Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Cl:13][S:14](O)(=[O:16])=[O:15]>>[CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[C:7]1[CH:8]=[CH:9][C:10]([S:14]([Cl:13])(=[O:16])=[O:15])=[CH:11][CH:12]=1
Reactant: O=S(=O)(O)Cl
Reactant: Cc1ncoc1-c1ccccc1
Product: Cc1ncoc1-c1ccc(S(=O)(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4-methyl-5-phenyl-oxazole (1.6 g, 10 mmol), prepared according to the literature (Heterocycles, 1977, 7, 77-80), was dissolved in chlorosulfonic acid (10 mL) and stirred at room temperature for 4 h. The reaction mixture was added to crushed ice (50 g) and the product was extracted with ether (3×50 mL). The combined organic extract was dried over anhydrous Na2SO4 and ether was evaporated. The product was purified by flash chromatography (silica-gel, 5-20% ethylacetate/hexane mobile phase) to yield 0.91 g of the desired-title compound light yellow solid. MS: m/z 258.0 (M++1).
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].Cl.[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH2:15])=[CH:12][C:11]=1[N+:18]([O-:20])=[O:19]>C1COCC1>[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH:15][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])=[CH:12][C:11]=1[N+:18]([O-:20])=[O:19]
Reactant: NCc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
TEA (8.00 mL, 57.5 mmol) followed by pivaloyl chloride (2.80 mL, 22.8 mmol) in THF (25 mL) were added to 4-chloro-3-nitrobenzylamine hydrochloride (5.00 g, 22.4 mmol) in THF (100 mL). The reaction mixture was diluted with THF and stirred at rt for 1.5 h. The mixture was filtered and washed. The filtrate was concentrated to give the sub-title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11].C([O-])([O-])=O.[Na+].[Na+].[CH3:31][O:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1>COCCOC>[CH:22]([N:12]([C:10](=[O:11])[CH2:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:37]1[CH:36]=[CH:35][CH:34]=[C:33]([O:32][CH3:31])[CH:38]=1)[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:24])[CH3:23]
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)CCc1ccccc1Br
Reactant: COc1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cccc(-c2ccccc2CCC(=O)N(NC(=O)c2ccccc2)C(C)C)c1
Yield: 59.1 %

Procedure:
A solution of benzoic acid N′-[3-(2-bromo-phenyl)-propionyl]-N′-isopropyl-hydrazide (50 mg, 0.13 mmol) in DME (4 ml)/2M Na2CO3 (225 μL, 0.45 mmol) was treated with 3-methoxy-phenylboronic acid (29 mg, 0.19 mmol) and Pd[PPh3]4 (15 mg, 0.013 mmol) for 18 hours at 90° C. The reaction mixture was partitioned between water and dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-50% ethyl acetate/hexanes gradient to afford the product as a solid (32 mg, 60%). LC-MS m/e 417.35 (M+H+)
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1.Cl[CH:15]([C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=1)[CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1>CN(C)C=O>[F:31][C:28]([F:29])([F:30])[C:25]1[CH:26]=[CH:27][C:22]([CH:15]([S:3][C:4]2[CH:5]=[CH:6][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:12][CH:13]=2)[CH2:16][N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)=[CH:23][CH:24]=1
Reactant: FC(F)(F)c1ccc(C(Cl)Cn2ccnc2)cc1
Reactant: COC(=O)c1ccc(S)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(SC(Cn2ccnc2)c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.4 %

Procedure:
292 mg of a 55% w/w suspension of sodium hydride in mineral oil were added to 1.13 g of methyl 4-mercaptobenzoate in 8 ml of dry dimethylformamide, whilst ice-cooling, and the resulting mixture was stirred at room temperature for 30 minutes. 1.61 g of 1-[2-chloro-2-(4-trifluoromethylphenyl)ethyl]imidazole in 7 ml of dry dimethylformamide was added to this solution and the resulting mixture was heated at 60°-70° C. for 6 hours. At the end of this time, the reaction mixture was treated and purified by the same method as described in Example 1, to give 844 mg of the title compound as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:7]3[CH2:15][CH:10]([C:11](=O)[C:12]=2[CH:13]=1)[CH:9]=[CH:8]3.[OH-].[K+].O.NN>C(O)CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:7]3[CH2:15][CH:10]([CH2:11][C:12]=2[CH:13]=1)[CH:9]=[CH:8]3
Reactant: COc1ccc2c(c1)C(=O)C1C=CC2C1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: COc1ccc2c(c1)CC1C=CC2C1
Temperature: 25 °C

Procedure:
5-Methoxytricyclo[7.2.1.02,7]dodeca-2(7),3,5,10-tetraene-8-one (9.41 g, 47 mmol) and pulverized potassium hydroxide (KOH) (6.17 g, 110 mmol) were warmed in ethylene glycol (50 mL) until solution occurred. The mixture was cooled to rt, treated with hydrazine hydrate (6 mL, 190 mmol) and heated to reflux for 2 hours. The reflux condenser was replaced with a distilling head and distillates were collected from 120-190° C. The distillates were diluted with H2O (100 mL) and extracted with EtOAc (4×40 mL). The organic layer was washed with H2O (4×30 mL), brine (25 mL), dried (MgSO4), filtered and concentrated to an oil (8.2 g, 94%). (TLC 25%EtOAc/hexanes Rf 0.68). 1H NMR (CDCl3) δ6.92 (d, J=8.0 Hz, 1H), 6.88 (m, 2H), 6.25 (dd, J=5.1,2.5 Hz, 1H), 5.79 (dd, J=5.1,2.4 Hz, 1H), 3.77 (s, 3H), 3.31 (br s, 1H), 3.01-2.94 (2H), 2.56 (d, J=16.5 Hz, 1H), 2.22 (m, 1H), 1.85 (d, J=10.0 Hz, 1H). GCMS m/e 186 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([Cl:11])[CH:3]=1.[C:12](=O)([O-])[O-].[K+].[K+].IC.O>CN(C)C=O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:12])=[O:7])=[C:4]([Cl:11])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COC(=O)c1ccc(Br)cc1Cl
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of 4-bromo-2-chlorobenzoic acid (450 g) in N,N-dimethylformamide (3000 mL) were added potassium carbonate (792.4 g) and iodomethane (271 g) at 10° C., and the mixture was stirred at the same temperature for 2 hr. Iodomethane (54.3 g) was added, and the mixture was stirred at the same temperature for 1 hr. Iodomethane (27.2 g) was added again, and the mixture was stirred at the same temperature for 1 hr. Iodomethane (27.2 g) was further added, and the mixture was stirred at the same temperature for 1 hr. The reaction mixture was poured into water, and partitioned and extracted with ethyl acetate. The organic layer was washed with 25% brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (477 g) as a pale-yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:19]=1)[NH:7][C:8](=[O:18])[CH2:9][N:10]=[C:11]2[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[H-].[Na+].[CH3:22]I>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:19]=1)[N:7]([CH3:22])[C:8](=[O:18])[CH2:9][N:10]=[C:11]2[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CI
Reactant: O=C1CN=C(c2ccccc2)c2ccc(Br)cc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)CN=C(c2ccccc2)c2ccc(Br)cc21
Yield: 59.2 %

Procedure:
Title compound 354 (3.1 g, 11.8 mmol), sodium hydride (565 mg, 14.14 mmol) and methyliodide (0.88 mL, 14.14 mmol) were stirred together in DMF (60 mL) at room temperature for 6 hours. DMF was removed and the residue was partitioned in EtOAc and water. The organic layer was dried, filtered and evaporated. The crude product was purified by flash chromatography (3:1 to 1:2 hexane:ethyl acetate) to afford title compound 357 (2.3 g, 60%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[F:10].[CH3:11][C@H:12]1[CH2:17][O:16][CH2:15][C@H:14]([CH3:18])[NH:13]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:13]2[C@@H:14]([CH3:18])[CH2:15][O:16][CH2:17][C@@H:12]2[CH3:11])=[CH:4][C:3]=1[F:10]
Reactant: C[C@H]1COC[C@H](C)N1
Reactant: O=Cc1ccc(Br)c(F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@H]1COC[C@H](C)N1Cc1ccc(Br)c(F)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 30.4 %

Procedure:
4-Bromo-3-fluorobenzaldehyde (0.250 g, 1.23 mmol) and (3S,5S)-3,5-dimethylmorpholine (0.205 g, 1.35 mmol) were dissolved in dichloromethane (10 mL). Sodium triacetoxyborohydride (0.378 g, 1.79 mmol) was added and the mixture was stirred under argon atmosphere at RT for 20 h. The mixture was diluted with dichloromethane and washed with NaHCO3 (aq). The organic phase was dried (MgSO4) and evaporated. The residue was purified by column chromatography on silica eluting with gradients of ammonia in methanol and dichloromethane. The fractions containing product were pooled and evaporated to give (3S,5S)-4-(4-bromo-3-fluorobenzyl)-3,5-dimethylmorpholine (0.113 g, 30%) as a liquid.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[C:11](=[O:12])[CH:10]2[C:5](=[C:6]3[N:16]=[C:15]([C:17]4[CH:22]=[C:21]([S:23][CH3:24])[CH:20]=[CH:19][C:18]=4[O:25][CH3:26])[N:14]=[C:7]3[C:8](=[O:13])[CH2:9]2)[CH:4]=[N:3]1.OO.C(=O)([O-])[O-:31].[K+].[K+]>C(O)(=O)C.O>[CH3:1][C:2]1([CH3:27])[C:11](=[O:12])[CH:10]2[C:5](=[C:6]3[N:16]=[C:15]([C:17]4[CH:22]=[C:21]([S:23]([CH3:24])=[O:31])[CH:20]=[CH:19][C:18]=4[O:25][CH3:26])[N:14]=[C:7]3[C:8](=[O:13])[CH2:9]2)[CH:4]=[N:3]1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(SC)cc1C1=NC2=C3C=NC(C)(C)C(=O)C3CC(=O)C2=N1
Agent: OO
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(S(C)=O)cc1C1=NC2=C3C=NC(C)(C)C(=O)C3CC(=O)C2=N1
Reaction time: 0.5 h

Procedure:
3.0 gm of 7,7-dimethyl-2-(2-methoxy-5-metylmercapto-phenyl)-5H,7H-imidazo[4,5-h]isoquinoline-4,6-dione were dissolved in 60 ml of glacial acetic acid and then 0.88 ml of 30% hydrogen peroxide were slowly added dropwise at room temperature. After stirring for 30 minutes, the solution was neutralized with an aqueous saturated potassium carbonate solution, diluted with water and extracted with chloroform. The residual crude product obtained after evaporation of the chloroform was purified on a silicagel column (eluant: chloroform with increasing content of acetone).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.O=P(Cl)(Cl)[Cl:12]>>[ClH:12].[C:1]([Cl:12])(=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1
Reactant: O=C(O)c1cccnc1
Reactant: O=P(Cl)(Cl)Cl
Product: Cl
Product: O=C(Cl)c1cccnc1

Procedure:
A solution of nicotinic acid (0.50 g, 4.0 mmol) and POCl3 (5 mL) was heated at reflux for 1.5 h and concentrated. The product obtained was directly used in the next reaction.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][SH:4].[C:5]1(=[O:11])[O:10][CH2:9][CH2:8][CH2:7][CH2:6]1>[Zn].O>[OH:11][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([NH:1][CH2:2][CH2:3][SH:4])=[O:10]
Reactant: O=C1CCCCO1
Reactant: NCCS
Agent: [Zn]
Solvent: O
Product: O=C(CCCCO)NCCS
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture, stirred under an inert atmosphere, of 5 g of cysteamine and 6.05 cm3 of δ-valerolactone is brought to a temperature of about 60°-70° C. for 15 hours. The disappearance of the δ-valerolactone is followed by VPC. The reaction mixture is then poured into 100 cm3 of water and 10 g of acid resin, "Dowex 50" and 3 g of zinc powder are added. The resulting mixture is stirred for 4 hours at ambient temperature and then left overnight. The next day the mixture is filtered and the water is evaporated under reduced pressure.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][S:9]([C:11]1[C:19]2[C:14](=[CH:15][C:16]([C:20]([N:22]3[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]3)=[O:21])=[CH:17][CH:18]=2)[N:13]([C:35]2[N:40]=[CH:39][C:38]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[CH:37][N:36]=2)[CH:12]=1)=[O:10].C(=O)([O-])O.[Na+]>ClCCl.O>[CH3:8][S:9]([C:11]1[C:19]2[C:14](=[CH:15][C:16]([C:20]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[O:21])=[CH:17][CH:18]=2)[N:13]([C:35]2[N:36]=[CH:37][C:38]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[CH:39][N:40]=2)[CH:12]=1)=[O:10]
Reactant: CS(=O)c1cn(-c2ncc(-c3ccccc3)cn2)c2cc(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)ccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)c1cn(-c2ncc(-c3ccccc3)cn2)c2cc(C(=O)N3CCNCC3)ccc12
Reaction time: 2 h

Procedure:
TFA (0.5 mL) was added to compound 12d) (170 mg, 0.311 mmol) in dichloromethane (5 mL) at room temperature and the solution was stirred for 2 h. The reaction mixture was then diluted with water, adjusted to pH 8 via addition of saturated sodium hydrogen carbonate solution and extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and evaporated. The remnant was purified by preparative TLC using a blend of 5% methanol in dichloromethane as eluent. White solid. Yield: 75 mg (51% of theory). Melting range: 193-197° C. HPLC (method 3): Rt=4.02 min. Mass spectroscopy: m/z: [M+H]+=446.1.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[S:11][C:12]3[CH:18]=[C:17]([CH:19]=O)[CH:16]=[CH:15][C:13]=3[N:14]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].CC(O)=O.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.[BH3-]C#N.[Na+]>C1COCC1>[CH:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[S:11][C:12]3[CH:18]=[C:17]([CH2:19][N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[CH:16]=[CH:15][C:13]=3[N:14]=2)[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCN(c2nc3ccc(C=O)cc3s2)CC1
Reactant: C1COCCN1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)N1CCN(c2nc3ccc(CN4CCOCC4)cc3s2)CC1
Temperature: 63 °C
Yield: 20.8 %

Procedure:
To a solution of 2-(4-isopropylpiperazin-1-yl)benzothiazole-6-carboxaldehyde (0.5 g, 1.73 mmol) and AcOH (11 mg, 0.173 mmol) in THF (5 mL), morpholine (0.31 mL, 3.46 mmol) and NaCNBH3 (132 mg, 2.08 mmol) were added in turn. The reaction mixture was heated at 63° C. for 12 hours. The solvent was removed and the residue was extracted with ethyl acetate, washed with water and brine and dried (MgSO4). The volatiles were evaporated and the residue was purified by preparative HPLC to yield 130 mg (21%) of 2-(4-isopropylpiperazin-1-yl)-6-(morpholin-4-ylmethyl)benzothiazole as a trifluoroacetate salt.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[N:10]([CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:9]2[CH:17]=[CH:18][C:19]([C:21]([OH:23])=O)=[CH:20][C:8]=2[N:7]=1)(=[O:3])[CH3:2].C(Cl)(=O)C(Cl)=O.C(NC(C)C)(C)C.[NH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[OH:44]>O1CCCC1.CN(C)C=O>[C:1]([O:4][CH2:5][C:6]1[N:10]([CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:9]2[CH:17]=[CH:18][C:19]([C:21]([NH:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[OH:44])=[O:23])=[CH:20][C:8]=2[N:7]=1)(=[O:3])[CH3:2]
Reactant: Nc1ccccc1O
Reactant: CC(=O)OCc1nc2cc(C(=O)O)ccc2n1C1CCOCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(=O)OCc1nc2cc(C(=O)Nc3ccccc3O)ccc2n1C1CCOCC1
Temperature: 50 °C
Reaction time: 14 h
Yield: 124.5 %

Procedure:
A 4-neck flask (200 mL) equipped with a reflux condenser was charged with 2-acetoxymethyl-1-(tetrahydropyran-4-yl)benzimidazole-5-carboxylic acid (see Working Example 7-1) (1.50 g, 4.71 mmol), anhydrous tetrahydrofuran (40 mL), and oxalyl chloride (0.657 g, 5.18 mmol), and anhydrous N,N-dimethylformamide (0.4 mL) was then added dropwise at room temperature, after which the reaction mixture was stirred at 50° C. for 14 hours. After being allowed to cool to room temperature, the solvent was distilled off under reduced pressure to give a pale yellow residue which was cooled to 0 to 5° C., which was taken up in anhydrous tetrahydrofuran (40 mL) and diisopropylamine (0.79 mL, 5.65 mmol), followed by 2-aminophenol (0.57 g, 5.81 mmol), and this was stirred for 24 hours at room temperature. The precipitated crystals were filtered off, these were washed with tetrahydrofuran and dried under reduced pressure with heating to yield the title compound (2.40 g, quant.) as a white powder.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:20]3[C:15](=[CH:16][C:17]4[O:23][CH2:22][O:21][C:18]=4[CH:19]=3)[CH:14]([CH2:24][CH3:25])[N:13]([C:26](=[O:29])[NH:27][CH3:28])[N:12]=2)=[CH:7][CH:6]=1)(=O)C>[OH-].[Na+].CO.CCOC(C)=O>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:20]3[C:15](=[CH:16][C:17]4[O:23][CH2:22][O:21][C:18]=4[CH:19]=3)[CH:14]([CH2:24][CH3:25])[N:13]([C:26](=[O:29])[NH:27][CH3:28])[N:12]=2)=[CH:7][CH:6]=1
Reactant: CCC1c2cc3c(cc2C(c2ccc(NC(C)=O)cc2)=NN1C(=O)NC)OCO3
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCC1c2cc3c(cc2C(c2ccc(N)cc2)=NN1C(=O)NC)OCO3
Temperature: 25 °C
Yield: 90.3 %

Procedure:
A solution of 4-(4-acetylaminophenyl)-1,2-dihydro-1-ethyl-2-methylcarbamoyl-6,7-methylendioxyphthalazine (45 mg, 0.11 mmole) in 1N sodium hydroxide (4 mL) and methanol (6 mL) was heated to reflux for 72 hours. The mixture was cooled to ambient temperature, diluted with EtOAc (30 mL), washed with water (25 mL), dried (MgSO4) and evaporated in vacuo. The residue was chromatographed on silica gel with 25% hexanes/EtOAc to afford the product as a light yellow foamy solid (35 mg, 90%). 200 MHz 1H NMR (CDCl3); δ7.42 (d, 2H, J=8.1 Hz, ArH), 6.82 (s, 1H, ArH), 6.76 (d, 2H, J=8.1 Hz, ArH), 6.70 (s, 1H, ArH), 6.50 (brq, 1H, J=5.4 Hz, NHCH3), 5.59 (d, 2H, J=2.7 Hz, OCH2O), 5.48 (t, 1H, J=6.8 Hz, CHCH2), 2.93 (d, 3H, J=5.4 Hz, NHCH3), 1.64 (m, 2H, CHCH2 CH3), 0.87 (t, 3H, J=8.1 Hz, CH2CH3).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[N-:11][CH:12]=[C:13]([CH3:15])[CH3:14])[CH3:2].[Li+].O1[C:19](C)([CH3:20])[CH2:18]1.[F:22][C:23]([F:36])([F:35])[S:24]([O:27]S(C(F)(F)F)(=O)=O)(=[O:26])=[O:25]>CCOCC>[O-:27][S:24]([C:23]([F:36])([F:35])[F:22])(=[O:26])=[O:25].[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[N+:11]1[C:19]([CH3:20])([CH3:18])[CH2:14][C:13]([CH3:23])([CH3:15])[CH:12]=1)[CH3:2]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCc1cccc(CC)c1[N-]C=C(C)C
Reactant: CC1(C)CO1
Agent: [Li+]
Solvent: CCOCC
Product: CCc1cccc(CC)c1[N+]1=CC(C)(C)CC1(C)C
Product: O=S(=O)([O-])C(F)(F)F
Temperature: -80 °C
Reaction time: 8 h
Yield: 27.6 %

Procedure:
Et2O (100 mL) was added to compound B (5.50 g, 26.3 mmol) to form a clear yellow solution. A solution of 1,2-epoxy-2-methylpropane (1.90 g, 26.3 mmol) in Et2O (5 mL) was added dropwise over about 10 seconds, and the mixture was stirred overnight. The mixture was then cooled to −80° C. and trifluoromethanesulfonic anhydride (7.42 g, 26.3 mmol) was added dropwise. The mixture was warmed to ambient temperature over 1 hour. A thick suspension formed. After stirring for an additional hour, a solid was collected on a glass frit and washed with Et2O (3×15 mL). The solid was dried under reduced pressure. The dried solid was then extracted with CH2Cl2 (60 mL) and filtered through diatomaceous earth. The filter cake was washed with CH2Cl2 (2×30 mL). The combined CH2Cl2 extracts were evaporated to an oil and Et2O (15 mL) was added which caused a white crystalline solid to form. The ether solution was cooled to −10° C. overnight. The white solid was then collected and dried under reduced pressure to afford 1.48 g of product C. To obtain additional product the filter cake was loaded into a thimble. This was placed in a Soxhlet extractor and the solid was extracted with hot CH2Cl2 overnight. The resulting CH2Cl2 extract was evaporated and Et2O (10 mL) was added to afford additional product as off-white crystals. The combined yield of compound C was 3.28 g (30.6%). 1H NMR (C6D6): δ 7.21 (1H, d), 7.02 (2H, m), 2.47 (4H, q), 2.39 (1H, m), 1.11 (6H, t), 1.01 (6H, d).
Reaction SMILES: [O:1]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([C:19]2[O:20][C:21]([C:24]3[N:29]=[CH:28][C:27]([C:30]([O:32]C)=[O:31])=[CH:26][CH:25]=3)=[CH:22][N:23]=2)=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-].Cl>C1COCC1.O.CCOC(C)=O>[O:1]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][C:17]([C:19]2[O:20][C:21]([C:24]3[N:29]=[CH:28][C:27]([C:30]([OH:32])=[O:31])=[CH:26][CH:25]=3)=[CH:22][N:23]=2)=[O:18])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(-c2cnc(C(=O)CCc3ccc(COc4ccccc4)cc3)o2)nc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(-c2cnc(C(=O)CCc3ccc(COc4ccccc4)cc3)o2)nc1
Yield: 81.7 %

Procedure:
Methyl 6-(2-(3-(4-(phenoxymethyl)phenyl)propanoyl)oxazol-5-yl)pyridine-3-carboxylate (46 mg, 0.10 mmol) was dissolved in THF/H2O (3:2, 10 mL) and LiOH (7 mg, 0.3 mmol) was added. The reaction solution was stirred at room temperature under an atmosphere of Ar for 15 min before the addition of 1 N HCl to adjust the solution to an acidic pH to quench the reaction. The reaction solution was diluted with EtOAc and the organic and aqueous layers were separated. The aqueous layer was extracted with EtOAc (3×). The organic phases were combined and washed with saturated aqueous NaCl, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by tritration in ether to provide 6-(2-(3-(4-(phenoxymethyl)phenyl)propanoyl)oxazol-5-yl)pyridine-3-carboxylic acid as a white solid (35 mg, 79%): 1H NMR (THF-d8, 600 MHz) δ 9.18 (d, 1H, J=1.3 Hz), 8.41 (dd, 1H, J=8.2, 2.0 Hz), 7.97 (s, 1H), 7.94 (d, 1H, J=8.2 Hz), 7.35 (d, 2H, J=7.9 Hz), 7.28 (d, 2H, J=7.8 Hz), 7.22 (t, 2H, J=8.0 Hz), 6.95 (d, 2H, J=8.1 Hz), 6.87 (t, 1H, J=7.3 Hz), 2.09 (s, 2H), 3.43 (t, 2H, J=7.6 Hz), 3.06 (t, 2H, J=7.6 Hz); 13C NMR (THF-d8, 150 MHz) δ 187.1, 166.1, 160.1, 158.9, 153.5, 152.2, 150.3, 141.5, 139.2, 136.4, 130.0, 129.3, 129.1, 128.4, 127.5, 121.3, 120.1, 115.5, 70.2, 41.4, 30.1; HR ESI-TOF m/z 429.1443 (M+H+, C25H20N2O5, requires 429.1445).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:39])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27]([OH:29])=O)([CH3:26])[CH3:25])[CH2:14][C:13](=[O:30])[NH:12][CH:11]3[C:31]3[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=3[CH3:38])[C:5]2=[CH:4][CH:3]=1.CC[N:42]=[C:43]=[N:44]CCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.N#CN>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:39])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27](=[O:29])[NH:44][C:43]#[N:42])([CH3:26])[CH3:25])[CH2:14][C:13](=[O:30])[NH:12][CH:11]3[C:31]3[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=3[CH3:38])[C:5]2=[CH:4][CH:3]=1
Reactant: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OC(C)(C)C(=O)O)C12C(=O)Nc1cc(Cl)ccc12
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N#CN
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OC(C)(C)C(=O)NC#N)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
To a mixture of racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-hydroxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (30 mg, 0.05 mmol) prepared in Example 1f, EDCl (20 mg, 0.1 mmol), HOBt (16 mg, 0.1 mmol) and DIPEA (20 mg, 0.15 mmol) in THF (1 mL) was added cyanamide (50% in H2O) (20 mg, 0.24 mmol). The mixture was stirred at room temperature overnight and purified by prep-HPLC to give the title compound as a white solid (14 mg).