Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([O:19][C:20]2[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=2[O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:23]#[N:24])=[N:4][C:5](F)=[C:6]([F:17])[C:7]=1[O:8][CH2:9][CH:10]1[CH2:14][O:13][C:12]([CH3:16])([CH3:15])[O:11]1.C([O-])([O-])=O.[Cs+].[Cs+].[OH:42][C:43]1[CH:44]=[C:45]([C:49]2[N:50]([CH3:54])[CH2:51][CH2:52][N:53]=2)[CH:46]=[CH:47][CH:48]=1>CS(C)=O>[F:1][C:2]1[C:3]([O:19][C:20]2[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=2[O:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:23]#[N:24])=[N:4][C:5]([O:42][C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([C:49]3[N:50]([CH3:54])[CH2:51][CH2:52][N:53]=3)[CH:44]=2)=[C:6]([F:17])[C:7]=1[O:8][CH2:9][CH:10]1[CH2:14][O:13][C:12]([CH3:16])([CH3:15])[O:11]1
Reactant: CC1(C)OCC(COc2c(F)c(F)nc(Oc3cc(C#N)ccc3OCc3ccccc3)c2F)O1
Reactant: CN1CCN=C1c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CN1CCN=C1c1cccc(Oc2nc(Oc3cc(C#N)ccc3OCc3ccccc3)c(F)c(OCC3COC(C)(C)O3)c2F)c1
Temperature: 55 °C
Reaction time: 24 h
Yield: 66.7 %

Procedure:
To 3-[[3,5,6-trifluoro-4-[(2,2-dimethyidioxolan-4-yl)methoxy]pyridin-2-yl]oxy]-4-(benzyloxy)benzonitrile (1.0 g, 2.1 mmol) in DMSO (6 mL) was added Cs2CO3 (0.7 g, 2.1 mmol) and 2-(3-hydroxyphenyl)-1-methylimidazoline (0.4 g, 2.2 mmol). After stirring in an oil bath at 55° C. for 24 hours, the reaction was partitioned with water and ethyl acetate. The layers were separated, washed with water and brine, dried (Na2SO4), and the solvent was removed in vacuo. The residue was chromatographed on silica with CH2Cl2/MeOH/NH4OH (240/10/1) to give 3-[[3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-[(2,2-dimethyldioxolan-4-yl)methoxy]pyridin-2-yl]oxy]-4-(benzyloxy)benzonitrile (0.9 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:11]O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH2:13]([N:15](CC)CC)C.CS(Cl)(=O)=O.[C-]#N.[Na+]>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:11][C:13]#[N:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: OCC1(c2ccc(Br)cc2)CC1
Agent: CS(=O)(=O)Cl
Agent: [C-]#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#CCC1(c2ccc(Br)cc2)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
[1-(4-Bromo-phenyl)-cyclopropyl]-methanol (11.42 g, 50.29 mmol) was dissolved in CH2Cl2 (171 mL) and the solution was cooled to −78° C. Triethylamine (8.41 mL, 60.35 mmol) was added followed by methanesulfonyl chloride (4.30 mL, 55.31 mmol) and the reaction stirred at −78° C. for 1 hour. The reaction was allowed to slowly warm to 0° C. while stirring for an addition 1.5 hours. The reaction was submitted to standard aqueous workup and was then diluted with DMF (90 mL) and evaporated to remove any residual CH2Cl2. Sodium cyanide (7.39 g, 150.8 mmol) and DMF (20 mL) were added and the reaction was heated to 70° C. for 3 hours. The reaction was cooled and submitted to standard aqueous workup to give the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7](B3OC(C)(C)C(C)(C)O3)=[CH:8][CH:9]=2)[CH2:4][C:3]1=[O:20].Br[C:22]1[CH:23]=[N:24][CH:25]=[C:26]([O:28][CH2:29][CH3:30])[CH:27]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C=O)C>ClCCl.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>[CH2:29]([O:28][C:26]1[CH:27]=[C:22]([C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[N:2]([CH3:1])[C:3](=[O:20])[CH2:4]3)[CH:23]=[N:24][CH:25]=1)[CH3:30]
Reactant: CN1C(=O)Cc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: CCOc1cncc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOc1cncc(-c2ccc3c(c2)CC(=O)N3C)c1
Temperature: 100 °C

Procedure:
To 1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-indol-2-one (137 mg, 0.5 mmol) was added 3-bromo-5-ethoxy-pyridine (CAS#17117-17-8, 112 mg, 0.55 mmol), tripotassium phosphate (266 mg, 1.25 mmol) and DMF (2.5 mL). The reaction mixture was degassed and placed under an argon atmosphere, at which time resin bound tetrakis(triphenylphosphine)palladium(0), specifically polystyrene triphenylphosphine palladium (0) [PS—PPh3-Pd(0) (Biotage), 0.09 mmol/g loading, (300 mg, 0.027 mmol)] was added. The reaction vessel was sealed and was heated by microwave irradiation at 100° C. for 75 minutes. The reaction mixture was then cooled to room temperature, diluted with dichloromethane and filtered through glass wool. The filtrate was further diluted with saturated aqueous sodium bicarbonate and the layers were separated. The aqueous layer was extracted two times with dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (ethanol-dichloromethane, 0 to 5%) to furnish 5-(5-ethoxy-pyridin-3-yl)-1-methyl-1,3-dihydro-indol-2-one; HRMS: (ESI) m/z 269.1287 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 1.49 (t, J=6.9 Hz, 3H), 3.27 (s, 3H), 3.62 (s, 2H), 4.18 (q, J=66 Hz, 2H), 6.93 (d, J=8.1 Hz, 1H), 7.43 (s, 1H), 7.46-7.57 (m, 2H), 8.26 (d, J=2.5 Hz, 1H), 8.43 (d, J=1.5 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]([OH:14])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].S(Cl)([Cl:17])=O>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]([Cl:17])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CC(=O)O)cc1OC
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: COc1ccc(CC(=O)Cl)cc1OC
Temperature: 50 °C

Procedure:
To a solution of 20 g. (0.10 mole) of 3,4-dimethoxyphenylacetic acid in 100 ml. of benzene was added dropwise 70 ml. (115 g., 0.98 mole) of thionyl chloride. The solution was heated to 50° C. for two hours, then evaporated in vacuo to give a residue of 3,4-dimethoxyphenylacetyl chloride. A solution of 21.4 g. (0.10 mole) of the acid chloride in 70 ml. of chloroform was added with stirring to a solution of 70 ml. of chloroform and 22.2 ml. (30.0 g., 0.30 mole) of N,N-di-(n-propyl)amine at 0° C. The resulting mixture was heated at 50° C. for two hours, cooled, diluted and washed with dilute hydrochloric acid, dilute sodium carbonate solution and water. The dried chloroform solution was evaporated in vacuo to give N,N-di(n-propyl)-3,4-dimethoxyphenylacetamide.
Reaction SMILES: [Mg].[CH:2]1(Br)[CH2:4][CH2:3]1.[CH:6]1[C:16]2[CH2:15][CH2:14][C:13]3[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=3[C:11](=[O:21])[C:10]=2[CH:9]=[CH:8][CH:7]=1.[Cl-].[NH4+].O>C1COCC1>[CH:2]1([C:11]2([OH:21])[C:12]3[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=3[CH2:14][CH2:15][C:16]3[CH:6]=[CH:7][CH:8]=[CH:9][C:10]2=3)[CH2:4][CH2:3]1
Reactant: O=C1c2ccccc2CCc2ccccc21
Reactant: BrC1CC1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: OC1(C2CC2)c2ccccc2CCc2ccccc21
Temperature: 60 °C
Yield: 52 %

Procedure:
In a three neck round bottom flask equipped with stirrer, (0.243 g, 0.009 mol) of magnesium turnings and 2.5 mL of dry THF was added. The reaction was stirred to allow the metal to dissolve. At this point the temperature was raised to 60° C. and cyclopropyl bromide (1.21 g, 0.010 mol) was added dropwise. The reaction mixture was allowed to reflux for 1.5 h at 70° C. and then lowered to 60° C. Then (1.04 g, 0.005 mol) of 10,11-dihydro-dibenzo[a,d]cyclohepten-5-one was added dropwise. Upon addition, the solution turned purple in color. The temperature was raised to 70° C. after addition was complete. The reaction refluxed for an additional 2 h and HPLC was used to monitor reaction progress. Ammonium chloride/H2O (7.5 mL) was added to quench the reaction and the flask placed in an ice bath. The resulting solution was filtered and the filtrate was transferred to a 250-mL separatory funnel charged with DCM (100 mL). Then finally NaCl/H2O solution (80 mL) was added. The organic phase was removed and dried over Na2SO4 for 2 h. The solvent was removed under reduced pressure and the product was dried under vacuum overnight. 1H NMR and LC/MS confirmed the product. (Yield ˜52%).
Reaction SMILES: [N:1]1([C:5]2[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][N:6]=2)[CH2:4][CH2:3][CH2:2]1.[H][H]>C(O)C.[Pd]>[NH2:11][C:8]1[CH:7]=[N:6][C:5]([N:1]2[CH2:4][CH2:3][CH2:2]2)=[CH:10][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(N2CCC2)nc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(N2CCC2)nc1

Procedure:
A suspension of 11.5 g (64.18 mmol) of 2-(azetidin-1-yl)-5-nitropyridine, prepared in the preceding stage, and 1 g of Pd/C at 10% in 400 mL of ethanol is stirred vigorously at 20° C. under 5 atm of hydrogen for 4 hours. After this time, the mixture is filtered on a Celite pad and then concentrated at reduced pressure. We thus obtain 9.3 g of the expected product, which is used as it is in the rest of the synthesis.
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]([C:14]([O:16][CH3:17])=[O:15])[C:7](=[CH:12][CH:13]=1)[C:8]([O:10][CH3:11])=[O:9])([O-])=O.[C:18]1([O-:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Na+].Cl>CN(C)C=O>[O:24]([C:4]1[CH:5]=[C:6]([C:14]([O:16][CH3:17])=[O:15])[C:7](=[CH:12][CH:13]=1)[C:8]([O:10][CH3:11])=[O:9])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1C(=O)OC
Reactant: [O-]c1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Oc2ccccc2)cc1C(=O)OC

Procedure:
0.1 Mole of dimethyl 4-nitrophthalate and 0.1 mole of sodium phenolate were reacted with each other in a solvent of dimethylformamide at 100° C. over a 3-hour period under a stream of nitrogen. After being allowed to stand at room temperature and thereby cooled, the reaction mixture was poured into a dilute aqueous solution of hydrochloric acid, and extracted with ethyl acetate. The solvent was distilled away from the extract to yield dimethyl 4-phenoxyphthalate. Then, dimethyl 4-phenoxyphthalate thus-obtained was refluxed in a mixture of ethanol and an aqueous solution of potassium hydroxide to result in conversion into 4-phenoxyphthalic acid. Thereafter, the acid underwent reaction in an acetic acid/acetic anhydride mixture at a temperature of 100° C., and the solvent was distilled away from the reaction solution to yield 4-phenoxyphthalic anhydride. Subsequently, equimolar amounts of 4-phenoxyphthalic anhydride. Subsequently, equimolar amounts of 4-phenoxyphthalic anhydride and m-diethylaminophenol were refluxed in toluene to yield a 2-(2-hydroxy-4-diethylaminobenzoyl)-4- or -5-aryloxybenzoic acid.
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[Cl:16][C:17]1[CH:22]=[C:21](O)[CH:20]=[CH:19][C:18]=1[CH:24]([CH3:43])[C:25]([C:31]1[CH:42]=[CH:41][C:34]2[N:35]([CH3:40])[C:36](=[O:39])[CH2:37][O:38][C:33]=2[CH:32]=1)([OH:30])[C:26]([F:29])([F:28])[F:27].C(N(CC)CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[Cl:16][C:17]1[CH:22]=[C:21]([O:6][S:7]([C:10]([F:11])([F:12])[F:13])(=[O:8])=[O:9])[CH:20]=[CH:19][C:18]=1[CH:24]([CH3:43])[C:25]([OH:30])([C:31]1[CH:42]=[CH:41][C:34]2[N:35]([CH3:40])[C:36](=[O:39])[CH2:37][O:38][C:33]=2[CH:32]=1)[C:26]([F:28])([F:29])[F:27]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc2c(c1)OCC(=O)N2C)C(F)(F)F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(c1ccc(OS(=O)(=O)C(F)(F)F)cc1Cl)C(O)(c1ccc2c(c1)OCC(=O)N2C)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoromethanesulfonic anhydride (0.12 ml) was added to 7-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (150 mg, Example 158 step 2) and triethylamine (0.2 ml) in DCM (5 ml). The mixture was stirred for 2 h at room temperature. 10% aqueous citric acid was added and extracted with DCM. The combined organic layers were dried over Na2SO4 and then concentrated to give the title compound (140 mg) as light yellow foam. MS (m/e, ISP neg. ion)=546.2 [M−H+].
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:19]([OH:21])=O)[CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCCC1.CN1CCOCC1>[CH2:22]([NH:29][C:19](=[O:21])[C@@H:9]([CH2:10][O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H](COCc1ccccc1)C(=O)O
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N[C@H](COCc1ccccc1)C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 50 %

Procedure:
To a cooled (−20° C.) solution of N-Boc-O-benzyl-D-serine (26 g) in tetrahydrofuran (208 mL), N-methylmorpholine (15 mL) was added and reaction mixture was stirred for 5 minutes. isobutylchloformate (18 mL) was added to the reaction mixture in 5 minutes at −20° C. The solution was further stirred for 5 minutes at −20° C. and benzyl amine (15.01 mL) was added to in it in 5 minutes at −20° C. The solution was stirred for 1 hr at −20° C. The solution was allowed to warm at room temperature and stirred for 1 hour. The precipitated hydrochloride salt of N-methylmorpholine was filtered. The filtrate was concentrated under vacuum to obtain solid 17 g N-benzyl-O-benzyl-N2-Boc-D-serinamide after crystallization from diisopropylether.
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=O.C(OC([N:15]1[C:23]2[CH:22]=[CH:21][N:20]=[CH:19][C:18]=2[CH:17]=[C:16]1[CH2:24][N:25]1[C:30](=[O:31])[CH2:29][N:28]([S:32]([CH:35]=[CH:36][C:37]2[S:38][C:39]([Cl:42])=[CH:40][CH:41]=2)(=[O:34])=[O:33])C[CH:26]1CO)=O)(C)(C)C>C(Cl)Cl>[Cl:42][C:39]1[S:38][C:37]([CH:36]=[CH:35][S:32]([N:28]2[CH:2]([CH2:3][OH:5])[CH2:26][N:25]([CH2:24][C:16]3[NH:15][C:23]4[CH:22]=[CH:21][N:20]=[CH:19][C:18]=4[CH:17]=3)[C:30](=[O:31])[CH2:29]2)(=[O:34])=[O:33])=[CH:41][CH:40]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)n1c(CN2C(=O)CN(S(=O)(=O)C=Cc3ccc(Cl)s3)CC2CO)cc2cnccc21
Solvent: ClCCl
Product: O=C1CN(S(=O)(=O)C=Cc2ccc(Cl)s2)C(CO)CN1Cc1cc2cnccc2[nH]1
Reaction time: 4 h

Procedure:
Trifluoroacetic acid (1.8 mL) is added to a solution of 2-{4-[2-(5-chloro-thiophen-2-yl)-ethenesulfonyl]-2-(±)-hydroxymethyl-6-oxo-piperazin-1-ylmethyl}-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester (0.04 g) in CH2Cl2 (4.2 mL) at RT. The reaction mixture is stirred for 4 h then concentrated in vacuo. The title compound is purified by RP-HPLC eluting in a gradient of 10% CH3CN/H2O (0.1% TFA) to 100% CH3CN and lyophilizing the appropriate product fractions. 1H NMR (DMSO-d6, 300 MHz) δ9.10 (s, 1H), 8.46 (d, 1H), 7.82 (d, 1H), 7.50 (d, 1H) 7.43 (d, 1H), 7.14 (d, 1H), 7.01 (d, 1H), 6.94 (s, 1H), 5.12 (bs, 1H), 4.80 (AB, 2H), 3.98 (d, 2H0, 3.90 (m, 1H), 3.40-3.50 (m, 4H). APCI MS, [M+H]+=467, 469.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[C:17]#[N:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22](=O)([O-])[O-].[K+].[K+].CI.Cl>CN(C)C=O>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[C:17]#[N:18])[CH3:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1cccc(NCCCCOCc2ccccc2)c1
Agent: Cl
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN(CCCCOCc1ccccc1)c1cccc(C#N)c1
Temperature: 50 °C
Reaction time: 16 h
Yield: 95.2 %

Procedure:
3-(4-Benzyloxybutylamino)benzonitrile (0.22 g) and potassium carbonate (0.21 g) were suspended in N,N-dimethylformamide (5 mL). To the reaction mixture was added methyl iodide (0.16 g), and the mixture was stirred at 50° C. for 16 hours. To the reaction mixture was added 1 mol/L hydrochloric acid, and the resulting mixture was extracted with diethyl ether. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and brine successively and dried over anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by column chromatography on silica gel (ethyl acetate/hexane=1/1) to give the title compound (0.22 g).
Reaction SMILES: Br[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19]([NH:22][C:23]4[CH:27]=[CH:26][O:25][N:24]=4)(=[O:21])=[O:20])=[CH:16][CH:17]=3)[CH:12]=[CH:11][C:10]2=[O:28])=[C:4]([O:29][CH3:30])[CH:3]=1.[Cl:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][C:33]=1[CH3:41].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>[Cl:8][C:7]1[CH:6]=[C:5]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19]([NH:22][C:23]4[CH:27]=[CH:26][O:25][N:24]=4)(=[O:20])=[O:21])=[CH:16][CH:17]=3)[CH:12]=[CH:11][C:10]2=[O:28])[C:4]([O:29][CH3:30])=[CH:3][C:2]=1[C:35]1[CH:36]=[CH:37][C:32]([Cl:31])=[C:33]([CH3:41])[CH:34]=1
Reactant: Cc1cc(B(O)O)ccc1Cl
Reactant: COc1cc(Br)c(Cl)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ccon3)ccc21
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+]
Product: COc1cc(-c2ccc(Cl)c(C)c2)c(Cl)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ccon3)ccc21
Temperature: 90 °C

Procedure:
The following compounds were made via method 65. A vial was charged with 1-(4-bromo-5-chloro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.300 g, 0.587 mmol), (4-chloro-3-methylphenyl)boronic acid (0.150 g, 0.881 mmol), potassium carbonate (0.244 g, 1.762 mmol), and Pd(Ph3P)4 (0.068 g, 0.059 mmol). The vial was flushed with Ar (g), then 1,4-dioxane (2.2 mL) and water (0.73 mL) were added. The vial was sealed and heated to 90° C. for 2 h. The mixture was cooled, quenched with NH4Cl and extracted with EtOAc (5×). The combined organic extracts were concentrated, dried over magnesium sulfate and concentrated. The residue was purified by chromatography on silica gel (40-g Ultra SNAP column, 25-g silica gel loading column, 0-50% EtOAc/Heptane) to give 1-(2,4′-dichloro-5-methoxy-3′-methyl-[1,1′-biphenyl]-4-yl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide. This material was purified by chiral SFC on Chiralpak AS-H column (25% MeOH/75% CO2) to give (P)-1-(2,4′-dichloro-5-methoxy-3′-methyl-[1,1′-biphenyl]-4-yl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide as peak 1 and (M)-1-(2,4′-dichloro-5-methoxy-3′-methyl-[1,1′-biphenyl]-4-yl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide as peak 2, both as off-white solids. Data for peak 1: 1H NMR (400 MHz, DMSO-d6) δ=11.68 (br. s., 1H), 8.66 (s, 1H), 8.35 (d, J=1.96 Hz, 1H), 8.23 (d, J=9.68 Hz, 1H), 7.86 (dd, J=2.10, 8.95 Hz, 1H), 7.67 (s, 1H), 7.55-7.61 (m, 2H), 7.44 (dd, J=1.71, 8.27 Hz, 1H), 7.32 (s, 1H), 6.77-6.88 (m, 2H), 6.41 (d, J=1.66 Hz, 1H), 3.73 (s, 3H), 2.44 (s, 3H). m/z (ESI) 557.1 (M+H)+. Data for peak 2: 1H NMR (400 MHz, DMSO-d6) δ=11.68 (br. s., 1H), 8.63 (br. s., 1H), 8.33 (d, J=1.86 Hz, 1H), 8.22 (d, J=9.68 Hz, 1H), 7.82-7.88 (m, 1H), 7.67 (s, 1H), 7.57-7.60 (m, 2H), 7.41-7.47 (m, 1H), 7.32 (s, 1H), 6.77-6.85 (m, 2H), 6.39 (s, 1H), 3.72 (s, 3H), 2.44 (s, 3H). m/z (ESI) 557.1 (M+H)+.
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].[N+:15]([C:18]1[CH:28]=[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:21](O)=[CH:20][CH:19]=1)([O-:17])=[O:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>ClCCl.CCCCCC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:21]2[CH:20]=[CH:19][C:18]([N+:15]([O-:17])=[O:16])=[CH:28][C:22]=2[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CCOC(=O)c1cc([N+](=O)[O-])ccc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCCCCC
Product: CCOC(=O)c1cc([N+](=O)[O-])ccc1OC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.5 %

Procedure:
To a solution of 1-t-butoxycarbonyl-4-hydroxypiperidine (10.2 g), ethyl 5-nitrosalicylate (10.7 g) and triphenylphosphine (17.3 g) in dichloromethane (200 ml) was added dropwise diethyl azodicarboxylate (10.4 ml) in an ice bath and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated in vacuo. The residue was purified by chromatography on a silica gel column using hexane/ethyl acetate=3/1 as an eluant to afford a yellow solid. A suspension of the solid in hexane was filtered to give the desired compound (12.3 g, yield 61%) as a white solid.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[C:7]1([CH3:13])[CH:12]=[CH:11][CH:10]=CC=1.[Cl:14][CH2:15][C:16](Cl)=[O:17]>O>[Cl:14][CH2:15][C:16]([CH:10]1[CH2:11][CH2:12][CH2:7][CH2:13]1)=[O:17]
Reactant: Cc1ccccc1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C(CCl)C1CCCC1
Temperature: -5 °C
Reaction time: 0.5 h

Procedure:
To a cold (˜0° C.) solution of K2CO3 (31.2 g, 225 mmol, ) in water (125 mL) was added N, O-dimethylhydroxylamine hydrochloride (10 g, 100 mmol) and toluene (125 mL). The reaction mixture was further cooled to −5° C. and chloroacetyl chloride (10 mL, 125 mmol, )was added slowly under vigorous agitation. The reaction mixture was then warmed to ambient temperature over 45 min and analyzed by GC for completion. The layers were separated and the aqueous layer was extracted with toluene (3×50 mL). The combined organic layers were concentrated to a solid residue. The residue was dissolved in anhydrous THF (200 mL) cooled to ˜0° C. To the reaction mixture was then added a solution of the cyclopentylmagnesium chloride (60 mL, 2M in diethyl ether), drop-wise, maintaining the temperature at less than about 5° C. The resulting solution was then warmed to ambient temperature over a period of ˜1 hr and then slowly quenched into a cold 3N HCl (100 mL, ). The resulting mixture was then aged for ˜30 min. The layers were separated and the aqueous layer extracted with MTBE (50 mL). The combined organic layers were washed with brine (50 mL), dried over MgSO4 and concentrated to dryness to yield the title compound as a crude product, as a yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)[N:11]=[C:10]([C:23]([OH:25])=O)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.ClC1C=C(N2C(C3C=C(F)C=C(Cl)C=3)=CC(C([N:49]3[CH2:53][C:52](=[O:54])[NH:51][CH2:50]3)=O)=N2)C=CC=1F>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:20])([F:21])[F:22])[CH:14]=3)[N:11]=[C:10]([C:23]([N:49]3[CH2:53][C:52](=[O:54])[NH:51][CH2:50]3)=[O:25])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cc(-c2cccc(Cl)c2)n(-c2cccc(C(F)(F)F)c2)n1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccc(F)c(Cl)c3)n2)CN1
Product: O=C1CN(C(=O)c2cc(-c3cccc(Cl)c3)n(-c3cccc(C(F)(F)F)c3)n2)CN1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 82A in analogy to the synthesis of the compound of Example 1. 22 mg (58% of theory) of the title compound are obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][O:9][CH3:10])[N:5]=[CH:4][N:3]=1.[OH-].[NH4+:12]>>[CH3:10][O:9][CH2:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH2:12])[CH:7]=1
Reactant: COCc1cc(Cl)ncn1
Reactant: [NH4+]
Agent: [OH-]
Product: COCc1cc(N)ncn1
Temperature: 25 °C
Yield: 48 %

Procedure:
A mixture of 4-chloro-6-(methoxymethyl)pyrimidine (1.2 g, 7.57 mmol) and ammonium hydroxide (20 ml) was heated in a sealed tube for 3 hours. The mixture was cooled to ambient temperature and concentrated. The residue was triturated with ether to afford 6-(methoxymethyl)pyrimidin-4-amine (0.50 g, 3.59 mmol, 48% yield) as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.47 (1H, s), 6.55 (1H, s), 5.12 (2H, br. s.), 4.38 (2H, s), 3.45 (3H, s). MS (LC/MS) R.T.=0.42; [M+H]+=140.20.