Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([S:24]([NH:27][C:28]2[S:32][N:31]=[CH:30][N:29]=2)(=[O:26])=[O:25])=[CH:4][C:5]2[O:9][C:8](=[O:10])[N:7]([CH2:11][C:12]3[C:21]4[CH2:20][C:19](=O)[CH2:18][CH2:17][C:16]=4[CH:15]=[CH:14][CH:13]=3)[C:6]=2[CH:23]=1.[ClH:33].[F:34][C:35]1([F:39])[CH2:38][NH:37][CH2:36]1.CCN(C(C)C)C(C)C.C(O)(=O)C.C([BH3-])#N.[Na+]>CO.CS(C)=O.C(O)(C(F)(F)F)=O.O.CN(C=O)C>[ClH:33].[F:34][C:35]1([F:39])[CH2:38][N:37]([CH:19]2[CH2:20][C:21]3[C:12]([CH2:11][N:7]4[C:6]5[CH:23]=[C:2]([F:1])[C:3]([S:24]([NH:27][C:28]6[S:32][N:31]=[CH:30][N:29]=6)(=[O:25])=[O:26])=[CH:4][C:5]=5[O:9][C:8]4=[O:10])=[CH:13][CH:14]=[CH:15][C:16]=3[CH2:17][CH2:18]2)[CH2:36]1
Reactant: FC1(F)CNC1
Reactant: O=C1CCc2cccc(Cn3c(=O)oc4cc(S(=O)(=O)Nc5ncns5)c(F)cc43)c2C1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CO
Solvent: CC(=O)O
Product: O=c1oc2cc(S(=O)(=O)Nc3ncns3)c(F)cc2n1Cc1cccc2c1CC(N1CC(F)(F)C1)CC2
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a vial was added 5-fluoro-2-oxo-3-((7-oxo-5,6,7,8-tetrahydronaphthalen-1-yl)methyl)-N-(1,2,4-thiadiazol-5-yl)-2,3-dihydrobenzo[d]oxazole-6-sulfonamide (19-5) (41 mg, 0.086 mmol), then DMF (0.6 mL) followed by 3,3-DIFLUOROAZETIDINE HYDROCHLORIDE (38 mg, 0.293 mmol), then DIPEA (100 μL, 0.573 mmol). The reaction mixture was then permitted to stir at room temperature for 20 minutes, then added ACETIC ACID (150 μL, 2.62 mmol). The reaction mixture was then permitted to stir at room temperature for 2 hrs (capped, but not under N2). Followed by LC/MS. After 2 hours at room temperature added SODIUM CYANOBOROHYDRIDE (33 mg, 0.525 mmol) in one portion to the reaction mixture at room temperature. After another hour at room temperature; the reaction mixture was diluted with MeOH/DMSO/drops TFA/drops H2O, stirred for ˜10 minutes, then filtered (syringe filter), then purified (without workup) by reverse phase chromatography (5-65% MeCN/H2O; 0.1% TFA in AQ; 20 min gradient; Waters 30×150 mm Sunfire 5 micron C18 column); desired fractions concentrated (GENEVAC), then dissolved in MeOH/DCM & added a saturated solution of HCl in EtOAc (˜4N) & concentrated to yield 3-((7-(3,3-difluoroazetidin-1-yl)-5,6,7,8-tetrahydronaphthalen-1-yl)methyl)-5-fluoro-2-oxo-N-(1,2,4-thiadiazol-5-yl)-2,3-dihydrobenzo[d]oxazole-6-sulfonamide hydrochloride (19-6). HRMS [M+H] calculated; 552.0982, observed; 552.0982. 1H NMR (400 MHz, CD3 OD): δ 8.21 (s, 1H); 7.79 (d, J=5.5 Hz, 1H); 7.24-7.18 (m, 3H); 7.01 (d, J=9.3 Hz, 1H); 5.18-5.01 (m, 2H); 4.99-4.88 (m, 4H); 3.83-3.74 (m, 1H); 3.44-3.40 (m, 1H); 3.03-2.94 (m, 2H); 2.69-2.59 (m, 1H); 2.29-2.22 (m, 1H); 1.79-1.67 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][S:5][C:6]=1[C:7]1[S:8][CH:9]=[C:10]([CH2:12][OH:13])[N:11]=1>C(Cl)Cl.CO.O=[Mn]=O>[CH3:1][C:2]1[N:3]=[N:4][S:5][C:6]=1[C:7]1[S:8][CH:9]=[C:10]([CH:12]=[O:13])[N:11]=1
Reactant: Cc1nnsc1-c1nc(CO)cs1
Agent: O=[Mn]=O
Solvent: CO
Solvent: ClCCl
Product: Cc1nnsc1-c1nc(C=O)cs1

Procedure:
A mixture of [2-(4-methyl[1,2,3]thiadiazol-5-yl)thiazol-4-yl]methanol (1.06 g; 4.97 mmol) and MnO2 (8.64 g; 99.39 mmol) in CH2Cl2 (100 ml) and methanol (10 ml) was refluxed for 6 hours.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][O:10][CH3:11])=[CH:4][CH:3]=1.[Li]CCCC.CON(C)[C:20](=[O:30])[CH:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:22][CH3:23].O>C1COCC1>[CH3:11][O:10][CH2:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:20](=[O:30])[CH:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:22][CH3:23])=[CH:3][CH:4]=1
Reactant: CCC(C(=O)N(C)OC)c1ccccc1
Reactant: COCOc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCC(C(=O)c1ccc(OCOC)cc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.8 %

Procedure:
To a stirred solution of 13 (99.0 g, 0.46 mol) in anhydrous THF (750 mL) was added n-BuLi (1.6 M in hexanes, 310 mL, 0.50 mol) dropwise at −78° C. The reaction mixture was stirred for 30 min and 14 (90.1 g, 0.43 mol) dissolved in THF (500 mL) was added dropwise. The reaction mixture was stirred at −78° C. for 1 h and then slowly warmed to 0° C. H2O (500 mL) was added and the volatiles were removed under reduced pressure. The residue was extracted with Et2O (3×500 mL) and the combined extracts were washed with water (500 mL) and brine (500 mL). The mixture was dried over MgSO4 and concentrated. The residue was recrystallized from hexanes to afford 97.6 g (80%) of 15 as white needles. 1HNMR (400 MHz, DMSO-d6): δ 0.79 (t, J=7.3 Hz, 3H), 1.68 (h, J=7.0 Hz, 1H), 2.03 (h, J=7.0 Hz, 1H), 3.32 (s, 3H), 4.65 (t, J=7.3 Hz, 1H), 5.21 (s, 2H), 7.03 (d, J=8.8 Hz, 2H), 7.15 (t, J=7.1 Hz, 1H), 7.23-7.30 (m, 4H), 7.98 (d, J=8.8 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:19]=[CH:18][C:17](I)=[CH:16][C:11]=2[C:12]([O:14][CH3:15])=[O:13])=[CH:4][CH:3]=1.C([O:23][CH:24](OCC)[CH:25]=[CH2:26])C.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:19]=[CH:18][C:17](/[CH:26]=[CH:25]\[CH:24]=[O:23])=[CH:16][C:11]=2[C:12]([O:14][CH3:15])=[O:13])=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(I)ccc1OCc1ccc(F)cc1
Reactant: C=CC(OCC)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(/C=C\C=O)ccc1OCc1ccc(F)cc1
Temperature: 120 °C
Reaction time: 0.33 h

Procedure:
To a suspension of methyl 2-{[(4-fluorophenyl)methyl]oxy}-5-iodobenzoate (may be prepared as described in Description 112; 740 mg, 1.92 mmol) in N,N-dimethylformamide (5 ml) was added 3,3-bis(ethyloxy)-1-propene (0.88 ml, 5.8 mmol), potassium carbonate (397 mg, 2.87 mmol) and PdOAc2 (25.8 mg, 0.115 mmol). The reaction was heated in the microwave at 120° C. for 40 minutes, cooled and then 2M HCl (5 ml) was added and the mixture stirred for 20 minutes. The mixture was extracted with diethyl ether (2×10 ml), the organic layer dried (MgSO4), and the solvent removed in vacuo. Purification by column (Si, (solute, 6:1 cyclohexane/ethyl acetate) yielded the title compound. 163 mg.
Reaction SMILES: [CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[C:15]([C:19]#[N:20])=[N:14][C:13]([C:21]([NH:23][CH2:24][CH2:25][CH2:26][C:27]([OH:29])=O)=[O:22])=[C:12]([OH:30])[C:11]=2[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH2:46]([NH2:49])[CH2:47][CH3:48]>C(Cl)Cl>[CH2:46]([NH:49][C:27]([CH2:26][CH2:25][CH2:24][NH:23][C:21]([C:13]1[N:14]=[C:15]([C:19]#[N:20])[C:16]2[C:17](=[O:18])[N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:9]=[CH:10][C:11]=2[C:12]=1[OH:30])=[O:22])=[O:29])[CH2:47][CH3:48]
Reactant: N#Cc1nc(C(=O)NCCCC(=O)O)c(O)c2ccn(Cc3ccccc3)c(=O)c12
Reactant: CCCN
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCNC(=O)CCCNC(=O)c1nc(C#N)c2c(=O)n(Cc3ccccc3)ccc2c1O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A mixture of 4-[(7-benzyl-1-cyano-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carbonyl)-amino]-butyric acid (30 mg, 0.074 mmol) and triethylamine (0.015 mL, 0.11 mmol) in CH2Cl2 (3 mL) was cooled in an ice bath. Isobutyl chloroformate (0.014 mL, 0.11 mmol) was added, and the mixture was stirred at 0° C. for 10 min. Propylamine (0.1 mL) was then added, and the mixture was slowly warmed to r.t. and stirred for 16 h. The mixture was diluted with CH2Cl2 (30 mL) and washed with 1 M HCl. The organic layer was dried over MgSO4 and concentrated. The crude product was purified twice by silica gel chromatography (0-30% EtOAc/CH2Cl2, then 10-80% EtOAc/hexanes+2% AcOH) to give 23 mg of the title compound as a white solid. MS: (+) m/z 448.35 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].F[C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][C:27]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:24](=[O:34])[N:23]([CH2:35][C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=1)[CH:22]=[CH:21]2>CC(N(C)C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][C:27]=2[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:24](=[O:34])[N:23]([CH2:35][C:36]2[CH:37]=[CH:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=2)[CH:22]=[CH:21]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: COc1ccc(Cn2ccc3cc(F)c(-c4ccccc4)cc3c2=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1ccc(Cn2ccc3cc(OC4CCN(C(=O)OC(C)(C)C)CC4)c(-c4ccccc4)cc3c2=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
168 mg (0.83 mmol) 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester were dissolved in 5 mL of dimethylacetamide and 20 mg (0.83 mmol) of sodium hydride (60%) were added. The mixture was stirred at room temperature. After 30 minutes a solution of 240 mg (0.67 mmol) 6-fluoro-2-(4-methoxy-benzyl)-7-phenyl-2H-iso-quinolin-1-one (315) in 5 mL of dimethylacetamide was added and stirring was continued at room temperature. After standing overnight, 20 mg (0.83 mmol) of sodium hydride (60%) were added and the solution was stirred at 100° C. After 1 h, the solvent was removed i. vac. and saturated sodium bicarbonate solution was added. The aqueous phase was extracted three times with dichloromethane. The organic layers were dried with MgSO4 and evaporated. The crude product was purified by preparative HPLC. Rt=1.98 min (Method C). Detected mass: 541.7 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:15]([C:16]#[N:17])=[CH:14][N:13]=[C:12]3[S:18][C:19]4[CH2:20][N:21](C(OC(C)(C)C)=O)[CH2:22][CH2:23][C:24]=4[C:11]=23)[CH:5]=[CH:6][C:7]=1[F:8].Cl.O1CCOCC1>CC(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:15]([C:16]#[N:17])=[CH:14][N:13]=[C:12]3[S:18][C:19]4[CH2:20][NH:21][CH2:22][CH2:23][C:24]=4[C:11]=23)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(C)OC(=O)N1CCc2c(sc3ncc(C#N)c(Nc4ccc(F)c(Cl)c4)c23)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: N#Cc1cnc2sc3c(c2c1Nc1ccc(F)c(Cl)c1)CCNC3
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 105.4 %

Procedure:
tert-Butyl 4-[(3-chloro-4-fluorophenyl)amino]-3-cyano-5,8-dihydrothieno[2,3-b:5,4-c′]dipyridine-7(6H)-carboxylate from Example 54A (250 mg, 0.365 mmol) was dissolved in 2-propanol (2 mL), and 4 M gaseous hydrogen chloride in dioxane (0.18 mL, 0.72 mmol) was added. The mixture was stirred at 80° C. for 1.5 h. The solvent was removed, and the residue was treated with 1 M aqueous sodium hydroxide solution (5 mL). The precipitate was collected by suction filtration, washed with water and dried in vacuo to yield 138 mg (99%) of the title compound.
Reaction SMILES: C[O-].[Na+].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.[CH3:18][NH:19][CH:20]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:24]=1[CH3:30])[CH2:21][NH2:22].[CH3:31][O:32][C:33]([NH:35][C:36](=NC(OC)=O)SC)=[O:34]>C(Cl)(Cl)Cl.O.C(O)(C)C>[CH3:18][N:19]1[CH:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:24]=2[CH3:30])[CH2:21][N:22]=[C:36]1[NH:35][C:33]([O:32][CH3:31])=[O:34]
Reactant: CNC(CN)c1cccc(C)c1C
Reactant: COC(=O)N=C(NC(=O)OC)SC
Agent: C[O-]
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Solvent: O
Product: COC(=O)NC1=NCC(c2cccc(C)c2C)N1C
Reaction time: 0.25 h

Procedure:
This example illustrates methods according to the invention of preparing the dialkyl substituted phenyl compounds of the invention. In this example, 50 ml. of isopropanol and 1.8 g. of sodium methoxide is added to a solution contraining 4.2 g. of the dihydrochloride salt of β-methylamino-β-(2,3-dimethylphenyl)-ethylamine dissolved in 10 ml. of water. The mixture is stirred for 15 minutes and then a solution containing 3.4 g. of a mixture of 1-mono and 1,3-bis(methoxycarbonyl)-S-methylisothiourea in 50 ml. of chloroform is added and then stirred for about two weeks at room temperature. The mixture is then concentrated by evaporation to near dryness and swirled with water, collected, and stirred in 50 ml. of aqueous 1 Normal hydrochloric acid for one hour. The resulting mixture is washed with ethyl ether, then treated with aqueous sodium bicarbonate and filtered. The collected solid is then stirred with distilled water, refiltered and washed in this manner three more times, then dried overnight at room temperature affording a crude product which is then puriified by recrystallization from isopropanol affording 1-methyl-4,5-dihydro-5-(2,3-dimethylphenyl)-2-methoxycarbonylaminoimidazole.
Reaction SMILES: Cl.C(OC([NH:9][CH2:10][CH2:11][S:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=O)(C)(C)C>O1CCOCC1>[NH2:9][CH2:10][CH2:11][S:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)CSCCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)CSCCN

Procedure:
HCl (4M in dioxane, 6 mL, 24.00 mmol) was added to a solution of ethyl 2-((2-((tert-butoxycarbonyl)amino)ethyl)thio)acetate (intermediate 211, 765 mg, 2.805 mmol) in dioxane (4 ml) at room temperature for 19 h. The reaction mixture was concentrated to yield the title compound as a reddish oil. (UPLC-MS 3) ESI-MS 165.1 [M+H]+. 1H NMR (600 MHz, DMSO-d6) δ 8.06 (s, 2H), 4.16-4.09 (m, 2H), 3.46 (s, 2H), 3.04-2.98 (m, 2H), 2.83 (t, 2H), 1.22 (t, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.Cl[CH2:9][C:10]#[N:11].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[OH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:9][C:10]#[N:11])[CH2:4][CH2:3]1
Reactant: N#CCCl
Reactant: Oc1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CCN1CCC(O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
A mixture of 4-hydroxypyridine (4.04 g, 40 mmol), chloroacetonitrile (2.78 mL, 44 mmol) and potassium carbonate (22 g, 160 mmol) in acetonitrile (50 mL) was stirred at rt for overnight. The insolubles were filtered off, the filtrate was concentrated to give 5.6 g of (4-hydroxy-piperidin-1-yl)-acetonitrile.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[C:5](=[O:13])[N:4]([CH3:14])[CH:3]=1.[CH2:15]([S:17]([NH:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1)(=[O:19])=[O:18])[CH3:16].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:14][N:4]1[CH:3]=[C:2]([C:25]2[CH:26]=[C:21]([NH:20][S:17]([CH2:15][CH3:16])(=[O:18])=[O:19])[CH:22]=[CH:23][CH:24]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[C:5]1=[O:13]
Reactant: CCS(=O)(=O)Nc1cccc(B(O)O)c1
Reactant: Cc1ccc2c(=O)n(C)cc(Br)c2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: CCS(=O)(=O)Nc1cccc(-c2cn(C)c(=O)c3ccc(C)cc23)c1
Yield: 56.1 %

Procedure:
4-Bromo-2,6-dimethylisoquinolin-1-one (75.0 mg, 0.30 mmol), [3-(ethylsulfonylamino)phenyl]boronic acid (82.0 mg, 0.36 mmol), Pd(dppf)Cl2 (22 mg, 0.03 mmol) and aqueous 1M K3PO4 (0.75 mL) in dioxane (4 mL) were reacted in a manner similar to Example 72, step 3. Isolation, also in a similar manner, gave the title compound (60.0 mg, 48.1%) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 8.42 (d, J=8.4 Hz, 1H), 7.46 (t, J=8.0 Hz, 1H), 7.34 (d, J=8.0 Hz, 1H), 7.29-7.27 (m, 2H), 7.24 (d, J=8.0 Hz, 1H), 7.03 (s, 1H), 6.68 (s, 1H), 3.65 (s, 3H), 3.21 (q, J=7.2 Hz, 2H), 2.42 (s, 3H), 1.43 (t, J=7.2 Hz, 3H). LCMS: 357.0 (M+H)+
Reaction SMILES: [OH:1][C:2]1[C:3]([O:12][CH3:13])=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C(=O)([O-])[O-].[K+].[K+].[CH:20]1(Br)[CH2:24][CH2:23][CH2:22][CH2:21]1>CN(C)C=O.O>[CH:20]1([O:1][C:2]2[C:3]([O:12][CH3:13])=[N:4][CH:5]=[C:6]([CH:11]=2)[C:7]([O:9][CH3:10])=[O:8])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: BrC1CCCC1
Reactant: COC(=O)c1cnc(OC)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cnc(OC)c(OC2CCCC2)c1
Temperature: 60 °C

Procedure:
A mixture of methyl 5-hydroxy-6-methoxynicotinoate (250 mg), anhydrous potassium carbonate (600 mg) and cyclopentyl bromide (0.26 mL) in dry dimethylformamide (5 mL) is stirred and heated at 60±5° C. for 24 hours. The mixture is cooled to room temperature, diluted with water and extracted with ethyl acetate. The extracts are washed with water and dried (MgSO4). Concentration gave methyl 5-cyclopentyloxy-6-methoxynicotinoate (290 mg) as an oil.
Reaction SMILES: O[C:2]1([OH:20])[C:10](=[O:11])[C:9]2[C:4](=[C:5]([N+:16]([O-:18])=[O:17])[CH:6]=[CH:7][C:8]=2[NH:12][C:13](=[O:15])[CH3:14])[C:3]1=[O:19].[CH3:21][C:22]1[CH:23]=[C:24]([NH:29][C:30](=[O:34])[CH:31]([CH3:33])[CH3:32])[CH:25]=[CH:26][C:27]=1[CH3:28]>S(=O)(=O)(O)O>[C:13]([NH:12][C:8]1[CH:7]=[CH:6][C:5]([N+:16]([O-:18])=[O:17])=[C:4]2[C:9]=1[C:10](=[O:11])[C:2]([C:25]1[CH:26]=[C:27]([CH3:28])[C:22]([CH3:21])=[CH:23][C:24]=1[NH:29][C:30](=[O:34])[CH:31]([CH3:32])[CH3:33])([OH:20])[C:3]2=[O:19])(=[O:15])[CH3:14]
Reactant: CC(=O)Nc1ccc([N+](=O)[O-])c2c1C(=O)C(O)(O)C2=O
Reactant: Cc1ccc(NC(=O)C(C)C)cc1C
Agent: O=S(=O)(O)O
Product: CC(=O)Nc1ccc([N+](=O)[O-])c2c1C(=O)C(O)(c1cc(C)c(C)cc1NC(=O)C(C)C)C2=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 9.3 %

Procedure:
N-(2,2-dihydroxy-7-nitro-1,3-dioxo-2,3-dihydro-1H-inden-4-yl)acetamide (0.20 g, 0.71 mmol) and N-(3,4-dimethylphenyl)isobutyramide (136 mg, 0.71 mmol) were dissolved in conc. sulfuric acid (5 mL) and stirred at room temperature for 3 hrs. The reaction mixture was extracted with ethylacetate and ice-water, washed with brine. The washed organic layer dried over sodium sulfate, concentrated in a vacuum, and purified through silica gel column chromatography (30% ethylacetate in hexane) to afford the title compound (30 mg, 10%).
Reaction SMILES: Br[C:2]1[N:6]2[CH2:7][CH2:8][CH2:9][N:10]([CH3:12])[CH2:11][C:5]2=[C:4]([C:13]([NH:15][C@@H:16]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:17]([NH:19][CH3:20])=[O:18])=[O:14])[N:3]=1.[C:25]([Si:29]([CH3:45])([CH3:44])[O:30][CH2:31][CH2:32]/[CH:33]=[CH:34]/B1OC(C)(C)C(C)(C)O1)([CH3:28])([CH3:27])[CH3:26].C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.CCOC(C)=O.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>[Si:29]([O:30][CH2:31][CH2:32]/[CH:33]=[CH:34]/[C:2]1[N:6]2[CH2:7][CH2:8][CH2:9][N:10]([CH3:12])[CH2:11][C:5]2=[C:4]([C:13]([NH:15][C@@H:16]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:17]([NH:19][CH3:20])=[O:18])=[O:14])[N:3]=1)([C:25]([CH3:26])([CH3:27])[CH3:28])([CH3:44])[CH3:45]
Reactant: CC1(C)OB(/C=C/CCO[Si](C)(C)C(C)(C)C)OC1(C)C
Reactant: CNC(=O)[C@@H](NC(=O)c1nc(Br)n2c1CN(C)CCC2)C(C)(C)C
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: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CNC(=O)[C@@H](NC(=O)c1nc(/C=C/CCO[Si](C)(C)C(C)(C)C)n2c1CN(C)CCC2)C(C)(C)C
Temperature: 160 °C
Yield: 99.7 %

Procedure:
To a solution of compound 324 (0.10 g, 0.25 mmol) in dioxane (2 mL) was (E)-tert-butyldimethyl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-enyloxy)silane (0.115 g, 0.50 mmol), followed by K2CO3 (0.069 g, 0.50 mmol) and water (0.40 mL). The resulting mixture was degassed with nitrogen and Pd(PPh3)4 (0.023 g, 0.02 mmol) was added. The mixture was heated in microwave reactor at 160° C. for 20 min. The mixture was diluted with EtOAc, and filtered through celite. The organic layer was concentrated, washed with water, dried over anhydrous Na2SO4 and concentrated again. The residue was purified using PL-Thiol MP SPE tube to provide compound 47A (0.126 g, 99%). LCMS (+ESI) m/z 506.4 [M+H]+.
Reaction SMILES: [CH2:1]([S:8]([C:11]1[CH:12]=[C:13]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[C:14]([O:16]CC1C=CC=CC=1)=[O:15])(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[OH-].[Na+]>>[CH2:1]([S:8]([C:11]1[CH:12]=[C:13]([CH:24]=[C:25]([C:27]([F:30])([F:28])[F:29])[CH:26]=1)[C:14]([OH:16])=[O:15])(=[O:10])=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)c1cc(C(F)(F)F)cc(S(=O)(=O)Cc2ccccc2)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cc(C(F)(F)F)cc(S(=O)(=O)Cc2ccccc2)c1

Procedure:
0.10 moles of benzyl 3-benzylsulfonyl-5-trifluoromethylbenzoate is refluxed in a 10 percent sulfuric acid solution for 1 hour. The reaction mixture is cooled, made alkaline with sodium hydroxide and extracted with ether. The aqueous phase is acidified and extracted with ether. The ether extracts are dried over sodium sulfate and evaporated to give 3-benzylsulfonyl-5-trifluoromethylbenzoic acid, m.p. 184°-185.5°C.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[NH:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[C:12]1[CH2:20][C:21]([O:23]CC)=O.[NH2:26][C:27]1[NH:31][CH:30]=[N:29][C:28]=1[C:32]#[N:33]>C1COCC1>[NH2:33][C:32]1[C:28]2[N:29]=[CH:30][NH:31][C:27]=2[NH:26][C:21](=[O:23])[C:20]=1[C:12]1[NH:11][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=1
Reactant: CCOC(=O)Cc1nc2ccccc2[nH]1
Reactant: N#Cc1nc[nH]c1N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Nc1c(-c2nc3ccccc3[nH]2)c(=O)[nH]c2[nH]cnc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
LiHMDS (4.4 eq) was added to ethyl 1H-benzimidazol-2-ylacetate (1.0 eq) and 5-amino-1H-imidazole-4-carbonitrile (1.0 eq) in THF at 0° C. After 1 hour, the resulting mixture was warmed to room temperature and then stirred overnight. The mixture was quenched with an aqueous saturated NH4Cl solution and extracted with EtOAc. The organic layer was washed with H2O and brine, dried over Na2SO4, filtered, and concentrated in vacuo to yield a brown solid. LC/MS m/z 267.1 (MH+), Rt 1.47 minutes.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][CH:4]([C:6]([O:8][CH3:9])=[O:7])[CH2:3]1.[H-].[Na+].F[C:13]1[C:18]([CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[CH:17][C:16]([F:25])=[CH:15][N:14]=1>CN(C=O)C>[CH3:9][O:8][C:6]([CH:4]1[CH2:5][CH:2]([O:1][C:13]2[C:18]([CH:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)=[CH:17][C:16]([F:25])=[CH:15][N:14]=2)[CH2:3]1)=[O:7]
Reactant: Fc1cnc(F)c(C2CCOCC2)c1
Reactant: COC(=O)C1CC(O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1CC(Oc2ncc(F)cc2C2CCOCC2)C1
Temperature: 60 °C
Reaction time: 1 h
Yield: 114.9 %

Procedure:
To a solution of methyl 3-hydroxycyclobutanecarboxylate (1.2 g, 9.0 mmol) in DMF (20 mL) was added sodium hydride (60% wt in mineral oil) (1.8 g, 45 mmol) at RT. The mixture was stirred for 1 h and then 2,5-difluoro-3-(tetrahydro-pyran-4-yl)-pyridine (1.8 g, 9.0 mmol) was added. The reaction mixture was heated to 60° C. for 3 h and then quenched with saturated NH4Cl. The solution was diluted with EtOAc and water and extracted with EtOAc (2×10 mL). The organic extracts were combined, washed with brine (10 mL), dried over MgSO4, filtered, and concentrated to get a residue, which was purified by flash column chromatography on silica gel (5% to 30% EtOAc in hexanes) to give the product (3.2 g) as yellow oil.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH:22]=[CH:21][C:20]3[C:15](=[C:16]([C:24]4[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=4[Cl:31])[CH:17]=[C:18]([F:23])[CH:19]=3)[O:14]2)(=O)=O)=CC=1.[N-:32]=[N+:33]=[N-:34].[Na+]>CN(C=O)C>[N:32]([CH2:12][C@H:13]1[CH2:22][CH2:21][C:20]2[C:15](=[C:16]([C:24]3[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=3[Cl:31])[CH:17]=[C:18]([F:23])[CH:19]=2)[O:14]1)=[N+:33]=[N-:34]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2C=Cc3cc(F)cc(-c4cc(Cl)ccc4Cl)c3O2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC[C@H]1CCc2cc(F)cc(-c3cc(Cl)ccc3Cl)c2O1
Reaction time: 0.17 h
Yield: 80.2 %

Procedure:
A solution ((R)-8-(2,5-dichlorophenyl)-6-fluoro-2H-chromen-2-yl)methyl 4-methylbenzenesulfonate (410 mg, 0.85 mmol) and sodium azide (280 mg, 4.3 mmol) in anhydrous DMF (20 mL) was heated to 90° C. under nitrogen for 20 hours. The cooled reaction mixture was quenched by the addition of water (30 mL) and the resulting suspension stirred vigorously for 10 minutes. The mixture was then partitioned between ethyl acetate (100 mL) and water (100 mL), the organic phase separated, washed with water (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Chromatography with 0–30% ethyl acetate in hexanes afforded 240 mg (83%) of (2R)-2-azidomethyl-8-(2,5-dichloro-phenyl)-6-fluoro-chroman as a colorless oil. MS (APPI) m/z 322 ([M−N2+H]+).