Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=1[Cl:18].[C:19](=O)([O:23]CC)[O:20][CH2:21][CH3:22]>CCOCC>[Cl:18][C:8]1[CH:9]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:12]([Cl:13])[C:7]=1[C:19]([O:20][CH2:21][CH3:22])=[O:23]
Reactant: CCOC(=O)OCC
Reactant: FC(F)(F)c1cc(Cl)c(Br)c(Cl)c1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCOC(=O)c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a mixture of 65.2 ml of n-butyllithium (1.61M in hexane) and 100 ml of anhydrous ether was added dropwise 29.3 g of 4-bromo-3,5-dichlorobenzo-trifluoride (3) in 30 ml of anhydrous ether at -78° C., followed by stirring for 20 minutes. Subsequently, 13.3 ml of diethyl carbonate in 50 ml of anhydrous ether was added dropwise to the mixture, followed by stirring at -78° C. for 30 minutes and then at 0° C. for 30 minutes. Ice water was added to the reaction mixture, the mixture was extracted with ether, and the combined ethereal layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was distilled under reduced pressure, giving 18.3 g of the desired product in the form of a colorless oil (yield 63.8%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[F:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1.CCN(C(C)C)C(C)C.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH2:36][CH2:37][C:38]2[CH:39]=[C:40]([NH2:43])[NH:41][N:42]=2)[CH:31]=[C:32]([O:34][CH3:35])[CH:33]=1>ClCCl.CN(C=O)C>[CH3:35][O:34][C:32]1[CH:31]=[C:30]([CH2:36][CH2:37][C:38]2[CH:39]=[C:40]([NH:43][C:12](=[O:14])[C:11]3[CH:10]=[CH:9][C:8]([F:7])=[CH:16][CH:15]=3)[NH:41][N:42]=2)[CH:29]=[C:28]([O:27][CH3:26])[CH:33]=1
Reactant: COc1cc(CCc2cc(N)[nH]n2)cc(OC)c1
Reactant: O=C(O)c1ccc(F)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(CCc2cc(NC(=O)c3ccc(F)cc3)[nH]n2)cc(OC)c1
Temperature: 0 °C
Yield: 3 %

Procedure:
Oxalyl chloride (2M in DCM, 1.40 ml, 2.75 mmol, 1.1 eq) was added dropwise to a mixture of 4-fluorobenzoic acid (350 mg, 2.50 mmol, 1 eq) in dichloromethane (15 ml) at 0° C. containing a few drops of DMF (10 ul, 0.12 mmol, 0.05 eq) and DIPEA (937 μl, 5.25 mmol, 2.1 eq). After stirring for 60 mins at 0° C. a solution of 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (742 mg, 3 mmol, 1.2 eq) in DCM (10 ml) was added dropwise over 15 mins. The mixture was maintained at 0° C. for a further 2 h, then gradually allowed to warm to room temperature overnight. The mixture was diluted with DCM (50 ml) and washed with aqueous NaHCO3 solution (50 ml). The aqueous layer was extracted with DCM (50 ml). The combined organic layers were collected and concentrated. The crude product was purified by reverse-phase prep HPLC using a 30-50% gradient of acetonitrile in water containing 1% ammonium hydroxide solution. The desired fractions were evaporated to afford the title compound as a beige solid. (31.5 mg, 3% yield)
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15]O)[N:10]=[CH:9]2)C=CC=CC=1.[OH:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37](=[O:39])[CH3:38])=[CH:32][CH:31]=1>>[NH:8]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][O:29][C:30]2[CH:31]=[CH:32][C:33]([CH2:36][C:37](=[O:39])[CH3:38])=[CH:34][CH:35]=2)[N:10]=[CH:9]1
Reactant: CC(=O)Cc1ccc(O)cc1
Reactant: OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Product: CC(=O)Cc1ccc(OCCCc2c[nH]cn2)cc1

Procedure:
5 mmol of 3-(1-triphenylmethyl-1H-imidazol-4-yl)propanol and 6 mmol of 4-hydroxyphenylpropanone are treated as described in Example 76.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)[N:3]=1.[CH3:14][O:15][C:16]1[C:25]2[O:24][CH2:23][O:22][CH2:21][C:20]=2[CH:19]=[C:18]([CH:26]=O)[CH:17]=1.C[Si]([C:32]#[N:33])(C)C>C1COCC1.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Yb+3]>[CH3:14][O:15][C:16]1[C:25]2[O:24][CH2:23][O:22][CH2:21][C:20]=2[CH:19]=[C:18]([CH:26]([NH:13][C:10]2[CH:11]=[CH:12][C:7]([C:4]3[N:3]=[C:2]([CH3:1])[O:6][N:5]=3)=[CH:8][CH:9]=2)[C:32]#[N:33])[CH:17]=1
Reactant: Cc1nc(-c2ccc(N)cc2)no1
Reactant: C[Si](C)(C)C#N
Reactant: COc1cc(C=O)cc2c1OCOC2
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: C1CCOC1
Product: COc1cc(C(C#N)Nc2ccc(-c3noc(C)n3)cc2)cc2c1OCOC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3.5 g of Yb(OTf)3 in 250 ml of THF there were added 9.8 g of 4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamine, 10.8 g of 8-methoxy-4H-benzo[1,3]dioxine-6-carbaldehyde, 10 g of MS3A and 15 ml of trimethylsilyl cyanide under a nitrogen atmosphere, and the mixture was stirred overnight at room temperature. The reaction mixture was filtered through celite, and the celite was washed with 1000 ml of ethyl acetate. The organic layer was concentrated under reduced pressure to give the title compound (29.2 g, crude product) as a light yellow solid.
Reaction SMILES: O[CH:2]([CH2:23]O)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]N1C(=O)C2N(C)C=NC=2N(C)C1=O.C(O)CCCCCCC=C.[CH3:35][S:36](Cl)(=[O:38])=[O:37].C(N(CC)CC)C>ClCCl.O>[CH3:35][S:36]([CH2:23][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]=[CH2:9])(=[O:38])=[O:37]
Reactant: CS(=O)(=O)Cl
Reactant: Cn1cnc2c1c(=O)n(CCCCCCCC(O)CO)c(=O)n2C
Agent: C=CCCCCCCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: C=CCCCCCCCS(C)(=O)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
This example illustrates a synthesis procedure for 1-(8,9-dihydroxynonyl)-3,7-dimethylxanthine (CT1561). The synthesis began by adding a solution of 8-nonene-1-ol (1.50 g, 10.5 mmol) in dichloromethane (100 ml) at 0° C. to methanesulfonyl chloride (1.20 g, 813 μl, 10.5 mmol), followed by triethylamine (1.59 g, 15.8 mmol). After stirring for 1 hr at 0° C., the reaction mixture was allowed to warm to room temperature. The reaction mixture was poured into 100 ml of water and extracted with dichloromethane (3×50 ml). The organic portions were combined, dried with sodium sulfate, and evaporated to give 9-methanesulfonyl-1-nonene as a yellow oil (2.25 g, 97% yield, which was used without further purification.
Reaction SMILES: ClCCCl.[N:5]([C:8]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([Cl:26])[CH:19]=2)=[N:16][C:15]([Br:27])=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11])=[N+]=[N-]>ClCCl.CCCCCCCC(O)=O.CCCCCCCC(O)=O.CCCCCCCC(O)=O.CCCCCCCC(O)=O.[Rh].[Rh]>[Br:27][C:15]1[CH:14]=[C:9]([C:10]([O:12][CH3:13])=[O:11])[C:8]2[NH:5][C:23]3[CH:22]=[C:21]([O:24][CH3:25])[C:20]([Cl:26])=[CH:19][C:18]=3[C:17]=2[N:16]=1
Reactant: COC(=O)c1cc(Br)nc(-c2ccc(OC)c(Cl)c2)c1N=[N+]=[N-]
Agent: [Rh]
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCCCCCCC(=O)O
Product: COC(=O)c1cc(Br)nc2c1[nH]c1cc(OC)c(Cl)cc12
Temperature: 60 °C
Yield: 56 %

Procedure:
1,2-Dichloroethane (0.1 mL) was added to a mixture of methyl 3-azido-6-bromo-2-(3-chloro-4-methoxyphenyl)isonicotinate (56 mg, 0.14 mmol), rhodium octanoate dimer (11 mg, 0.014 mmol) and crushed 4 A° molecular sieves (56 mg) in a microwave vial. The vial was sealed and heated at 60° C. overnight. The reaction was diluted with dichloromethane, filtered, and the solvents removed from the filtrate. Radial silica gel chromatography (step gradient with hexane containing 50 to 100% methylene chloride) of the residue afforded methyl 2-bromo-8-chloro-7-methoxy-5H-pyrido[3,2-b]indole-4-carboxylate (29 mg). MS (ESI) m/z 370.9 (M+H). 1H NMR (CDCl3) δ ppm 9.51 (1H, br. s.), 8.31 (1H, s), 7.89 (1H, s), 6.99 (1H, s), 4.05 (3H, s), 4.01 (3H, s).
Reaction SMILES: [N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:20][C@H:21]4[C@H:27]([F:28])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[C:29]([O-])([O-])=O.[Na+].[Na+].C(O)=O.C=O>C(Cl)Cl>[N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:20][C@H:21]4[C@H:27]([F:28])[CH2:26][CH2:25][N:24]([CH3:29])[CH2:23][CH2:22]4)[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: O=C([O-])[O-]
Reactant: F[C@@H]1CCNCC[C@H]1Oc1cccc2ccc(-c3nnc4ccccn34)nc12
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=CO
Product: CN1CC[C@@H](F)[C@H](Oc2cccc3ccc(-c4nnc5ccccn45)nc23)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55 %

Procedure:
A mixture of Stereoisomers 1 and 2 of 2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((trans)-5-fluoroazepan-4-yloxy)quinoline (0.023 g, 0.0511 mmol) was slurried in CH2Cl2 (3 mL). A saturated aqueous Na2CO3 solution (5 mL) was added and the mixture was stirred at ambient temperature for 0.5 hours. The layers were separated and the aqueous phase was extracted with CH2Cl2. The combined organic layers were washed with brine and dried over Na2SO4, filtered and concentrated. The crude residue was treated with formic acid (0.289 mL, 7.66 mmol) and formaldehyde (0.0380 mL, 0.511 mmol). The mixture was stirred at 90° C. for 4 hours. The mixture was cooled to ambient temperature and carefully treated with a saturated aqueous Na2CO3 solution to adjust the mixture to about pH 11. The mixture was extracted with CHCl3 and the combined organic phases were washed with brine and dried over Na2SO4, filtered and concentrated. The crude product was purified by Preparative TLC (0.5 mm, 10% MeOH/CH2Cl2 with 1% 7N NH3/MeOH) to provide the desired product (0.011 g, 55%) as a white solid. MS ESI (+) m/z 392.1 (M+1) detected.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl.Cl.Cl[CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19]2[N:23]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[C:22]3[CH:32]=[CH:33][CH:34]=[CH:35][C:21]=3[N:20]=2)[CH2:14][CH2:13]1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>O>[F:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][N:23]2[C:22]3[CH:32]=[CH:33][CH:34]=[CH:35][C:21]=3[N:20]=[C:19]2[NH:18][CH:15]2[CH2:14][CH2:13][N:12]([CH2:11][CH2:10][N:3]3[CH:4]=[CH:5][N:6]=[C:2]3[CH3:1])[CH2:17][CH2:16]2)=[CH:26][CH:27]=1
Reactant: Fc1ccc(Cn2c(NC3CCN(CCCl)CC3)nc3ccccc32)cc1
Reactant: Cc1ncc[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nccn1CCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
A mixture of 1.64 parts of 2-methyl-1H-imidazole, 9.2 parts of N-[1-(2-chloroethyl)-4-piperidinyl]-1-(4-fluorophenylmethyl)-1H-benzimidazol-2-amine dihydrochloride, 6.4 parts of sodium carbonate and 135 parts of N,N-dimethylformamide was stirred overnight at 60° C. The reaction mixture was poured into water. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (96:4 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 2.6 parts (30% of 1-[(4-fluorophenyl)methyl]-N-[1-[2-(2-methyl-1H-imidazol-1-yl)ethyl]-4-piperidinyl]-1H-benzimidazol-2-amine; mp. 170.5° C. (compound 20).
Reaction SMILES: [CH2:1]([C:3]1[C:7]2[CH:8]=[N:9][C:10]([C:12]([O:14]CC)=O)=[CH:11][C:6]=2[N:5]([CH2:17][CH2:18][CH2:19][O:20][CH3:21])[CH:4]=1)[CH3:2].[OH-].[Na+].Cl.[CH3:25][NH:26][O:27][CH3:28]>>[CH2:1]([C:3]1[C:7]2[CH:8]=[N:9][C:10]([C:12]([N:26]([O:27][CH3:28])[CH3:25])=[O:14])=[CH:11][C:6]=2[N:5]([CH2:17][CH2:18][CH2:19][O:20][CH3:21])[CH:4]=1)[CH3:2]
Reactant: CNOC
Reactant: CCOC(=O)c1cc2c(cn1)c(CC)cn2CCCOC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCc1cn(CCCOC)c2cc(C(=O)N(C)OC)ncc12

Procedure:
Ethyl 3-ethyl-1-(3-methoxypropyl)-1H-pyrrolo[3,2-c]pyridine-6-carboxylate was treated with aqueous sodium hydroxide solution and N,O-dimethylhydroxyamine hydrochloride in the similar manner to Reference Example 105(7) to give 3-ethyl-N-methoxy-1-(3-methoxypropyl)-N-methyl-1H-pyrrolo[3,2-c]pyridine-6-carboxamide [REx(106-3)] as a pale yellow oil.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][OH:8])[NH2:6].C(N(CC)CC)C.[CH3:17][Si:18]([CH3:33])([CH3:32])[CH2:19][CH2:20][O:21][C:22](=O)[O:23]N1C(=O)CCC1=O>ClCCl>[CH3:2][O:3][C:4](=[O:9])[CH:5]([NH:6][C:22]([O:21][CH2:20][CH2:19][Si:18]([CH3:33])([CH3:32])[CH3:17])=[O:23])[CH2:7][OH:8]
Reactant: C[Si](C)(C)CCOC(=O)ON1C(=O)CCC1=O
Reactant: COC(=O)[C@@H](N)CO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(CO)NC(=O)OCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 108.2 %

Procedure:
To a mixture of 1.25 g serine methyl ester hydrochloride, 2.25 ml triethylamine and 10 ml dichloromethane was added at 0° C. a solution of 2.22 g carbonic acid 2,5-dioxo-pyrrolidin-1-yl ester 2-trimethylsilanyl-ethyl ester [R. E. Shute, D. H. Rich, Synthesis, 1987, 346]. After stirring for 24 h at rt the reaction mixture was washed two times with 1N potassium hydrogen sulfate, once with saturated sodium bicarbonate solution and once with brine. The organic phase was dried over magnesium sulfate, filtered and evaporated to give 2.29 g of a colorless liquid.
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([O:27][CH3:28])[C:12]=1[O:13][CH2:14][C:15]1[N:16]=[C:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:18][C:19]=1[CH3:20])[CH:8]=[O:9].CO.O>O1CCCC1>[CH3:28][O:27][C:11]1[CH:10]=[C:7]([CH:6]=[C:5]([O:4][CH3:3])[C:12]=1[O:13][CH2:14][C:15]1[N:16]=[C:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:18][C:19]=1[CH3:20])[CH2:8][OH:9]
Reactant: COc1cc(C=O)cc(OC)c1OCc1nc(-c2ccccc2)oc1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(CO)cc(OC)c1OCc1nc(-c2ccccc2)oc1C
Reaction time: 1 h
Yield: 92 %

Procedure:
Sodium borohydride (540 mg) was added to a solution of 3,5-dimethoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzaldehyde (10.0 g) in tetrahydrofuran (70 ml)-methanol (30 ml) at 0° C. After stirring for 1 hour, the reaction mixture was poured into water to give 3,5-dimethoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl alcohol (9.25 g, yield 92%) as crystals. Recrystallization from ethyl acetate-hexane gave colorless prisms. m.p. 113-114° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.Br[CH:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([OH:14])=[O:13]>O>[N:1]1[N:2]([CH:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([OH:14])=[O:13])[CH:3]=[C:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[CH:5]2
Reactant: CC(C)CC(Br)C(=O)O
Reactant: c1ccc2[nH]ncc2c1
Solvent: O
Product: CC(C)CC(C(=O)O)n1cc2ccccc2n1
Temperature: 160 °C

Procedure:
Referring to Scheme 1, a mixture of indazole (450 mg, 3.86 mmol) and 2-bromo-4-methylpentanoic acid (1.5 eq.) was heated to 160° C. for 4 hours. The mixture was cooled, diluted with water, extracted by EtOAc, and dried over MgSO4. The solvent was then removed to give the crude product, which was used for the next step without further purification. [M+H] calc'd for C14H16N2O4, 233; found, 233.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1)[N:6]=[CH:5]2.Br[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].[O:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][CH:34]=2)[CH2:29][CH2:28]1>>[O:27]1[CH2:28][CH2:29][N:30]([C:33]2[CH:34]=[CH:35][C:36]([C:37]([NH:1][C:2]3[CH:3]=[C:4]4[C:8](=[CH:9][CH:10]=3)[N:7]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:13][CH:12]=3)[N:6]=[CH:5]4)=[O:38])=[CH:40][CH:41]=2)[CH2:31][CH2:32]1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Nc1ccc(-n2ncc3cc(N)ccc32)cc1
Reactant: O=C(O)c1ccc(N2CCOCC2)cc1
Product: CC(C)(C)OC(=O)CNc1ccc(-n2ncc3cc(NC(=O)c4ccc(N5CCOCC5)cc4)ccc32)cc1

Procedure:
Compound 987 was prepared according to the procedure described in Scheme IV from 5-amino-1-(4-aminophenyl)indazole, t-butyl bromoacetate, and 4-morpholinobenzoic acid. 1H NMR (500 MHz, CDCl3) δ 8.15 (s, 1H), 8.09 (s, 1H), 7.98 (s, 1H), 7.84 (d, J=7.5 Hz, 2H), 7.55 (d, J=9 Hz, 1H), 7.48 (d, J=10 Hz, 1H), 7.46 (d, J=7 Hz, 2H), 7.26 (s, 1H), 6.90 (d, J=7.5 Hz, 2H), 6.71 (d, J=7 Hz. 2H), 4.45 (s, 1H), 3.87-3.83 (m, 6H), 3.27-3.25 (m, 4H), 1.51 (m, 9H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:21]=[CH:20][C:19]2[O:18][C:17]3[C:12](=[CH:13][C:14]([C:22](=[O:28])[CH2:23][CH2:24][CH2:25][CH2:26]Cl)=[CH:15][CH:16]=3)[S:11][C:10]=2[CH:9]=1)=[O:7].[I-].[K+].[NH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>O1CCCC1>[N:31]1([CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]2[CH:21]=[CH:20][C:19]3[O:18][C:17]4[C:12](=[CH:13][C:14]([C:22](=[O:28])[CH2:23][CH2:24][CH2:25][CH2:26][N:31]5[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]5)=[CH:15][CH:16]=4)[S:11][C:10]=3[CH:9]=2)=[O:7])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: O=C(CCCCCl)c1ccc2c(c1)Sc1cc(C(=O)CCCCCl)ccc1O2
Reactant: C1CCNCC1
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(CCCCN1CCCCC1)c1ccc2c(c1)Sc1cc(C(=O)CCCCN3CCCCC3)ccc1O2
Temperature: 110 °C

Procedure:
A mixture of 35 g (0.08 mole) of 2,8-bis(5-chlorovaleryl)phenoxathiin, 2 g potassium iodide, 100 ml piperidine and 100 ml tetrahydrofuran is heated for 24 hours with stirring in a Parr bomb at 110°C. After cooling the mixture is filtered and washed with tetrahydrofuran, and the filtrate is evaporated to dryness. The residue is cooled and diluted with water. The mixture is extracted twice with ether, the ether extracts combined and filtered. The filtrate is evaporated to dryness, cooled and diluted with pentane followed by filtering off of the solid, washing with pentane and drying. The residue is recrystallized from isopropanol to yield 2,8-bis(5-piperidinovaleryl)phenoxathiin, M.P. 128.5°-129.5°C.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]([NH:15][C:16]3[CH:21]=[N:20][CH:19]=[CH:18][N:17]=3)=[O:14])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[N:22]1([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH:26]2[CH2:27][NH:28][CH2:29][CH:25]2[CH2:24][CH2:23]1>>[N:17]1[CH:18]=[CH:19][N:20]=[CH:21][C:16]=1[NH:15][C:13](=[O:14])[NH:12][C:6]1[C:5]2[C:10](=[CH:11][C:2]([N:28]3[CH2:29][CH:25]4[CH:26]([N:22]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:23][CH2:24]4)[CH2:27]3)=[CH:3][CH:4]=2)[N:9]=[CH:8][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC2CNCC21
Reactant: O=C(Nc1cnccn1)Nc1ccnc2cc(Br)ccc12
Product: CC(C)(C)OC(=O)N1CCC2CN(c3ccc4c(NC(=O)Nc5cnccn5)ccnc4c3)CC21

Procedure:
The compound was prepared by the method described for Example 1 using 1-(7-bromoquinolin-4-yl)-3-(pyrazin-2-yl)urea and tert-butyl hexahydropyrrolo[2,3-c]pyrrole-1(2H)-carboxylate as starting compounds.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:9][OH:10])=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.[OH-].[K+].[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>O1CCCC1>[CH3:23][C:13]1[CH:18]=[CH:17][C:16]([S:19]([O:10][CH2:9][C:3]2[C:2]([F:1])=[CH:7][C:6]([F:8])=[CH:5][N:4]=2)(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: OCc1ncc(F)cc1F
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)OCc2ncc(F)cc2F)cc1
Reaction time: 18 h

Procedure:
To a solution of (3,5-difluoropyridin-2-yl)methanol (0.25 g, 0.7 mmol) in tetrahydrofuran (THF; 10 mL) was added potassium hydroxide (KOH; 0.14 g, 2.55 mmol) at RT, and the mixture was stirred for 15 min. p-Toluenesulfonyl chloride (0.42 g, 2.21 mmol) was added slowly at RT, and the reaction mixture was stirred for another 18 h. After complete consumption of the starting material (by TLC), the reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (2×25 mL). The combined organic extracts were washed with H2O (25 mL) and brine (25 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude material. Purification by silica gel column chromatography eluting with 15% EtOAc/hexane afforded compound I-5 (0.18 g, 0.25 mmol, 35%) as colorless liquid. 1H NMR (500 MHz, CDCl3): δ 8.29 (s, 1H), 7.82 (d, J=8.5 Hz, 2H), 7.34 (d, J=8.5 Hz, 2H), 7.20-7.16 (m, 1H), 5.20 (s, 2H), 2.45 (s, 3H)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:12](=[O:25])(=[O:24])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)=[C:6]([CH2:8][C:9]([OH:11])=O)[CH:7]=1.[CH:26]1([NH2:32])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:12](=[O:24])(=[O:25])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)=[C:6]([CH2:8][C:9]([NH:32][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[O:11])[CH:7]=1
Reactant: Nc1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c(CC(=O)O)c1
Reactant: NC1CCCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c(CC(=O)NC2CCCCC2)c1
Reaction time: 3 h

Procedure:
To the mixture of 2-(5-amino-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)acetic acid (1.09 g, 3 mmol) and cyclohexyl amine (1.4 ml, 12 mmol) in DMF (10 ml), added PyBOP (1.56 g, 3 mmol) then triethyl amine (0.4 ml, 3 mmol). Stirring was kept for 3 hours. Diluted with EtOAc, washed with 1N HCl, water and brine. Dried over anhydrous sodium sulfate. Concentrated, the residue was dissolved in DMSO and purified by prep HPLC (SunFire Prep C18 OBD 5 uM 30×50 mm column). The title compound was obtained as light yellow powder. MS calcd for (C21H26BN3O5S): 443.17. MS found (ESI negative): (M−H)−=442.2. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.87 (s, 1H), 7.90 (d, J=6 Hz, 1H), 7.41 (s, 1H), 7.39 (d, J=8.8 Hz, 1H), 7.20 (d, J=8 Hz, 1H), 7.08 (dd, J=8 Hz, 1H), 6.45 (d, J=2 Hz, 1H), 6.33 (dd, J=8.8 Hz, 1H), 4.85 (s, 2H), 3.75 (s, 2H), 3.55 (m, 1H), 1.80-1.50 (m, 5H), 1.30-1.10 (m, 5H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[C:16]([N+:18]([O-])=O)[CH:15]=[CH:14][C:4]=1[O:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[H][H]>CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3]1[CH:17]=[C:16]([NH2:18])[CH:15]=[CH:14][C:4]=1[O:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: [H][H]
Reactant: COc1cc([N+](=O)[O-])ccc1OCCN1CCOCC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cc(N)ccc1OCCN1CCOCC1

Procedure:
A solution of 10% Pd/C (0.25 g) was added to a solution of 4-[2-(2-methoxy-4-nitro-phenoxy)-ethyl]-morpholine Compound 42a3 (1.4 g, 5.0 mmol) in EtOAc (50 mL). The solution was exposed to 40 PSI of hydrogen gas for a period of 1 hr. The catalyst was removed by filtration through Celite 545 and the solvent was removed to give 3-methoxy-4-(2-morpholin-4-yl-ethoxy)-phenylamine Compound 42a (1.1 g). MS 253 (MH+).
Reaction SMILES: [C:1]([NH:5][C:6](=[O:38])[CH2:7][N:8]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[C:20]([O:25][CH3:26])[CH:19]=2)=[CH:16][C:15]2[C:10](=[CH:11][C:12]([O:27]CC3C=CC(OC)=CC=3)=[CH:13][CH:14]=2)[C:9]1=[O:37])([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O.C(Cl)Cl>>[C:1]([NH:5][C:6](=[O:38])[CH2:7][N:8]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[C:20]([O:25][CH3:26])[CH:19]=2)=[CH:16][C:15]2[C:10](=[CH:11][C:12]([OH:27])=[CH:13][CH:14]=2)[C:9]1=[O:37])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(COc2ccc3cc(-c4ccc(F)c(OC)c4)n(CC(=O)NC(C)(C)C)c(=O)c3c2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(-c2cc3ccc(O)cc3c(=O)n2CC(=O)NC(C)(C)C)ccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.3 %

Procedure:
N-tert-Butyl-2-(3-(4-fluoro-3-methoxyphenyl)-7-(4-methoxybenzyloxy)-1-oxo-1H-isoquinolin-2-yl)acetamide (120 mg, 0.231 mmol) was treated with TFA:DCM (1:1 v/v, 5 mL) and stirred at room temperature for 1 h. The mixture was concentrated in vacuo and the crude residue was purified by preparative HPLC giving N-tert-butyl-2-(3-(4-fluoro-3-methoxyphenyl)-7-hydroxy-1-oxo-1H-isoquinolin-2-yl)acetamide (INTERMEDIATE III.1) (25 mg, 0.063 mmol, 27%).