Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10](B(O)O)=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[N:16]12[CH2:23][CH2:22][CH:19]([CH2:20][CH2:21]1)[C@@H:18]([NH:24][C:25]([C:27]1[O:28][C:29]3[CH:35]=[C:34](Br)[CH:33]=[CH:32][C:30]=3[CH:31]=1)=[O:26])[CH2:17]2.[OH-].[Na+]>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].CN(C=O)C>[N:16]12[CH2:21][CH2:20][CH:19]([CH2:22][CH2:23]1)[C@@H:18]([NH:24][C:25]([C:27]1[O:28][C:29]3[CH:35]=[C:34]([C:10]4[CH:11]=[CH:12][C:7]([N:1]5[CH2:6][CH2:5][O:4][CH2:3][CH2:2]5)=[CH:8][CH:9]=4)[CH:33]=[CH:32][C:30]=3[CH:31]=1)=[O:26])[CH2:17]2
Reactant: OB(O)c1ccc(N2CCOCC2)cc1
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1cc2ccc(Br)cc2o1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2ccc(-c3ccc(N4CCOCC4)cc3)cc2o1
Temperature: 82.5 °C

Procedure:
A mixture of 180 mg (0.86 mmol) of 4-(4-morpholinyl)phenylboronic acid, 200 mg (0.57 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-bromo-1-benzofuran-2-carboxamide (Example 2A), 1.72 ml (1.72 mmol) of 1N sodium hydroxide solution, 40 mg (0.06 mmol) of 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) chloride and 2 ml of DMF is heated at 80-85° C. for 18 h. The solvent is removed under reduced pressure. The crude product is purified on silica gel 60 (Merck, Darmstadt; eluent: dichloromethane, dichloromethane/methanol 20:1, dichloromethane/methanol-/ammonia 80:20:2). The solvent is removed under reduced pressure. Finally, the last residues of solvent are removed under high vacuum. 79 mg (32% of theory) of the title compound are isolated.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=2)[CH2:3][CH2:2]1.[NH2:19][C:20]1[C:25]2[CH:26]=[C:27]([CH2:29][CH:30]([NH:40]S(C3C=CC(OC4CCOCC4)=CC=3)(=O)=O)[C:31]([N:33]3[CH2:38][CH2:37][CH:36]([CH3:39])[CH2:35][CH2:34]3)=[O:32])[S:28][C:24]=2[CH:23]=[CH:22][N:21]=1>>[NH2:19][C:20]1[C:25]2[CH:26]=[C:27]([CH2:29][CH:30]([NH:40][S:15]([C:12]3[CH:13]=[CH:14][C:9]([CH2:8][O:7][CH:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)=[CH:10][CH:11]=3)(=[O:17])=[O:16])[C:31]([N:33]3[CH2:34][CH2:35][CH:36]([CH3:39])[CH2:37][CH2:38]3)=[O:32])[S:28][C:24]=2[CH:23]=[CH:22][N:21]=1
Reactant: CC1CCN(C(=O)C(Cc2cc3c(N)nccc3s2)NS(=O)(=O)c2ccc(OC3CCOCC3)cc2)CC1
Reactant: O=S(=O)(Cl)c1ccc(COC2CCOCC2)cc1
Product: CC1CCN(C(=O)C(Cc2cc3c(N)nccc3s2)NS(=O)(=O)c2ccc(COC3CCOCC3)cc2)CC1

Procedure:
This compound was prepared from 218 mg of 4-(tetrahydropyran-4-yloxymethyl)-benzenesulfonyl chloride and 210 mg (0.5 mmol) 30a using the procedure described for 58c. Yield: 100 mg, m.p. 124-128° C., (+)-FAB-MS: 573 (MH+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[O:8][C:9]([NH:11][C:12]2[C:13]([NH2:18])=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:10])=[CH:3][CH:2]=1.N1C=CC=CC=1.[Br:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=1>C(Cl)(Cl)Cl>[Br:31][C:32]1[CH:40]=[CH:39][C:35]([C:36]([NH:18][C:13]2[C:12]([NH:11][C:9]([O:8][CH:7]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)=[O:10])=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:37])=[CH:34][CH:33]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: Nc1ccccc1NC(=O)OC(c1ccncc1)C1CCNCC1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: O=C(Nc1ccccc1NC(=O)c1ccc(Br)cc1)OC(c1ccncc1)C1CCNCC1
Reaction time: 20 h
Yield: 42.7 %

Procedure:
A solution of N1-[1-(4-pyridyl)piperidin-4-ylmethoxycarbonyl)-1,2-benzenediamine (300 mg, 0.920 mmol) and pyridine (0.74 mL) in chloroform (5 mL) was treated with 4-bromobenzoyl chloride (405 mg, 1.84 mmol). After 20 h, the mixture was concentrated and the residue partitioned between water and ethyl acetate. The aqueous layer was extracted three times with ethyl acetate and the combined organics were washed with 1 N aqueous sodium hydroxide, water, saturated sodium chloride solution. The solution was dried (potassium carbonate), filtered, and concentrated in vacuo. Recrystallization (methanol/chloroform and hexanes) yielded 200 mg (43%) of the title compound.
Reaction SMILES: O.[CH3:2][C:3]([CH2:7][CH2:8][CH:9]=[C:10]([CH3:15])[CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:4][CH:5]=[O:6]>[Ni].CO>[CH3:2][CH:3]([CH2:7][CH2:8][CH:9]=[C:10]([CH3:15])[CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:4][CH2:5][OH:6]
Reactant: CC(=CC=O)CCC=C(C)CC(C)C
Agent: [Ni]
Solvent: O
Solvent: CO
Product: CC(=CCCC(C)CCO)CC(C)C

Procedure:
5 g. of Raney nickel are suspended in 200 ml. of methanol and treated slowly with a solution of 2.5 g. of soda in 5 ml. of water. To this mixture are added 97 g. of 3,7,9-trimethyl-2,6-decadien-1-al dissolved in 0.8 liters of methanol and the resulting mixture is hydrogenated. After uptake 2 of equivalents of hydrogen, the catalyst is filtered off, rinsed with 50 ml. of methanol and the filtrate evaporated. The residue is taken up in 300 ml. of ether, washed three times with 200 ml. of water each time, dried over sodium sulphate and evaporated. By distillation there is obtained pure 3,7,9-trimethyl-6-decen-1-ol of boiling point 90° C/0.7 mm. Hg; nD25 = 1.4570.
Reaction SMILES: ClCl.[O:3]=[C:4]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][C:17]([OH:19])=[O:18])=[C:10]([Cl:14])[C:11]=2[Cl:13])[CH2:6][CH:5]1[CH2:20][CH:21]([CH3:23])[CH3:22].C([Cl:28])CCC>C(O)(=O)C.Cl>[O:3]=[C:4]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][C:17]([OH:19])=[O:18])=[C:10]([Cl:14])[C:11]=2[Cl:13])[CH2:6][C:5]1([CH2:20][CH:21]([CH3:23])[CH3:22])[Cl:28]
Reactant: CCCCCl
Reactant: CC(C)CC1Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Agent: Cl
Agent: ClCl
Solvent: CC(=O)O
Product: CC(C)CC1(Cl)Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Temperature: 0 °C
Yield: 56 %

Procedure:
A solution of glacial acetic acid (50 ml.) and chlorine (0.40 g., 0.00565 mole) is added with stirred over a 10-minute period to a suspension of (1-oxo-2-isobutyl-6,7-dichloro-5-indanyloxy)acetic acid (1.6 g., 0.00485 mole) in glacial acetic acid (50 ml.) and concentrated hydrochloric acid (1 drop). During the addition the reaction vessel is heated on a steam bath. After the addition is complete, the mixture is stirred without heating for 30 minutes and then poured into ice water (200 ml.). The white solid thatseparates is collected by filtration, washed in water and dried to afford 1.0 g. (56% yield) of (1-oxo-2-isobutyl-2,6,7-trichloro-5-indanyloxy)acetic acid which after recrystallization from n-butyl chloride melts at 166° C.
Reaction SMILES: [C:1]([C:4]1[N:5]([CH3:34])[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([NH:20][C:21](=[O:33])[C:22]3[CH:27]=[CH:26][C:25]([O:28][CH:29]([CH3:31])[CH3:30])=[C:24]([Cl:32])[CH:23]=3)[CH2:17][CH2:18][OH:19])=[CH:11][CH:10]=2)[N:8]=1)(=[O:3])[CH3:2].[P:35](Cl)([O:39][CH3:40])([O:37][CH3:38])=[O:36].CCOC(C)=O.CO>C(Cl)Cl.CN(C1C=CN=CC=1)C>[P:35]([O:39][CH3:40])([O:37][CH3:38])([O:19][CH2:18][CH2:17][C@@H:16]([NH:20][C:21]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH:29]([CH3:30])[CH3:31])=[C:24]([Cl:32])[CH:23]=1)=[O:33])[CH2:15][C:12]1[CH:13]=[CH:14][C:9]([C:7]2[N:8]=[C:4]([C:1](=[O:3])[CH3:2])[N:5]([CH3:34])[CH:6]=2)=[CH:10][CH:11]=1)=[O:36]
Reactant: CC(=O)c1nc(-c2ccc(C[C@@H](CCO)NC(=O)c3ccc(OC(C)C)c(Cl)c3)cc2)cn1C
Reactant: COP(=O)(Cl)OC
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COP(=O)(OC)OCC[C@H](Cc1ccc(-c2cn(C)c(C(C)=O)n2)cc1)NC(=O)c1ccc(OC(C)C)c(Cl)c1
Reaction time: 0.5 h
Yield: 77.1 %

Procedure:
To a solution of N-((1S)-1-{[4-(2-acetyl-1-methyl-1H-imidazol-4-yl)phenyl]methyl}-3-hydroxypropyl)-3-chloro-4-[(1-methylethyl)oxy]benzamide (500 mg, 1.04 mmol) in dry CH2Cl2 (10 mL) under N2, was added dimethyl chlorophosphate (748 mg, 5.18 mmol) followed by DMAP (660 mg, 5.41 mmol) at rt. After 30 min, TLC (95:5 EtOAc/MeOH) showed ˜50% conversion, so an additional portion of dimethyl chlorophosphate (748 mg, 5.18 mmol) and DMAP (660 mg, 5.41 mmol) were added. After an additional 30 min, the reaction was quenched with saturated aqueous NH4Cl and diluted with CH2Cl2. The aqueous layer was back-extracted with CH2Cl2 and the combined organics were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (100% EtOAc; isocratic on Analogix) to give 475 mg (77%) of the title compound as a pale yellow oil. LC/MS (ES) m/e 592.4 (M+H)+. Note that the product was contaminated with ˜1 eq of the starting dimethyl chlorophosphate/dimethyl hydrogenphosphate reagent and carried on as is.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH:11]=[C:10]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:24][CH:23]=2)[C:9]1=[O:36])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.CCCCCC.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH2:11][C@@H:10]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[CH:24][CH:23]=2)[C:9]1=[O:36])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1C(=O)C(c2ccc(OCc3ccccc3)cc2)=C[C@@H]1CO[Si](C)(C)C(C)(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1C(=O)[C@H](c2ccc(OCc3ccccc3)cc2)C[C@@H]1CO[Si](C)(C)C(C)(C)C
Yield: 99.7 %

Procedure:
A solution of (5R)-3-(4-benzyloxyphenyl)-5-(tert-butyldimethylsilanyloxymethyl)-2-oxo-2,5-dihydro-pyrrole-1-carboxylic acid tert-butyl ester (2.0 g, 3.92 mmol) in ethyl acetate (40 mL) and hexane (40 mL) was treated with 20% palladium hydroxide on carbon (200 mg) and hydrogenated in a Parr™ shaker at 3 atmospheres pressure for 2 hours. The catalyst was removed by filtration and the solvent was evaporated to provide the title compound as a yellow oil (2.0 g, 100%).
Reaction SMILES: [O:1]=[C:2]1[NH:3][C:4]2[C:9](/[C:10]/1=[CH:11]/[C:12]1[NH:16][C:15]([CH3:17])=[C:14]([C:18]([OH:20])=O)[C:13]=1[CH3:21])=[CH:8][CH:7]=[CH:6][CH:5]=2.Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.[NH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=1[NH:58][C:59](=[O:70])[C:60]1[CH:65]=[CH:64][C:63]([NH:66][CH2:67][CH2:68][NH2:69])=[N:62][CH:61]=1>[Cl-].[Na+].O.CN(C=O)C>[NH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=1[NH:58][C:59](=[O:70])[C:60]1[CH:65]=[CH:64][C:63]([NH:66][CH2:67][CH2:68][NH:69][C:18]([C:14]2[C:13]([CH3:21])=[C:12](/[CH:11]=[C:10]3\[C:2](=[O:1])[NH:3][C:4]4[C:9]\3=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:16][C:15]=2[CH3:17])=[O:20])=[N:62][CH:61]=1
Reactant: NCCNc1ccc(C(=O)Nc2ccccc2N)cn1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccccc32)c(C)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccccc32)c(C)c1C(=O)NCCNc1ccc(C(=O)Nc2ccccc2N)cn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 85.9 %

Procedure:
5-(2-Oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (282 mg, 1 mmol) and 8 ml of DMF were stirred at room temperature while 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (384 mg, 2 mmol), hydroxybenzotriazole (162 mg, 1.2 mmol), triethylamine (404 mg, 4 mmol) and N-(2-aminophenyl)-6-(2-aminoethylamino)nicotinamide (284 mg, 1.05 mmol) were added. The mixture was stirred for 20 hours at room temperature. The mixture was diluted with 400 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (460 mg, 86%) as a yellow solid. LC-MS (m/z) 536 (M+1).
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[C:15]([O:17][CH2:18][CH2:19][C:20]([OH:22])=O)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.C1CCCCC1.C(OCC)(=O)C.[CH2:39]([NH:41][CH2:42][CH3:43])[CH3:40]>C(Cl)(Cl)Cl>[CH2:39]([N:41]([CH2:42][CH3:43])[C:20](=[O:22])[CH2:19][CH2:18][O:17][C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:16]=1)[CH3:40]
Reactant: CCNCC
Reactant: O=C(O)CCOc1cc(-c2ccccc2)nc2ccccc12
Solvent: O=S(Cl)Cl
Solvent: C1CCCCC1
Solvent: ClC(Cl)Cl
Product: CCN(CC)C(=O)CCOc1cc(-c2ccccc2)nc2ccccc12

Procedure:
The procedure is as in Example 44, but starting with 3-[(2-phenyl-4-quinolyl)oxy]propanic acid (1.25 g), thionyl chloride (1.25 cc) in chloroform (100 cc) and diethylamine (2.66 cc). After chromatography of the residue on silica gel using the eluant cyclohexane/ethyl acetate (50:50 by volume), N,N-diethyl-3-[(2-phenyl-4-quinolyl)oxy]propanamide (0.43 g), m.p. 94° C., is isolated.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH2:5][CH2:6][CH2:7][CH2:8][CH:9]([CH2:13][C:14]1[CH:19]=[C:18]([F:20])[C:17]([O:21][Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])=[C:16]([F:32])[CH:15]=1)[C:10](O)=[O:11])[CH3:2].O>C1COCC1>[F:32][C:16]1[CH:15]=[C:14]([CH:19]=[C:18]([F:20])[C:17]=1[O:21][Si:22]([CH:29]([CH3:31])[CH3:30])([CH:23]([CH3:25])[CH3:24])[CH:26]([CH3:28])[CH3:27])[CH2:13][CH:9]([CH2:10][OH:11])[CH2:8][CH2:7][CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:33]
Reactant: CCOC(=O)CCCCC(Cc1cc(F)c(O[Si](C(C)C)(C(C)C)C(C)C)c(F)c1)C(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CCCCC(CO)Cc1cc(F)c(O[Si](C(C)C)(C(C)C)C(C)C)c(F)c1
Temperature: -10 °C

Procedure:
1.6 g (3.29 mmol) of 2-(3,5-difluoro-4-triisopropylsilanyloxybenzyl)heptanedioic acid 7-ethyl ester are dissolved in 30 ml of THF and cooled to −10° C. under argon. Then, 4.27 ml (4.27 mmol) of a 1 M borane-THF complex solution are added dropwise, and the mixture is stirred at 0° C. until reaction is complete. The mixture is hydrolyzed with water and extracted with ethyl acetate, and the combined organic phases are concentrated. The resulting crude product is purified by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 7:1, 3:1). 1.18 g (76% of theory) of the title compound are obtained.
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][CH:19]([OH:22])[CH2:20][OH:21])[CH:15]=2)[O:10][C:9]([C:23]2[N:28]=[CH:27][N:26]3[CH:29]=[CH:30][CH:31]=[C:25]3[CH:24]=2)=[CH:8]1)(C)(C)C.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[OH:22][CH:19]([CH2:20][OH:21])[CH2:18][O:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[O:10][C:9]([C:23]1[N:28]=[CH:27][N:26]3[CH:29]=[CH:30][CH:31]=[C:25]3[CH:24]=1)=[CH:8][C:7]2=[N:6][OH:5]
Reactant: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(OCC(O)CO)cc12
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: OCC(O)COc1ccc2oc(-c3cc4cccn4cn3)cc(=NO)c2c1
Temperature: 60 °C
Yield: 43.8 %

Procedure:
A solution of 6-(2,3-Dihydroxy-propoxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one O-tert-butyl oxime (example 86A) (100 mg, 0.236 mmol) in toluene (8 ml) was treated at 0° C. with trifluoro acetic acid (2 ml) and heated at 60° C. for 5.5 hours. The solution was concentrated under vacuum, the residue dissolved in ethyl acetate and washed successively with a saturated solution of sodium hydrogenocarbonate, brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel flash chromatography (gradient cyclohexane/ethyl acetate: 0-100% then ethyl acetate/methanol:90/10) to yield the title compound (38 mg, 44%) as a brown-yellow solid.
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[F:8][C:9]1[CH:36]=[CH:35][C:12]([CH2:13][N:14]2[CH2:19][CH2:18][N:17]3[C:20](=[O:33])[C:21]([CH2:26][CH:27]4[CH2:32][CH2:31][CH2:30][NH:29][CH2:28]4)=[C:22]([OH:25])[C:23]([OH:24])=[C:16]3[C:15]2=[O:34])=[CH:11][CH:10]=1.[CH:37]1([CH:40]=O)[CH2:39][CH2:38]1.C([BH3-])#N.[Na+]>CO>[OH:3][C:2]([C:4]([F:7])([F:6])[F:5])=[O:1].[CH:37]1([CH2:40][N:29]2[CH2:30][CH2:31][CH2:32][CH:27]([CH2:26][C:21]3[C:20](=[O:33])[N:17]4[CH2:18][CH2:19][N:14]([CH2:13][C:12]5[CH:11]=[CH:10][C:9]([F:8])=[CH:36][CH:35]=5)[C:15](=[O:34])[C:16]4=[C:23]([OH:24])[C:22]=3[OH:25])[CH2:28]2)[CH2:39][CH2:38]1
Reactant: O=C1c2c(O)c(O)c(CC3CCCNC3)c(=O)n2CCN1Cc1ccc(F)cc1
Reactant: O=CC1CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: O=C1c2c(O)c(O)c(CC3CCCN(CC4CC4)C3)c(=O)n2CCN1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(4-fluorobenzyl)-8,9-dihydroxy-7-(piperidin-3-ylmethyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione mono TFA salt (50 mg, 0.097 mmol) in anhydrous methanol (2 mL) under nitrogen, cyclopropanecarboxaldehyde (9 μL, 0.116mmol) was added and the solution was stirred at room temperature for one hour. Sodium cyanoborohydride (8 mg, 0.129 mmol) was added and the solution was stirred for another hour. The reaction mixture was concentrated under vacuum and the residue was purified by prep “HPLC [Gilson semi preparative HPLC system using a Waters Nova Pak column (10×40 mm I.D. cartridge, C18, 6 μM pore size) eluting with 95-5% water (0.10% TFA)/acetonitrile (0.10% TFA) gradient at 35 mL/min]. The product fractions were collected and lyophilized to provide the title compound as white solid.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[C:11]([O:13][C@H:14]1[CH2:18][CH2:17][NH:16][CH2:15]1)=[N:10][C:9]([C:19]1[NH:23][C:22](=[O:24])[NH:21][N:20]=1)=[CH:8]2.CC1C=CC=C(C)N=1.[C:33](Cl)(=[O:36])[CH:34]=[CH2:35]>C(Cl)Cl>[C:33]([N:16]1[CH2:17][CH2:18][C@H:14]([O:13][C:11]2[C:12]3[C:7](=[CH:6][CH:5]=[CH:4][C:3]=3[F:2])[CH:8]=[C:9]([C:19]3[NH:23][C:22](=[O:24])[NH:21][N:20]=3)[N:10]=2)[CH2:15]1)(=[O:36])[CH:34]=[CH2:35]
Reactant: O=c1[nH]nc(-c2cc3cccc(F)c3c(O[C@H]3CCNC3)n2)[nH]1
Reactant: C=CC(=O)Cl
Agent: Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: C=CC(=O)N1CC[C@H](Oc2nc(-c3n[nH]c(=O)[nH]3)cc3cccc(F)c23)C1
Temperature: -40 °C
Yield: 52.9 %

Procedure:
To a mixture of (S)-3-(8-fluoro-1-(pyrrolidin-3-yloxy)isoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one hydrochloride (80 mg, 0.22 mmol) in DCM (5 mL) was added 2,6-dimethylpyridine (70 mg, 0.6 mmol). The mixture was cooled to −40° C. Acryloyl chloride (25 mg, 0.28 mmol) was added and the reaction mixture was warmed to 0° C. over a 30 minute period. The reaction was quenched with MeOH (5 mL) and the mixture concentrated in vacuo. The crude product was purified by preparative HPLC to give the title compound (43 mg, 54%). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.07 (s, 1H), 11.88 (s, 1H), 8.01 (s, 1H), 7.85-7.83 (d, J=8 Hz, 1H), 7.78-7.76 (t, J=4 Hz, 1H), 7.39 (m, 1H), 6.67-6.64 (m, 1H), 6.19-6.14 (m, 2H), 5.72-5.66 (m, 1H), 4.06 (m, 0.5H), 3.85-3.58 (m, 3.5H), 2.29-2.25 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]3=[O:20])[CH:11]=[C:10]([C:21](O)=[O:22])[CH:9]=2)=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.Cl.[CH3:48][C:49]1[N:54]=[CH:53][C:52]([C@H:55]([NH2:57])[CH3:56])=[CH:51][CH:50]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]3=[O:20])[CH:11]=[C:10]([C:21]([NH:57][C@@H:55]([C:52]3[CH:53]=[N:54][C:49]([CH3:48])=[CH:50][CH:51]=3)[CH3:56])=[O:22])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc([C@@H](C)N)cn1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(N3CCCCC3=O)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(C(=O)N[C@H](C)c3ccc(C)nc3)cc(N3CCCCC3=O)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4′-methyl-5-(2-oxopiperidin-1-yl)biphenyl-3-carboxylic acid (45 mg, 0.14 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (56 mg, 0.29 mmol), 1-hydroxybenzotriazole hydrate (22 mg, 0.14 mmol), and CH2Cl2 (3 mL) were added (R)-1-(6-methylpyridin-3-yl)ethanamine hydrochloride (38 mg, 0.22 mmol) and N,N-diisopropylethylamine (51 μL, 0.29 mmol). The mixture was stirred at room temperature overnight and then concentrated. The residue was purified by preparative HPLC (100×20.2 mm, C18 column; 30-80% CH3CN-water [10 mM Et2NH]) to afford a white foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([OH:14])=[CH:12][C:11]([C:15]([F:18])([F:17])[F:16])=[N:10]2)=[CH:5][CH:4]=1.Br[CH2:20][N:21]1[C:25](=[O:26])[C:24]2[C:27]([CH:33]([CH3:35])[CH3:34])=[CH:28][C:29]([O:31][CH3:32])=[CH:30][C:23]=2[S:22]1(=[O:37])=[O:36].[F-].[K+]>CN(C=O)C.O>[CH:33]([C:27]1[C:24]2[C:25](=[O:26])[N:21]([CH2:20][O:14][C:13]3[N:9]([C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)[N:10]=[C:11]([C:15]([F:18])([F:16])[F:17])[CH:12]=3)[S:22](=[O:37])(=[O:36])[C:23]=2[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=1)([CH3:35])[CH3:34]
Reactant: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(CBr)C2=O
Reactant: COc1ccc(-n2nc(C(F)(F)F)cc2O)cc1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-n2nc(C(F)(F)F)cc2OCN2C(=O)c3c(C(C)C)cc(OC)cc3S2(=O)=O)cc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 46.2 %

Procedure:
A mixture of 1-(4-methoxyphenyl)-3-trifluoromethyl-5-hydroxy pyrazole (489 mg; 1.89 mmol), 2-bromomethyl-4-isopropyl-6-methoxy-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (600 mg, 1.72 mmol), and KF (200 mg; 3.44 mmol) in DMF (8 ml) was stirred at 20° C. for 2 hours and the mixture was diluted with water. The above mixture was extracted with ether (3×) and the organic layer was dried over sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography (silica gel; 25-50% ethyl acetate/hexane) and recrystallized from ethyl acetate/hexane to afford 418 mg (46%) of 4-isopropyl-6-methoxy-2-[1-(4-methoxyphenyl)-3-trifluoromethylpyrazol-5-yl-oxymethyl)-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (Formula I: R1 =4-CH3O--Ph; R2 =CF3 ; R3 =H; R4 =CH(CH3)2 ; R5 =6-OCH3) as a white solid, m.p. 111°-113° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:9][CH3:10])=[N:4][C:5](Cl)=[N:6][CH:7]=1.[NH2:11][CH2:12][CH2:13][OH:14]>C1COCC1>[Br:1][C:2]1[C:3]([O:9][CH3:10])=[N:4][C:5]([NH:11][CH2:12][CH2:13][OH:14])=[N:6][CH:7]=1
Reactant: NCCO
Reactant: COc1nc(Cl)ncc1Br
Solvent: C1CCOC1
Product: COc1nc(NCCO)ncc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.4 %

Procedure:
A mixture of 5-bromo-2-chloro-4-methoxypyrimidine (5 g, 22.4 mmol) and 2-amino ethanol (1.76 mL, 29.1 mmol) in THF (50 mL) was stirred for 18 h at rt. 2-Amino ethanol (2 mL) was added. The reaction mixture was stirred for 18 h at rt and concentrated. The residue was purified by flash chromatography (hexane/EtOAc, 3:2) to afford 4.08 g of the title compound. tR: 0.70 min (LC-MS 2); ESI-MS: 248.2 [M+H]+ (LC-MS 2); Rf: 0.06 (hexane/EtOAc 3:2).