Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]([C:11](=[O:16])NCOC)([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].OS([O-])(=O)=O.[K+]>CCOCC>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]([CH3:10])([CH3:9])[CH:11]=[O:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCNC(=O)C(C)(C)NC(=O)OC(C)(C)C
Agent: O=S(=O)([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: CC(C)(C=O)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
To a solution of [1-(methoxymethyl-carbamoyl)-1-methyl-ethyl]-carbamic acid tert-butyl ester (1.6 g, 7 mmol) in ether (30 mL) at −78° C. is added lithium aluminum hydride (9.8 mL of 1.0M in ether) dropwise. The mixture is warmed to 0° C. and stirred for 40 min. Aqueous KHSO4 (20 mL of 0.5M solution) is added and the mixture is extracted with ether. The organic solution is washed sequentially with 10% citric acid (2×), 5% NaHCO3 (2×) and brine. The solution is dried over magnesium sulfate and the solvent is removed under reduced pressure to afford the title compound.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1.[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][N:21]([C:24]2[CH:32]=[C:31]3[C:27]([C:28]4[CH2:37][CH2:36][NH:35][CH2:34][C:29]=4[N:30]3[CH3:33])=[CH:26][CH:25]=2)[C:20](=[O:38])[CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(C(C)C)CC)(C)C>CCO>[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][N:21]([C:24]2[CH:32]=[C:31]3[C:27]([C:28]4[CH2:37][CH2:36][N:35]([CH2:3][CH2:4][N:5]5[CH2:9][CH2:8][CH2:7][CH2:6]5)[CH2:34][C:29]=4[N:30]3[CH3:33])=[CH:26][CH:25]=2)[C:20](=[O:38])[CH:19]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc31)CCNC2
Reactant: ClCCN1CCCC1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc31)CCN(CCN1CCCC1)C2
Temperature: 65 °C
Yield: 7.7 %

Procedure:
1-(2-Chloroethyl)pyrrolidine hydrochloride (50 mg, 0.29 mmol) was added to a solution of 4-(benzyloxy)-1-(9-methyl-2,3,4,9,-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridine-2(1H)-one (0.10 g, 0.27 mmol) and diisoproylethyl amine (0.14 mL) in EtOH (4 mL), and the resulting solution was heated at 65° C. for 2 h. The reaction mixture was concentrated to dryness under reduced pressure. Purification by flash column chromatography (40 g ISCO column, CH2Cl2/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 hold 5 column volumes increased to 0:100 over 20 column volumes) followed by preparative TLC (Analtech, 20×20 cm, 1000 microns, uV 254, 80:18:2 CH2Cl2/MeOH/NH4OH) followed by preparative HPLC (Phenomenex Luna C18 (2), 250.0×21.2 mm, 10 micron, H2O with 0.05% TFA and CH3CN with 0.05% TFA) and filtration through SCX-2 column gave the title compound (10 mg, 7%) as a yellow solid:
Reaction SMILES: [NH2:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]([C:14]3[N:15]=[CH:16][C:17]4[C:22]([CH:23]=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[O:13])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:24]1([S:30](Cl)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>N1C=CC=CC=1.C(Cl)Cl.[Cl-].[Na+].O>[C:24]1([S:30]([NH:1][C:2]2[C:10]3[NH:9][C:8]([NH:11][C:12]([C:14]4[N:15]=[CH:16][C:17]5[C:22]([CH:23]=4)=[CH:21][CH:20]=[CH:19][CH:18]=5)=[O:13])=[N:7][C:6]=3[CH:5]=[CH:4][CH:3]=2)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1cccc2[nH]c(NC(=O)c3cc4ccccc4cn3)nc12
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1nc2cccc(NS(=O)(=O)c3ccccc3)c2[nH]1)c1cc2ccccc2cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.9 %

Procedure:
66 mg (0.2 mmol) of isoquinoline-3-carboxylic acid (4-amino-1H-benzoimidazol-2-yl)-amide was dissolved in pyridine (0.6 mL). To this stirred solution at 0° C., 0.2 mmol of phenylsulfonyl chloride in 0.2 mL of DCM was added in one portion. The reaction mixture was stirred at room temperature for 2 h. Brine (5 mL) was added and stirred for 10 min. The resulting solid was collected by filtration, washed with water (3×2 ml) and EtOAc (3×3 mL) and dried to yield 46 mg (52%) of isoquinoline-3-carboxylic acid (7-benzenesulfonylamino-1H-benzoimidazol-2-yl)-amide. LCMS: 444 (M+1)+.
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:20]=[CH:19][C:10]([CH2:11][CH:12]2[S:16][C:15](=[O:17])[NH:14][C:13]2=[O:18])=[CH:9][CH:8]=1)(OC)=O.[CH3:21][NH:22][C:23](=[O:31])[C:24]1[C:25](=[CH:27][CH:28]=[CH:29][CH:30]=1)[NH2:26].C1(C)C(C)=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:21][N:22]1[C:23](=[O:31])[C:24]2[C:25](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:26]=[C:1]1[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:11][CH:12]2[S:16][C:15](=[O:17])[NH:14][C:13]2=[O:18])=[CH:19][CH:20]=1
Reactant: COC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: CNC(=O)c1ccccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: Cc1ccccc1C
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccccc2c1=O
Temperature: 175 °C

Procedure:
A suspension of 5-[4-[(carbomethoxy)methoxy]benzyl]thiazolidine-2,4-dione obtained by following a procedure described in Examples 23 or 24 (100 g, 0.34 M), N-methyl anthranilamide (58.7 g, 0.39 M), xylene (100 ml) and p-toluenesulfonic acid (200 mg) was taken in a round bottom flask fitted with a mechanical stirrer, oil bath and Dean-Stark condenser. The reaction mixture was heated to reflux (internal temperature 150-155° C., oil bath temperature 170-180° C.) for a period of 10-15 h while monitoring the reaction by TLC. After completion of the reaction, reaction mass was cooled to 80° C. and methanol (700 ml) was added slowly through a dropping funnel. The reaction mass was allowed to attain room temperature while stirring and the solid thus obtained was filtered and washed with methanol (150 ml) and dried at 100-120° C. for 1 h to afford 5-[4-[[3-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]methoxy]benzyl]thiazolidine-2,4-dione as a white solid (30 g, Y=23%, P=98%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[O:10][C:11]3[CH:17]=[C:16]([O:18][CH2:19][C@@H:20]([NH:22][C:23](=[O:25])[CH3:24])[CH3:21])[CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][C:7]=1[OH:8].Br[CH2:27][CH:28]1[CH2:30][C:29]1([F:32])[F:31].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[F:31][C:29]1([F:32])[CH2:30][CH:28]1[CH2:27][O:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[O:10][C:11]3[CH:17]=[C:16]([O:18][CH2:19][C@@H:20]([NH:22][C:23](=[O:25])[CH3:24])[CH3:21])[CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:3][C:2]=1[F:1]
Reactant: FC1(F)CC1CBr
Reactant: CC(=O)N[C@@H](C)COc1ccc2nc(-c3ccc(O)c(F)c3)oc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)N[C@@H](C)COc1ccc2nc(-c3ccc(OCC4CC4(F)F)c(F)c3)oc2c1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 76.3 %

Procedure:
A suspension of N-((2S)-1-((2-(3-fluoro-4-hydroxyphenyl)-1,3-benzoxazol-6-yl)oxy)propan-2-yl)acetamide (290 mg), 1-bromomethyl-2,2-difluorocyclopropane (288 mg) and potassium carbonate (175 mg) in DMF (10 mL) was stirred at 70° C. for 1 hr and 30 min. The reaction mixture was diluted with ethyl acetate, and washed with saturated brine, and the organic layer was subjected to silica gel column chromatography (NH, ethyl acetate), and the solvent was evaporated. The obtained solid was washed with diethyl ether to give the title compound (279 mg).
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:33]2[CH2:45][CH2:44][N:36]3[C:37]4[CH2:38][CH2:39][CH2:40][CH2:41][C:42]=4[CH:43]=[C:35]3[C:34]2=[O:46])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[CH:21][N:20]=2)[C:15](=[O:31])[N:14]([CH3:32])[CH:13]=1)(=O)C.[Li+].[OH-]>CC(O)C.C1COCC1.O>[OH:4][CH2:5][C:6]1[C:7]([N:33]2[CH2:45][CH2:44][N:36]3[C:37]4[CH2:38][CH2:39][CH2:40][CH2:41][C:42]=4[CH:43]=[C:35]3[C:34]2=[O:46])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[CH:21][N:20]=2)[C:15](=[O:31])[N:14]([CH3:32])[CH:13]=1
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCNCC4)cn3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(C)O
Solvent: O
Product: Cn1cc(-c2ccnc(N3CCn4c(cc5c4CCCC5)C3=O)c2CO)cc(Nc2ccc(N3CCNCC3)cn2)c1=O
Temperature: 35 °C
Reaction time: 0.5 h
Yield: 27.8 %

Procedure:
A mixture of 127a (190 mg, 0.31 mmol) and LiOH (571 mg, 13.6 mmol) in iPrOH/THF (1:1, 3.5 mL) and H2O (0.5 mL) was stirred at 35° C. for 0.5 h. It was then evaporated in vacuo and the residue was extracted with EtOAc (5 mL×2). The combined EtOAc extract was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 127 (50 mg, 26.9%). MS: [M+H]+ 581.3. 1H NMR (500 MHz, CDCl3) δ 8.63 (d, J=2.0, 1H), 8.49 (d, J=5.0, 1H), 7.91 (d, J=3.5, 1H), 7.82 (d, J=2.0, 1H), 7.77 (s, 1H), 7.37 (d, J=5.0, 1H), 7.20-7.25 (m, 1H), 6.89 (s, 1H), 6.81 (d, J=9.0, 1H), 5.04-5.02 (m, 1H), 4.64-4.61 (m, 1H), 4.50 (d, J=5.0, 1H), 4.34-4.31 (m, 1H), 4.18-4.08 (m, 2H), 3.89-3.86 (m, 1H), 3.71 (s, 3H), 3.05-3.06 (m, 8H), 2.62-2.56 (m, 4H), 1.92-1.88 (m, 2H), 1.81-1.78 (m, 3H)
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[N:59]1[CH:64]=[CH:63][N:62]=[CH:61][C:60]=1[CH2:65]O>C(OCC)(=O)C.O1CCCC1>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:65][C:60]2[CH:61]=[N:62][CH:63]=[CH:64][N:59]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: OCc1cnccn1
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCc1nc(C)n(Cc2cnccn2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.2 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), 1,1′-(azodicarbonyl)dipiperidine (1.41 g), tributylphosphine (1.56 mL), pyrazin-2-ylmethanol (0.46 g) and tetrahydrofuran (50 mL) was stirred at room temperature for 4 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.87 g, 69%).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([O:11][CH3:12])[N:5]=[C:4]([O:13][CH3:14])[N:3]=1.[C:15]([CH2:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([CH3:26])[CH:25]=1)[C:21]#[N:22])#[N:16].[H-].[Na+]>CN(C=O)C>[C:15]([CH:17]([C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([O:11][CH3:12])[N:5]=[C:4]([O:13][CH3:14])[N:3]=1)[C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([CH3:26])[CH:25]=1)[C:21]#[N:22])#[N:16]
Reactant: COc1nc(Cl)c([N+](=O)[O-])c(OC)n1
Reactant: Cc1cc(C#N)cc(CC#N)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nc(OC)c([N+](=O)[O-])c(C(C#N)c2cc(C)cc(C#N)c2)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
4-Chloro-2,6-dimethoxy-5-nitro-pyrimidine (0.45 g, 2.05 mmol, 1.05 eq., prepared according to Cushman et al. J. Org. Chem. 2004, 69, 601-612) and 3-cyanomethyl-5-methyl-benzonitrile (0.305 g, 1.95 mmol, 1.0 eq.) was dissolved in DMF (3.36 mL) and cooled to 0° C. 60% Sodium hydride (0.157 g, 3.92 mmol, 2.0 eq.) was added portionwise and the reaction was stirred at 0° C. for 1 h, then rt for 1 h. The reaction was cooled to 0° C. and quenched with saturated ammonium chloride solution. The pH was adjusted to ˜6.0 with 1N HCl and mixture was extracted with ethyl ether. The organic layer was washed with water (2×), dried (MgSO4) and concentrated. The resulting residue was purified by flash column chromatography (silica gel, 20 to 50% ethyl acetate/hexane) to give a yellow foam (0.6514 g, 98%). 1H NMR (300 MHz, CDCl3): δ 7.56 (s, 1H), 7.54 (s, 1H), 7.40 (s, 1H), 5.64 (s, 1H), 4.05 (s, 6H), 2.34 (s, 3H). Mass spectrum: 338.0 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][CH2:11][NH:10][C:9]2=[O:13])[CH:5]=[CH:6][CH:7]=1.[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(O)(=O)C.[BH4-].[Na+]>O1CCCC1>[CH2:14]([NH:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][CH2:11][NH:10][C:9]2=[O:13])[CH:5]=[CH:6][CH:7]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Nc1cccc(N2CCNC2=O)c1
Reactant: O=Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C1NCCN1c1cccc(NCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1-(3-amino-phenyl)-imidazolidin-2-one (0.27 g, 1.5 mmol), benzaldehyde (0.17 ml, 1.7 mmol) and acetic acid (0.13 ml, 2.2 mmol) in dry tetrahydrofuran (10 ml) was stirred at room temperature for 6 hrs. Sodium borohydride (0.14 g, 3.8 mmol) was added and the reaction stirred at room temperature overnight. The reaction mixture was quenched with water (25 ml) then extracted with dichloromethane (3×50 ml). The organic extracts were combined, dried (magnesium sulphate) and concentrated in vacuo. HPLC retention time 7 min. Mass spectrum (ES+) m/z 268 (M+H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][P:11]([OH:13])[OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[Mn]([O-])(=O)(=O)=[O:17].[K+].Cl.S(=O)(O)[O-].[Na+]>CC(C)=O.O.C(OCC)(=O)C>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][P:11](=[O:17])([OH:13])[OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OP(O)CCCCc1ccccc1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: Cl
Agent: O=S([O-])O
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=P(O)(O)CCCCc1ccccc1
Temperature: 20 °C

Procedure:
4-Phenylbutylphosphonous acid (47.19 gm, 0.238 mole) was dissolved in acetone (250 ml) and diluted with water (50 ml). Sodium hydroxide solution (9.5 gm, 0.238 mole) in water (50 ml) was added to it to get pH=7.0. The reaction mixture was cooled to 20° C. and potassium permanganate solution (22.5 gm, 0.142 mole) in water (250 ml) was added to it with stirring and maintaining the temperature around 20°-2 ° C. After the addition (15 minutes), the reaction mixture was stirred for 15 minutes at room temperature, acidified to pH 0 using concentrated HCl acid and saturated sodium bisulphite solution was added to it to get a white cloudy precipitate. Standard extractive workup using ethyl acetate followed by crystallization from ethyl acetate/hexane produced the title compound in 87% (44.16 gm) yield, m.p. 93° C.
Reaction SMILES: [I:1][C:2]1[C:7]([C:8]([OH:10])=O)=[C:6]([O:11][CH3:12])[N:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.Cl.[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([CH2:29][NH:30][NH2:31])=[CH:27][CH:26]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[I:1][C:2]1[C:7]([C:8]([NH:31][NH:30][CH2:29][C:28]2[CH:32]=[CH:33][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)=[O:10])=[C:6]([O:11][CH3:12])[N:5]=[CH:4][CH:3]=1
Reactant: COc1nccc(I)c1C(=O)O
Reactant: COc1ccc(CNN)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CNNC(=O)c2c(I)ccnc2OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.2 %

Procedure:
To a solution of 4-iodo-2-methoxynicotinic acid (3.00 g) obtained in Step C of Example 6 in DMF (100 mL) were added DIEA (1.88 mL), (4-methoxybenzyl)hydrazine hydrochloride (2.06 g), EDCI hydrochloride (2.03 g) and HOBt (1.45 g) at 0° C., and the mixture was stirred overnight at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was washed with ethyl acetate/diisopropyl ether to give the title compound (1.52 g).
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][O:5][C:3]1=[O:4].[H][H]>C1COCC1>[OH:1][CH:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][O:5][C:3]1=[O:4]
Reactant: CC1(C)COC(=O)C1=O
Reactant: [H][H]
Solvent: C1CCOC1
Product: CC1(C)COC(=O)C1O

Procedure:
2-Oxo-3,3-dimethyl-γ-butyrolactone (18) was hydrogenated according to General Procedure B in THF at 20.7 barg (300 psig) hydrogen at ambient temperature using bis(1,5-cyclooctadiene)rhodium trifluoromethanesulfonate (2.3 mg; 5 μmol; 0.01 equiv) and ligand (S,R)-2g (3.7 mg; 6 μmol; 0.012 equiv) for 6 hours to afford 99.6% conversion to 2-hydroxy-3,3-dimethyl-γ-butyrolactone (19) with 97.2% ee as determined by chiral GC analysis.
Reaction SMILES: [F:1][C:2]1[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:3]=1[C:4](N(OC)C)=[O:5].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([Mg]Br)=[CH:19][CH:18]=1>>[F:1][C:2]1[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:3]=1[C:4]([C:20]1[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=1)=[O:5]
Reactant: COc1ccc([Mg]Br)cc1
Reactant: CON(C)C(=O)c1cccc(F)c1F
Product: COc1ccc(C(=O)c2cccc(F)c2F)cc1

Procedure:
Prepared according to Method A step B from 2,3-difluoro-N-methoxy-N-methylbenzamide (3.0 g, 15 mmol) and 4-methoxyphenylmagnesium bromide (35 mL, 0.5 M in THF) to give 1.44 g of the title compound as a white solid.
Reaction SMILES: [C:1]1([P:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:18]=2[NH:17][CH:16]([CH3:19])[CH2:15][CH2:14]3)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(CC)CC.Cl[SiH](Cl)Cl.[OH-].[Na+]>C(Cl)Cl>[C:20]1([P:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:18]=2[NH:17][CH:16]([CH3:19])[CH2:15][CH2:14]3)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC1CCc2cccc(P(=O)(c3ccccc3)c3ccccc3)c2N1
Agent: Cl[SiH](Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1CCc2cccc(P(c3ccccc3)c3ccccc3)c2N1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 80.5 %

Procedure:
To a solution of 8-diphenylphosphinoyl-2-methyl-1,2,3,4-tetrahydroquinoline (6) (1.5 g, 4.5 mmol) in dry degassed toluene (40 mL) was added degassed Et3N (3.15 mL, 22.5 mmol) followed by trichlorosilane (2.25 mL, 22.5 mmol). The mixture was stirred at 80° C. for 30 minutes before cautiously adding 2N NaOH (150 mL) and cooling down to room temperature. Products were then extracted with EtOAc, washed with water and saturated aqueous NaCl, dried (MgSO4) and evaporated to give a yellow oil. This oil was taken up in CH2Cl2 (100 mL), and filtered over silica gel (˜25 mL) eluting with further portions of CH2Cl2 (4×100 mL). The combined filtrates were then evaporated to give compound 7 (1.2 g) as a light yellow oil in 80% yield. 1H NMR (400.13 MHz, CDCl3) δ 7.4-7.3 (m, 10H, Ph-H), 6.99 (d, 1H, J=7.2 Hz, C5—H), 6.62 (ddd, 1H, J=7.2, 6.0, 1.2 Hz, C7—H), 6.52 (t, 1H, J=7.6 Hz, C6—H), 4.65 (bs, 1H, N1—H), 3.4-3.3 (m, 1H, C2—H), 2.9-2.7 (m, 2H, C4a/b—H), 2.0-1.9 (m, 1H, C3a—H), 1.6-1.5 (m, 1H, C3b—H), 1.11 (d, 3H, J=6.4 Hz, C1′—CH3) ppm; 13C NMR (100.61 MHz, CDCl3) δ 147.9 (d, J=18.2 Hz), 147.7 (d, J=18.2 Hz), 136.1 (d, J=12.1 Hz), 136.0 (d, J=13.1 Hz), 135.8 (d, J=13.1 Hz), 135.7 (d, J=13.1 Hz), 134.1-133.5 (m), 132.5 (d, J=12.1 Hz), 132.4 (d, J=12.1 Hz), 130.5, (d, J=13.1 Hz), 128.7-128.4 (m), 120.7 (d, J=12.1 Hz), 117.0, (d, J=12.1 Hz), 116.3 (d, J=12.1 Hz), 47.4, 39.6, 26.8, 22.4 ppm; 31P NMR (161.97 MHz, CDCl3) δ −21.9 ppm.
Reaction SMILES: [CH:1]([Mg]Cl)([CH3:3])[CH3:2].CO[C:8]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[CH:10][C:9]=1[C:16]1[O:17][CH2:18][C:19]([CH3:22])([CH3:21])[N:20]=1>O1CCCC1>[CH:1]([C:8]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[CH:10][C:9]=1[C:16]1[O:17][CH2:18][C:19]([CH3:21])([CH3:22])[N:20]=1)([CH3:3])[CH3:2]
Reactant: COc1cccc(C2=NC(C)(C)CO2)c1OC
Reactant: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COc1cccc(C2=NC(C)(C)CO2)c1C(C)C
Reaction time: 8 h
Yield: 95.4 %

Procedure:
Isopropylmagnesium chloride (2.0M in diethyl ether) (18.75 ml, 37.5 mmol) was added dropwise to a solution of 2-(2,3-dimethoxyphenyl)-4,4-dimethyl-4,5-dihydrooxazole (7.06 g, 30.0 mmol) in freshly distilled tetrahydrofuran at room temperature. The mixture was stirred overnight, quenched with water, and diluted with diethyl ether. The layers were separated, and the aqueous layer was washed twice with diethyl ether. The combined organic extracts were dried over anhydrous sodium sulfate, and concentrated in vacuo. Purification by silica gel flash chromatography, eluting with hexane/ethyl acetate, gave 2-(2-isopropyl-3-methoxyphenyl)-4,4-dimethyl-4,5-dihydrooxazole as a clear oil (7.08 g, 95.4%).
Reaction SMILES: C([O:3][C:4](=[O:25])[CH:5]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH2:21][CH2:22][CH2:23][CH3:24])(=[O:20])=[O:19])=[CH:14][CH:13]=1)[CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)C.[OH-].[Li+].Cl>O1CCCC1.O.CO>[CH2:21]([S:18]([C:15]1[CH:16]=[CH:17][C:12]([CH:5]([CH2:6][CH:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)[C:4]([OH:25])=[O:3])=[CH:13][CH:14]=1)(=[O:19])=[O:20])[CH2:22][CH2:23][CH3:24]
Reactant: CCCCS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)OCC)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCCCS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.4 %

Procedure:
A solution of 2-[4-(butane-1-sulfonyl)-phenyl]-3-cyclopentyl-propionic acid ethyl ester (140 mg, 0.38 mmol in tetrahydrofuran/water/methanol (0.95 mL, 3:1:1) was treated with a 1N aqueous lithium hydroxide solution (0.76 mL, 0.76 mmol). The reaction was stirred at 25° C. for 8 h. At this time, the reaction was acidified to pH=1 with a 1N aqueous hydrochloric acid solution and extracted with chloroform (3×50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 90/10 chloroform/methanol) afforded 2-[4-(butane-1-sulfonyl)-phenyl]-3-cyclopentyl-propionic acid (88.3 mg, 68.4%) as a clear oil: FAB-HRMS m/e calcd for C18H26O4S (M+H)+ 339.1631 found 339.1638.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH:22]=O)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].[NH2:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][OH:30].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl.ClCCl>[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][NH:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][OH:30])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5]
Reactant: O=Cc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Reactant: NCCOCCO
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Solvent: O
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(CNCCOCCO)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-chloro-5-formyl-N-(tricyclo [3.3.1.13,7] dec-1-ylmethyl)-benzamide (0.150 g, Example 1b) and 2-(2-aminoethoxy)ethanol (0.065 ml) in 1,2-dichloroethane (6 ml) was added sodium triacetoxyborohydride (0.134 g), and the mixture was stirred overnight at room temperature. Water (20 ml) and dichloromethane (20 ml) were added and the layers were partitioned. The organics were washed with brine (30 ml), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by NPHPLC eluting with a gradient of 0-10% ethanol in dichloromethane to give the title compound as a white powder (0.016 g).