-].[Na+].[CH3:12][O:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([C:22]2[O:23][C:24]([CH3:32])=[C:25]([CH2:27][CH2:28][C:29](O)=[O:30])[N:26]=2)=[CH:18][CH:17]=1)=[O:15]>O1CCCC1>[OH:30][CH2:29][CH2:28][CH2:27][C:25]1[N:26]=[C:22]([C:19]2[CH:18]=[CH:17][C:16]([C:14]([O:13][CH3:12])=[O:15])=[CH:21][CH:20]=2)[O:23][C:24]=1[CH3:32]
Reactant: COC(=O)c1ccc(-c2nc(CCC(=O)O)c(C)o2)cc1
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)c1ccc(-c2nc(CCCO)c(C)o2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
Boron trifluoride etherate (4 g) was added dropwise with stirring to a mixture of sodium borohydride (720 mg, 19.03 mmol, 2.02 equiv) in tetrahydrofuran (35 mL) maintained under nitrogen at 0° C. The resulting solution was warmed to room temperature and stirred for 2 h. The above mixture was cooled to 0° C. then 3-[2-[4-(methoxycarbonyl)phenyl]-5-methyl-1,3-oxazol-4-yl]propanoic acid (2.72 g, 9.40 mmol, 1.00 equiv) was added in several batches. The reaction mixture was stirring at room temperature overnight and then quenched with 5 mL of methanol and 60 mL of water. The resulting solution was extracted with 50 mL of ethyl acetate. The organic layer was dried over anhydrous calcium chloride and concentrated under vacuum to give 2.2 g (85%) of methyl 4-[4-(3-hydroxypropyl)-5-methyl-1,3-oxazol-2-yl]benzoate as a white solid. LC-MS: (ES, m/z): 276 [M+H]+, 146, 115.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1([NH2:15])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5].[CH3:16][O:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][C:19]=1[N+:27]([O-:29])=[O:28].CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[CH3:2][O:3][C:4]([C:6]1([NH:15][C:22](=[O:23])[C:21]2[CH:25]=[CH:26][C:18]([O:17][CH3:16])=[C:19]([N+:27]([O-:29])=[O:28])[CH:20]=2)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5]
Reactant: COc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: COC(=O)C1(N)Cc2ccccc2C1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)C1(NC(=O)c2ccc(OC)c([N+](=O)[O-])c2)Cc2ccccc2C1
Temperature: 60 °C
Yield: 65.6 %

Procedure:
To 2-amino-indane-2-carboxylic acid methyl ester hydrochloride (0.40 g, 1.77 mmol) and 4-methoxy-3-nitrobenzoic acid (0.35 g, 1.77 mmol) in 4 ml of DMF were added NMM (0.59 ml, 5.32 mmol), HOBT (0.31 g, 2.31 mmol) and EDC (0.44 g, 2.31 mmol). The mixture was stirred at 60° C. until LC/MS analysis showed complete conversion. The crude product was purified by silica gel chromatography (HEP/EA gradient) to give 0.43 g of the title compound.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][NH:6][C:7](=O)OC(C)(C)C)#[N:2].[C:14]([O:18][C:19]([NH:21][CH2:22][CH2:23][C:24]1[C:25]([C:36]2[CH:37]=[C:38]3[C:43](=[CH:44][CH:45]=2)[CH:42]=[N:41][CH:40]=[CH:39]3)=[N:26][O:27][C:28]=1[NH:29][C:30](=O)OCC=C)=[O:20])([CH3:17])([CH3:16])[CH3:15].C1C2[C:50](=[CH:51][C:52](C3C=C(NC(=O)OCC=C)ON=3)=CC=2)[CH:49]=[CH:48]N=1>>[NH2:2][C@@H:1]([CH2:3][C:4]1[C:52]2[C:7](=[CH:48][CH:49]=[CH:50][CH:51]=2)[NH:6][CH:5]=1)[CH2:30][NH:29][C:28]1[O:27][N:26]=[C:25]([C:36]2[CH:37]=[C:38]3[C:43](=[CH:44][CH:45]=2)[CH:42]=[N:41][CH:40]=[CH:39]3)[C:24]=1[CH2:23][CH2:22][NH:21][C:19](=[O:20])[O:18][C:14]([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)NCCCC#N
Reactant: C=CCOC(=O)Nc1cc(-c2ccc3cnccc3c2)no1
Reactant: C=CCOC(=O)Nc1onc(-c2ccc3cnccc3c2)c1CCNC(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)NCCc1c(-c2ccc3cnccc3c2)noc1NC[C@@H](N)Cc1c[nH]c2ccccc12

Procedure:
This compound was synthesized in an analogous manner to Example 32 but using tert-butyl 3-cyanopropylcarbamate instead of acetonitrile in the preparation of 2-propen-1-yl (4-(2-((tert-butoxycarbonyl)amino)ethyl)-3-(6-isoquinolinyl)-5-isoxazolyl)carbamate according to Scheme 6 instead of allyl 3-(isoquinolin-6-yl)isoxazol-5-ylcarbamate. MS m/z: 527 (M+1); 1H NMR (400 MHz, CD3OD) δ ppm 9.75 (s, 1H), 8.63 (d, J=6.26 Hz, 1H), 8.51-8.57 (m, 3H), 8.20 (d, J=8.61 Hz, 1H), 7.61 (d, J=8.02 Hz, 1H), 7.40 (d, J=8.22 Hz, 1H), 7.26-7.29 (m, 1H), 7.15 (t, J=7.53 Hz, 1H), 7.08 (t, J=7.43 Hz, 1H), 3.73-3.86 (m, 3H), 3.13-3.24 (m, 4H), 2.62 (t, J=6.94 Hz, 2H), 1.33 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][S:9][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[OH:17])[N:7]1[C:18](=[O:24])[CH2:19][CH2:20][C:21](O)=[O:22])=[O:5])[CH3:2].CN1CCOCC1.[NH2:32][OH:33].Cl>O1CCCC1.ClC(OCC(C)C)=O.CO>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][S:9][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[OH:17])[N:7]1[C:18](=[O:24])[CH2:19][CH2:20][C:21](=[O:22])[NH:32][OH:33])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CSC(c2ccccc2O)N1C(=O)CCC(=O)O
Reactant: NO
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: CO
Product: CCOC(=O)[C@@H]1CSC(c2ccccc2O)N1C(=O)CCC(=O)NO
Reaction time: 2 h
Yield: 63.3 %

Procedure:
To a stirred solution of (4R)-3-(3-carboxypropanoyl)-2-(2-hydroxyphenyl)-4-thiazolidinecarboxylic acid ethyl ester (compound 8a) (1.06 g) and N-methylmorpholine (0.33 ml) in 20 ml of anhydrous tetrahydrofuran, isobutyl chloroformate (0.39 ml) was added dropwise at -15° C., and stirred for additional 2 hours at this temperature. To this solution, the methanol solution of hydroxylamine (0.3 g) was added dropwise at -50° C. The reaction mixture was stirred for 1 hour at room temperature, acidified with N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residual oil was purified by silica gel column chlromatography to give 0.7 g (63%) of the titled compound. IR (KBr, cm-1) 3220, 1727, 1625, 1595, 1200, 1092, 753. NMR (acetone-d6, δ): 1.24 (3H, t, J=7.5 Hz, CO2CH2CH3), 2.17-3.07 (4H, m, CO--CH2)2CO), 3.30 (1H, ABq (A part), d, J=10.0, 2.0 Hz, C5 --HA), 3.47 (1H, ABq (B part), d, J=10.0, 7.0 Hz, C5 --HB), 4.14 (2H, q, J=7.5 Hz, CO2CH2), 5.18 (1H, dd, J=2.0, 7.0 Hz, C4 --H), 6.40 (1H, S, C2 --H), 6.88-7.27 (4H, m, arom. H), 8.60 (2H, br. s, NHOH), 9.77 (1H, br. s, OH )
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([NH:13][C:14](=[O:17])[CH2:15][OH:16])[S:11][CH:12]=2)=[CH:4][CH:3]=1.CO[C:20](OC)([CH3:22])[CH3:21].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([N:13]3[C:14](=[O:17])[CH2:15][O:16][C:20]3([CH3:22])[CH3:21])[S:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: O=C(CO)Nc1nc(-c2ccc(Br)cc2)cs1
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C)OCC(=O)N1c1nc(-c2ccc(Br)cc2)cs1
Temperature: 90 °C
Yield: 53.1 %

Procedure:
N-[4-(4-Bromophenyl)-1,3-thiazol-2-yl]-2-hydroxyacetamide (0.35 g, 1.12 mmol), prepared in the previous step, was suspended in 10 mL of toluene, dimethoxypropane (2.0 mL, 16.7 mmol) was added, which was followed by a catalytic amount of p-toluenesulfonic acid monohydrate (20 mg). The mixture was heated to 90° C. for 16 h, then cooled and concentrated under reduced pressure. Flash chromatography (5% acetone/hexane) provided the title compound (210 mg, 53%) as a white solid. HRMS: calcd for C14H13BrN2O2S+H+, 352.99538; found (ESI, [M+H]+), 352.9957. Analytical HPLC: retention time 11.1 min, 210-370 nm the Xterra® RP18 column, 3.5μ, 150×4.6 mm 40° C. 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min, 1.2 mL/min 5 μL injection.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](Cl)=[N:7]2.[CH3:13][O:14][C:15]1[C:20]2[C:21](=[N:24]O)[CH2:22][O:23][C:19]=2[CH:18]=[CH:17][CH:16]=1.[NH2:26][CH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[CH3:13][O:14][C:15]1[C:20]2[CH:21]([NH:24][C:6]3[CH:5]=[CH:4][C:3]4[C:2]([NH:26][CH:27]5[CH2:32][CH2:31][O:30][CH2:29][CH2:28]5)=[CH:11][CH:10]=[CH:9][C:8]=4[N:7]=3)[CH2:22][O:23][C:19]=2[CH:18]=[CH:17][CH:16]=1
Reactant: Clc1ccc2c(I)cccc2n1
Reactant: COc1cccc2c1C(=NO)CO2
Reactant: NC1CCOCC1
Product: COc1cccc2c1C(Nc1ccc3c(NC4CCOCC4)cccc3n1)CO2

Procedure:
The title compound, light yellow foam, MS: m/e=392.3 (M+H+), was prepared in accordance with the general method of example 1 from 5-iodo-2-chloroquinoline, (RS)-4-methoxy-2,3-dihydro-benzofuran-3-ylamine (example 39, step A and B) and commercially available 4-amino-tetrahydropyran.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[O:5])#[N:2].[H-].[Na+].C([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22](=O)[CH:23]=[C:24]([S:27][CH3:28])SC)C1C=CC=CC=1.C[CH:31]([OH:33])[CH3:32]>Cl>[CH2:31]([O:33][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[NH:6][C:4](=[O:5])[C:3](=[C:24]([S:27][CH3:28])[CH:23]=1)[C:1]#[N:2])[C:32]1[CH:20]=[CH:21][CH:16]=[CH:17][CH:18]=1
Reactant: CSC(=CC(=O)c1ccccc1Cc1ccccc1)SC
Reactant: N#CCC(N)=O
Reactant: CC(C)O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: CSc1cc(-c2ccccc2OCc2ccccc2)[nH]c(=O)c1C#N
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 84 %

Procedure:
To a suspension of cyanoacetamide (1.27 g, 15.1 mmol) in 2-propanol (50 mL) was added sodium hydride (60% suspension, 0.605 g, 15.1 mmol). The mixture was stirred at room temperature for 10 min. To this mixture, 1-[2-(benzyl)phenyl]-3,3-bis(methylthio)-2-propene-1-one (5.00 g, 15.1 mmol) was added in one portion. The resulting mixture was refluxed for 4 hrs. After being cooled to room temperature, the mixture was diluted with 1N HCl. The resulting precipitates were collected by filtration and washed with EtOH to give 6-[2-(benzyloxy)phenyl]-4-(methylthio)-2-oxo-1,2-dihydro-nicotinonitrile as a yellow crystalline solid (4.43 g, yield; 84%).
Reaction SMILES: [C@H:1]12[CH2:9][C@H:5]([O:6][C:7]1=[O:8])[CH2:4][O:3][CH2:2]2.[OH-:10].[Na+].Cl>CO>[OH:10][C@H:5]1[CH2:4][O:3][CH2:2][C@@H:1]([C:7]([OH:6])=[O:8])[CH2:9]1
Reactant: [OH-]
Reactant: O=C1O[C@@H]2COC[C@H]1C2
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=C(O)[C@@H]1COC[C@H](O)C1

Procedure:
A solution of 25.5 mmol of (cis)-3,6-dioxabicyclo[3.2.1]-octan-7-one in 500 ml of methanol is adjusted to pH 9 with 0.1M NaOH. The solution is stirred at constant pH until conversion is complete, and is adjusted to pH 6.5 with 0.1 M HCl before the methanol is evaporated off. The title compound is identified from the aqueous solution by means of the Rf by ion exchange chromatography (Amberlite XAD-2 resin).
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:17])=[CH:4][C:5]([O:11][C@H:12]([CH2:14][CH:15]=[CH2:16])[CH3:13])=[C:6](B(O)O)[CH:7]=1.[CH2:18]([O:21][C:22]1([CH3:55])[CH2:27][CH2:26][N:25]([C:28]2[N:33]3[CH:34]=[C:35]([C:37]4[CH:42]=[CH:41][CH:40]=[C:39](Br)[CH:38]=4)[N:36]=[C:32]3[CH:31]=[C:30]([CH3:44])[C:29]=2[C@H:45]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])[C:46]([O:48][CH3:49])=[O:47])[CH2:24][CH2:23]1)[CH:19]=[CH2:20].C(OC1(C)CCN(C2N3C=C(C4C=C(C5C=CC(F)=CC=5O[C@H](CC=C)C)C=CC=4)N=C3C=C(C)C=2[C@H](OC(C)(C)C)C(OC)=O)CC1)C=C>>[CH2:18]([O:21][C:22]1([CH3:55])[CH2:23][CH2:24][N:25]([C:28]2[N:33]3[CH:34]=[C:35]([C:37]4[CH:38]=[C:39]([C:6]5[CH:7]=[C:2]([F:1])[C:3]([CH3:17])=[CH:4][C:5]=5[O:11][C@H:12]([CH2:14][CH:15]=[CH2:16])[CH3:13])[CH:40]=[CH:41][CH:42]=4)[N:36]=[C:32]3[CH:31]=[C:30]([CH3:44])[C:29]=2[C@H:45]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])[C:46]([O:48][CH3:49])=[O:47])[CH2:26][CH2:27]1)[CH:19]=[CH2:20]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(-c4cccc(Br)c4)cn23)CC1
Reactant: C=CC[C@H](C)Oc1cc(C)c(F)cc1B(O)O
Agent: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(-c4cccc(-c5ccc(F)cc5O[C@@H](C)CC=C)c4)cn23)CC1
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(-c4cccc(-c5cc(F)c(C)cc5O[C@@H](C)CC=C)c4)cn23)CC1
Yield: 72 %

Procedure:
Prepared in 72% yield from (S)-(5-fluoro-4-methyl-2-(pent-4-en-2-yloxy)phenyl)boronic acid and (S)-methyl 2-(5-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(3-bromophenyl)-7-methylimidazo[1,2-a]pyridin-6-yl)-2-(tert-butoxy)acetate following the procedure for (S)-methyl 2-(5-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(4′-fluoro-2′-((S)-pent-4-en-2-yloxy)-[1,1′-biphenyl]-3-yl)-7-methylimidazo[1,2-a]pyridin-6-yl)-2-(tert-butoxy)acetate. 1H NMR (400 MHz, CDCl3) δ 8.02 (s, 2H), 7.96-7.92 (m, 1H), 7.56-7.51 (m, 1H), 7.48-7.41 (m, 1H), 7.32 (s, 1H), 7.14-7.09 (m, 1H), 6.81 (d, J=6.5 Hz, 1H), 6.14-5.96 (m, 2H), 5.72 (ddt, J=17.1, 10.2, 7.0 Hz, 1H), 5.43 (dd, J=17.3, 1.8 Hz, 1H), 5.12-4.95 (m, 3H), 4.22-4.10 (m, 1H), 4.07-3.94 (m, 3H), 3.82 (t, J=10.5 Hz, 1H), 3.69 (s, 3H), 3.02 (d, J=7.8 Hz, 1H), 2.73 (d, J=8.5 Hz, 1H), 2.47 (d, J=0.8 Hz, 3H), 2.40-2.33 (m, 1H), 2.31 (d, J=1.5 Hz, 3H), 2.28-2.17 (m, 1H), 1.98 (dd, J=13.9, 2.6 Hz, 2H), 1.86-1.72 (m, 2H), 1.33 (s, 3H), 1.27 (s, 9H), 1.14 (d, J=6.0 Hz, 3H); LCMS (ESI, M+1): 698.35.