Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:15])[NH:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14])([CH3:6])([CH3:5])[CH3:4].F[C:17]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:18]=1[N:26]1[CH:30]=[N:29][C:28]([CH3:31])=[N:27]1>C1COCC1>[CH3:31][C:28]1[N:29]=[CH:30][N:26]([C:18]2[CH:17]=[CH:22][C:21]([N+:23]([O-:25])=[O:24])=[CH:20][C:19]=2[O:14][CH2:13][CH2:12][CH2:11][CH2:10][NH:9][C:8](=[O:15])[O:7][C:3]([CH3:6])([CH3:4])[CH3:5])[N:27]=1
Reactant: CC(C)(C)OC(=O)NCCCCO
Reactant: Cc1ncn(-c2ccc([N+](=O)[O-])cc2F)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ncn(-c2ccc([N+](=O)[O-])cc2OCCCCNC(=O)OC(C)(C)C)n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 99.4 %

Procedure:
Sodium hydride (0.405 g, 10.13 mmol) was suspended in THF (6 mL), and then tert-butyl-(4-hydroxybutyl)carbamate (1.278 g, 6.75 mmol) in THF (6.0 mL) was added. The reaction mixture was stirred at 0° C. for 10 min, followed by the addition of 1-(2-fluoro-4-nitrophenyl)-3-methyl-1H-1,2,4-triazole (1.0 g, 4.50 mmol) in THF (10.0 mL). The mixture was stirred at 0° C. for 1 h and then stirred for an additional 2 h at rt. The reaction was quenched with water and extracted with EtOAc three times. After concentrating the combined EtOAc layers, the residue was purified by flash chromatography (silica gel, 300 g, 0 to 80% EtOAc/Hexane) to get tert-butyl (4-(2-(3-methyl-1H-1,2,4-triazol-1-yl)-5-nitrophenoxy)butyl)carbamate (1.75 g, 99% yield). LC-MS (M+Na)+=414.5. 1H NMR (500 MHz, chloroform-d) δ 8.88 (s, 1H), 8.10 (d, J=8.8 Hz, 1H), 8.00 (dd, J=8.9, 2.3 Hz, 1H), 7.95 (d, J=2.3 Hz, 1H), 4.28 (t, J=6.5 Hz, 2H), 3.22 (d, J=6.4 Hz, 2H), 2.52 (s, 3H), 2.01-1.92 (m, 2H), 1.74-1.68 (m, 2H), 1.46 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([CH3:11])=[CH:9][CH:10]=1)=[O:5])[CH3:2].S(Cl)([Cl:15])(=O)=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([CH3:11])=[C:9]([Cl:15])[CH:10]=1)=[O:5])[CH3:2]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)c1ccc(C)s1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)c1cc(Cl)c(C)s1
Reaction time: 1.5 h

Procedure:
5-Methyl-2-thiophenecarboxylic acid (2.84 g) was dissolved in N,N-dimethylformamide (30 ml), and iodoethane (1.68 ml) and potassium carbonate (2.76 g) were added. The mixture was stirred at room temperature for 15 hours, poured into water and extracted with diethyl ether. The extract was washed with 5% aqueous potassium hydrogen sulfate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 2-methyl-3-thiophenecarboxylic acid ethyl ester (1.84 g). 5-Methyl-2-thiophenecarboxylic acid ethyl ester (1.84 g) was dissolved in acetonitrile (30 ml), and sulfuryl chloride (1.31 ml) in acetonitrile (20 ml) was added dropwise. The mixture was stirred for 1.5 hour over a water bath, and 10% aqueous sodium thiosulfate (100 ml) was added. The mixture was stirred at room temperature for 2 hours and extracted with diethyl ether. The extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and the desired fractions were concentrated under reduced pressure to give 4-chloro-5-methyl-2-thiophenecarboxylic acid ethyl ester (1.67 g). 4-Chloro-5-methyl-2-thiophenecarboxylic acid ethyl ester (1.67 g) was dissolved in a mixture of ethanol (10 ml) and tetrahydrofuran (10 ml), and 1N aqueous sodium hydroxide (16 ml) was added. The mixture was stirred at 60° C. for 2 hours and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 4-chloro-5-methyl-2-thiophenecarboxylic acid (0.98 g) as crystals.
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][CH2:22][CH2:23][NH:24][C:25]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:26])=[O:19])C1C=CC=CC=1>CO.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][CH2:22][CH2:23][NH:24][C:25]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:26])=[O:19]
Reactant: CC(C)(C)OC(=O)NC(=O)NCCONC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NC(=O)NCCONC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2O
Reaction time: 3 h
Yield: 100.8 %

Procedure:
A mixture of tert-butyl ({2-[({[(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}carbamoyl)carbamate 85 (0.31 g, 0.64 mmol) and Pd/C (10%, 0.11 g) in methanol (10 mL) was hydrogenated at 1 atm at room temperature for 3 h. The mixture was filtered through Celite pad and concentrated to provide 86 (0.25 g, quantitative) as a white foam.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[N:6][CH:5]=[N:4]1.[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Cl)=[CH:12][CH:11]=1>CN(C=O)C>[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][N:3]2[CH:7]=[N:6][CH:5]=[N:4]2)=[CH:12][CH:11]=1
Reactant: c1nc[nH]n1
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2cncn2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.8 %

Procedure:
To a suspension of 4 g (0.16 mol) of sodium hydride in 200 ml of DMF at 0° C. was added 10 g (0.145 mol) of 1,2,4-triazole in 75 ml of DMF dropwise over a period of 30 minutes, and the mixture was allowed to warm to room temperature and stirred for 1 h. The above mixture was cooled to 0° C., 25 g (0.16 mol) of p-methoxybenzyl chloride was added, the mixture was allowed to warm to room temperature, and stirred for 16 h. The reaction mixture was concentrated in vacuo and the residue was purified by chromatography on silica (hexane/ethyl acetate) to afford 21.9 g (64.5%) of 1-(p-methoxybenzyl)-1,2,4-triazole.
Reaction SMILES: [C@H:1]1([OH:7])[CH2:5][CH2:4][CH2:3][C@@H:2]1[OH:6].Cl[C:9]1[N:18]=[C:17](Cl)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[H-].[Na+].[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CN(C)C=O.C(OCC)(=O)C.O1CCOCC1>[OH:6][C@H:2]1[CH2:3][CH2:4][CH2:5][C@@H:1]1[O:7][C:17]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[N:18]=1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: O[C@H]1CCC[C@@H]1O
Reactant: C1CNCCN1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O[C@H]1CCC[C@@H]1Oc1nc(N2CCNCC2)nc2ccccc12
Yield: 35.2 %

Procedure:
To a solution of (1S,2S)-cyclopentane-1,2-diol [manufactured by Fluka Co., cf. J. Org. Chem., 53, 1823 (1988)] (1.00 g) and 2,4-dichloroquinazoline (1.85 g) in dimethylformamide (9 ml) is added gradually 60% sodium hydride (in oil) (409 mg) with stirring under ice-cooling, and the mixture is stirred at room temperature for 1 hour and 20 minutes. The reaction mixture is diluted with ethyl acetate and washed with water 5 times. The resulting ethyl acetate solution is dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure, and the residue is briefly purified with medium pressure column chromatography (eluent, chloroform) to give an oily substance. The oily substance thus obtained is dissolved in dioxane (8 ml), and the mixture is slowly added dropwise to a solution of piperazine (2.21 g) in dioxane (10 ml) with stirring at 70° C., and the mixture is stirred at the same temperature for 40 minutes. The reaction mixture is diluted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. The resulting solution is evaporated to dryness under reduced pressure, and the residue is purified by medium pressure liquid column chromatography (eluent, chloroform:methanol=10:1, 5:1, v/v) to give 4-[(1S,2S)-(2-hydroxycyclopentan-1-yl)oxy]-2-(1-piperazinyl)-quinazoline (1.03 g) as crystals.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[Cl:7].[OH-].[K+].[Br:10][CH2:11][CH3:12].[K+].[Br-].Br[CH2:16][CH2:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=1>C(#N)C>[Br-:10].[CH2:16]([N+:3]1[C:2]([Cl:1])=[C:6]([Cl:7])[N:5]([C:18]2([CH2:17][CH3:16])[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19]2)[CH:4]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:11][CH3:12]
Reactant: Clc1nc[nH]c1Cl
Reactant: BrCCc1ccc2ccccc2c1
Reactant: CCBr
Agent: [Br-]
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: CCCCCCCCCCCC[n+]1cn(C2(CC)C=Cc3ccccc3C2)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4,5-Dichloroimidazole (1.23 g, 9 mmol) will be dissolved into acetonitrile. Potassium hydroxide (0.61 g, 9.9 mmol) will be added and the mixture will be allowed to stir for 0.5 h. 1-bromethane (9 mmol) will be added and the solution will be allowed to reflux overnight. The solution will be filtered hot to remove a white precipitate (presumed to be KBr) and 2-(2-bromoethyl)naphthalene (9 mmol) will be added and the mixture will be returned to reflux overnight. The mixture will be allowed to cool to room temperature, and the volatiles will be removed en vacuo resulting in the product.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[C@H:15]([OH:24])[CH2:16][C@H:17]([OH:23])[CH2:18][C:19]([O:21]C)=[O:20])=[C:11]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH3:3].[OH-].[Na+:33].CC(OC)(C)C>O.CC(O)C>[CH3:3][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[CH:15]([OH:24])[CH2:16][CH:17]([OH:23])[CH2:18][C:19]([O-:21])=[O:20])=[C:11]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2)[CH3:1].[Na+:33]
Reactant: COC(=O)C[C@@H](O)C[C@@H](O)/C=C/c1c(-c2ccc(F)cc2)c2ccccc2n1C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Solvent: COC(C)(C)C
Product: CC(C)n1c(/C=C/C(O)CC(O)CC(=O)[O-])c(-c2ccc(F)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
Fluvastatin methyl ester (3.0 g) was added to a solution of NaOH (1 eq.) in water (0.75 ml) and propan-2-ol (7.5 ml). The mixture was heated to reflux and 1 ml of propan-2-ol was added. After 2 h, the mixture was cooled to room temperature and stirred for 2 h. MTBE (60 ml) was dripped into the solution over 20 min and the resulting mixture was stirred for another 1.5 h. The product was isolated by filtration under nitrogen, washed with MTBE and dried at 50° C. in a vacuum oven for 24 h to obtain 1.9 g (62%) of fluvastatin sodium Form XIV.
Reaction SMILES: [CH2:1]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N(OC(C)(C)C)=[O:14].ON1C(=O)C2=CC=CC=C2C1=O.C1(=NO)CCCCCCCCCCC1.[N+](C1CCCCCCCCCCC1)([O-])=O>C(O)(=O)C>[C:1]1(=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)ON=O
Reactant: C1CCCCCCCCCCC1
Agent: O=C1c2ccccc2C(=O)N1O
Agent: O=[N+]([O-])C1CCCCCCCCCCC1
Agent: ON=C1CCCCCCCCCCC1
Solvent: CC(=O)O
Product: O=C1CCCCCCCCCCC1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
Cyclododecane (1 ml), t-butyl nitrite (1 mmol), N-hydroxyphthalimide (0.2 mmol), and acetic acid (1 ml) were placed in a flask and were stirred at 80° C. in an atmosphere of argon gas (1 atm=0.101 MPa) for 20 hours. The resulting reaction mixture was analyzed to find that cyclododecanone oxime, nitrocyclododecane, and cyclododecanone were formed in yields of 41%, 4%, and 9%, respectively.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[S:9]([N:12]([CH2:14][C:15]1[O:19][CH:18]=[C:17]([C:20](O)=[O:21])[CH:16]=1)[CH3:13])(=[O:11])=[O:10].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:35][N:36]1[CH2:41][CH2:40][CH:39]([CH2:42][N:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[CH2:38][CH2:37]1>ClCCCl>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[S:9]([N:12]([CH3:13])[CH2:14][C:15]1[O:19][CH:18]=[C:17]([C:20]([N:46]2[CH2:45][CH2:44][N:43]([CH2:42][CH:39]3[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]3)[CH2:48][CH2:47]2)=[O:21])[CH:16]=1)(=[O:10])=[O:11]
Reactant: CN1CCC(CN2CCNCC2)CC1
Reactant: CN(Cc1cc(C(=O)O)co1)S(=O)(=O)c1c(Cl)cccc1Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCCl
Product: CN1CCC(CN2CCN(C(=O)c3coc(CN(C)S(=O)(=O)c4c(Cl)cccc4Cl)c3)CC2)CC1
Reaction time: 1 h

Procedure:
5-({[(2,6-dichlorophenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (465 mg, 1.3 mmol) was dissolved in DCE (40 mL) and CDI (422 mg, 2.6 mmol) was added. The reaction was stirred for 1 h. 4 mL of activated acid solution in DCE was added to a vial containing 1-[(1-methylpiperidin-4-yl)methyl]piperazine (51 mg, 0.258 mmol). The reaction was stirred at ambient temperature for 3 days, then washed with saturated aqueous NaHCO3. The organic layer was dried over MgSO4 and shaken with PL-MIA and Ambersep resins, then filtered. The solvent was removed in vacuo and a portion of the crude product purified using prep method B.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:11](Cl)(=[O:13])=[O:12])[CH:7]=[CH:8][C:9]=1[Cl:10])([O-])=O.[Cl:15][C:16]1[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=1[NH2:18].N1C=CC=CC=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:10][C:9]1[CH:8]=[CH:7][C:6]([S:11]([C:16]2([Cl:15])[CH:22]=[CH:21][CH:20]=[CH:19][CH:17]2[NH2:18])(=[O:13])=[O:12])=[CH:5][C:4]=1[NH2:1]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Reactant: Nc1ccccc1Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Nc1cc(S(=O)(=O)C2(Cl)C=CC=CC2N)ccc1Cl
Yield: 14.7 %

Procedure:
A solution of 3-nitro-4-chlorobenzenesulphonyl chloride (768 mg, 3.0 mmol), 2-chloroaniline (383 mg, 3.0 mmol), 4-dimethylaminopyridine (10 mg, 0.08 mmol) and pyridine (0.30 ml, 3.6 mmol) in DCM (35 ml) was stirred at ambient temperature overnight. The solution was evaporated to dryness, the residue dissolved in EtOAc and washed with 1.0 M aqueous hydrochloric acid and brine, dried and evaporated to dryness. The residue was dissolved in EtOAc (30 ml) and hydrogenated over 10% Pd/C for 4 h at ambient temperature. The catalyst was removed by filtration and the EtOAc evaporated to dryness. The residue was purified by column chromatography on basic alumina using 5% methanol in EtOAc to give, as a solid, the title compound (140 mg, 0.44 mmol). MS: 315.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[C:15][C:16]2[C:21]([Cl:22])=[CH:20][N:19]=[C:18](Cl)[CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:24][C:25]1[CH:30]=[C:29]([S:31]([CH3:34])(=[O:33])=[O:32])[CH:28]=[CH:27][C:26]=1B(O)O>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[C:15][C:16]2[C:21]([Cl:22])=[CH:20][N:19]=[C:18]([C:26]3[CH:27]=[CH:28][C:29]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:30][C:25]=3[F:24])[CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C#Cc2cc(Cl)ncc2Cl)CC1
Reactant: CS(=O)(=O)c1ccc(B(O)O)c(F)c1
Product: CC(C)(C)OC(=O)N1CCC(C#Cc2cc(-c3ccc(S(C)(=O)=O)cc3F)ncc2Cl)CC1

Procedure:
The title compound is prepared from 4-(2,5-dichloro-pyridin-4-ylethynyl)-piperidine-1-carboxylic acid tert-butyl ester and 2-fluoro-4-(methanesulfonyl)phenylboronic acid following a procedure analogous to that described for Intermediate 14. LC (method 7): tR=1.63 min; Mass spectrum (ESI+): m/z=493 [M+H]+.
Reaction SMILES: CCN(C(C)C)C(C)C.[I:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[O:17][C:16](=[O:21])[C:15]([C:22]([OH:24])=O)=[CH:14]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:49]1[C:50]([C:58]2[CH:59]=[C:60]([NH2:64])[CH:61]=[CH:62][CH:63]=2)=[CH:51][N:52]2[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=12>CN(C=O)C>[N:49]1[C:50]([C:58]2[CH:59]=[C:60]([NH:64][C:22]([C:15]3[C:16](=[O:21])[O:17][C:18]4[C:13]([CH:14]=3)=[CH:12][C:11]([I:10])=[CH:20][CH:19]=4)=[O:24])[CH:61]=[CH:62][CH:63]=2)=[CH:51][N:52]2[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=12
Reactant: Nc1cccc(-c2cn3ccccc3n2)c1
Reactant: O=C(O)c1cc2cc(I)ccc2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(-c2cn3ccccc3n2)c1)c1cc2cc(I)ccc2oc1=O
Temperature: 25 °C
Yield: 33.8 %

Procedure:
DIEA (30.3 μL, 0.17 mmol) was added to 6-iodo-3-carboxy-coumarin (50.0 mg, 0.16 mmol) and HATU (66.2 g, 0.17 mmol) in 1 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-Imidazo[1,2-a]pyridin-2-yl-phenylamine (33.1 mg, 0.16 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 27.4 mg of product in 34% yield: LCMS (ESI) m/z 508 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.Cl[C:31](=[O:37])[C:32]([O:34][CH2:35][CH3:36])=[O:33]>>[CH2:35]([O:34][C:32]([C:31](=[O:37])[NH:21][C@@H:19]([CH3:20])[C@H:18]([O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[N:9]=[CH:10]2)[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1)=[O:33])[CH3:36]
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Reactant: CCOC(=O)C(=O)Cl
Product: CCOC(=O)C(=O)N[C@@H](C)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1cccc(OC)c1

Procedure:
Prepared as described in Example 1 using (1R,2S)-1-[1-(4-fluorophenyl)-indazol-5-yl]oxy-1-(3-methoxyphenyl)-propan-2-amine (52 mg, 0.13 mmol) and ethyl 2-chloro-2-oxoacetate (0.030 mL, 0.27 mmol). Yield 53 mg (81%).
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[NH:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([NH2:18])=[C:4]([C:19]([OH:21])=[O:20])[C:3]=1[C:22]([OH:24])=[O:23].C[O-].[Na+].CN(C)C=O.Cl[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][OH:40]>O>[OH:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][N:16]=[C:14]1[C:15]2[C:2]([NH2:1])=[C:3]([C:22]([OH:24])=[O:23])[C:4]([C:19]([OH:21])=[O:20])=[C:5]([NH2:18])[C:6]=2[C:7](=[O:17])[C:8]2[C:13]1=[CH:12][CH:11]=[CH:10][CH:9]=2
Reactant: N=C1c2ccccc2C(=O)c2c(N)c(C(=O)O)c(C(=O)O)c(N)c21
Reactant: OCCCCCCCl
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1c(C(=O)O)c(C(=O)O)c(N)c2c1C(=O)c1ccccc1C2=NCCCCCCO
Temperature: 100 °C

Procedure:
A mixture of 9.2 g of 1,4-diaminoanthraquinone-2,3-dicarboxylic acid imide, 1.8 g of sodium methylate and 50 g of dimethylformamide is heated to 100° C., 4.9 g of 6-chlorohexan-1-ol are added, the mixture is heated at 100° C. for 3 hours, allowed to cool and poured onto 300 g of water, and the precipitated product is filtered off under suction, washed with water, dried and then recrystallized from 1,1,2-trichloroethane.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=O.[CH:12]1([CH2:15][CH:16]([C:19]2[CH:20]=[N:21][C:22]([CH3:25])=[N:23][CH:24]=2)[CH2:17][NH2:18])[CH2:14][CH2:13]1>>[Cl:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:2]([Cl:1])[C:3]=1[C:4]([NH:18][CH2:17][CH:16]([C:19]1[CH:24]=[N:23][C:22]([CH3:25])=[N:21][CH:20]=1)[CH2:15][CH:12]1[CH2:14][CH2:13]1)=[O:6]
Reactant: O=C(O)c1c(Cl)cccc1Cl
Reactant: Cc1ncc(C(CN)CC2CC2)cn1
Product: Cc1ncc(C(CNC(=O)c2c(Cl)cccc2Cl)CC2CC2)cn1

Procedure:
The racemic mixture which was prepared in a similar manner to example 3a from 2,6-dichlorobenzoic acid and 3-cyclopropyl-2-(2-methylpyrimidin-5-yl)propan-1-amine was separated into the two enantiomers by preparative SFC to yield the title compound. LCMS (MH+): m/z=364.1, tR (minutes, Method F)=2.43. [α]D20=+15.42 (c=2.4 mg/mL,CHCl3)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.FC1C=CC(C2C=CN=C([Cl:27])C=2)=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][N:11]=[C:12]([Cl:27])[CH:13]=2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(-c2ccncc2)cc1
Reactant: Fc1ccc(-c2ccnc(Cl)c2)cc1
Product: Clc1ccc(-c2ccnc(Cl)c2)cc1

Procedure:
4-(4-Chlorophenyl)-2-chloropyridine is prepared from 4-(4-chlorophenyl)-pyridine using the same reaction sequence as that described for the preparation of 4-(4-fluorophenyl)-2-chloropyridine (Example 21, steps b and c).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:13][C@@H:14]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:15]([O:17][CH3:18])=[O:16])[C:5]([CH2:11]O)=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.[Cl:24]CCl>S(Cl)(Cl)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:13][C@@H:14]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:15]([O:17][CH3:18])=[O:16])[C:5]([CH2:11][Cl:24])=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2
Reactant: ClCCl
Reactant: COC(=O)C[C@H](Cc1cc(Br)c2[nH]ncc2c1CO)C(=O)OC
Solvent: O=S(Cl)Cl
Product: COC(=O)C[C@H](Cc1cc(Br)c2[nH]ncc2c1CCl)C(=O)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
(S)-dimethyl 2-((7-bromo-4-(hydroxymethyl)-1H-indazol-5-yl)methyl)succinate (2.25 g, 5.8 mmol) was dissolved in 2M thionyl chloride in dichloromethane (42 mL, 84 mmol). Reaction stirred at room temperature for 2.0 hours. Mixture was concentrated. Residue was treated with toluene and then concentrated by roto-vap. Residue was dissolved in ethyl acetate. Mixture was washed twice with aqueous sodium bicarbonate. Organic was dried (magnesium sulfate), filtered and concentrated in vacuo. Title compound was obtained as amber solid in 99% yield.
Reaction SMILES: CO.[C:3](Cl)(=O)C.[O:7]=[C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][N:9]1[CH:17]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH2:31][CH3:32])[CH:23]=1)[CH2:18][C:19]([OH:21])=[O:20]>CCCCCC.CCOCC>[O:7]=[C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][N:9]1[CH:17]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH2:31][CH3:32])[CH:23]=1)[CH2:18][C:19]([O:21][CH3:3])=[O:20]
Reactant: CCOc1cc(C(CC(=O)O)N2Cc3ccccc3C2=O)ccc1OC
Reactant: CC(=O)Cl
Solvent: CCCCCC
Solvent: CCOCC
Solvent: CO
Product: CCOc1cc(C(CC(=O)OC)N2Cc3ccccc3C2=O)ccc1OC
Reaction time: 4 h
Yield: 87.3 %

Procedure:
To an ice bath cooled solution of 50 mL of methanol was added acetyl chloride (7.2 mL, 100 mmol). After stirring for 10 minutes 3-(1-oxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionic acid (6.00 g, 16.9 mmol) was added to the mixture. After 30 minutes the ice bath was removed and the reaction was monitored by HPLC (Waters radial pak phenyl 8×100 mm column, 240 mm, 1.5 mL/min, 35/65 acetonitrile/0.1% phosphoric acid). After 4 hours the reaction had reached completion. The methanol was removed in vacuo and the resulting residue was diluted with 50 mL of methylene chloride. The mixture was extracted with aqueous sodium bicarbonate (50 mL) and brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford a thick oil. Hexane (50 mL) and ether (5 mL) were added to the oil and the mixture stirred overnight in an open flask. An additional 25 mL of hexane were added to facilitate stirring. After 6 hours the slurry was filtered and the solid air dried and then dried in vacuo (60° C.,<1 mm) to afford 5.45 g (87%) of methyl 3-(1-oxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate as a white solid: mp 78-80° C.; 1H NMR (DMSO-d6)δ 7.75-7.40 (m, 4H), 7.10-6.80 (m, 3H), 5.72 (t, J=7.8 Hz, 1H), 4.51 (d, J=1.7.7 Hz, 1H), 4.09 (d, J=17.7 Hz, 1H), 3.97 (m, 2H), 3.73 (s, 3H), 3.55 (s, 3H), 3.24 (m, 2H), 1.30 (m, 3H); 13C NMR (DMSO-d6)δ 170.8, 166.8, 148.5, 147.9, 141.6, 132.0, 131.3, 131.2, 127.8, 123.4, 122.8, 119.3, 112.2, 111.8, 63.7, 55.4, 51.5, 51.0, 46.3, 36.2, 14.6; Anal. Calcd. for C21H23NO5. Theoretical: C, 68.28; H, 6.28; N, 3.79. Found: C, 68.13; H, 6.27; N, 3.70.