Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:10])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[CH:8].[OH:11][CH2:12][C:13]1([CH2:17][CH2:18][CH3:19])[CH2:16]O[CH2:14]1>>[CH2:2]([C:1]12[O:11][CH2:12][C:13]([CH2:17][CH2:18][CH3:19])([CH2:16][O:10]1)[CH2:14][O:9]2)[CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[CH:8]
Reactant: CCCC1(CO)COC1
Reactant: C#CCCCCCC(=O)O
Product: C#CCCCCCC12OCC(CCC)(CO1)CO2

Procedure:
1-(Hept-6-ynyl)-4-n-propyl-2,6,7-trioxabicyclo[2.2.2]octane was prepared from oct-7-ynoic acid and 3-hydroxymethyl-3-n-propyloxetane using methodology described in Example I.
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:18]I>CN(C)C=O>[CH3:18][N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[CH:10]1
Reactant: c1ccc(-c2c[nH]c3ccccc23)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cc(-c2ccccc2)c2ccccc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
Sodium hydride (60% in mineral oil, 200 mg, 5 mmol) was added at 0° C. to a solution of 3-phenyl-1H-indole (1a) (940 mg, 4.86 mmol) in N,N-dimethylformamide (20 mL) under a nitrogen atmosphere. The suspension was stirred for 15 minutes at 0° C. and methyliodide (311 μL, 5 mmol) was then added. The reaction mixture was warmed to room temperature, stirred for 6 hours and then concentrated in vacuo. The residue was partitioned between ethyl acetate (30 mL) and water (10 mL). The organic layer was washed with water (2×10 mL), brine (10 mL), dried over sodium sulfate, filtered and evaporated to dryness to give the desired product (1b) as a yellow oil (1 g, 4.86 mmol, 100%) which was used without further purification.
Reaction SMILES: [CH3:1][CH2:2][O:3][P:4]([O:19][CH2:20][CH3:21])([CH:6]([P:11]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][CH2:8][CH2:9]I)=[O:5].[OH:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:32])[CH:30]=[CH2:31])=[CH:25][CH:24]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:2]([O:3][P:4]([CH:6]([P:11]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][CH2:8][CH2:9][O:22][C:23]1[CH:24]=[CH:25][C:26]([C:29](=[O:32])[CH:30]=[CH2:31])=[CH:27][CH:28]=1)([O:19][CH2:20][CH3:21])=[O:5])[CH3:1]
Reactant: CCOP(=O)(OCC)C(CCCI)P(=O)(OCC)OCC
Reactant: C=CC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CC(=O)c1ccc(OCCCC(P(=O)(OCC)OCC)P(=O)(OCC)OCC)cc1
Yield: 98.8 %

Procedure:
A mixture of iodide 33 (3.1 g, 6.8 mmol), phenol 27 (1.21 g, 8.17 mmol) and K2CO3 (1.033 g, 7.47 mmol) in acetone (75 mL) was refluxed for 6.5 h. The mixture was cooled, filtered and evaporated. The residue was redissolved in CH2Cl2 (170 mL), filtered through Celite and evaporated to give crude 34 (3.2 g, 99%) which was used directly in the next step. 1H NMR (400 MHz, CDCl3) δ 1.28-1.39 (m, 12H), 1.89-2.25 (m, 4H), 2.26-2.48 (m, 1H), 4.05 (t, J=5.7, 2H), 4.12-4.26 (m, 8H), 5.87 (dd, J=10.6, 1.8, 1H), 6.42 (dd, J=16.9, 1.8, 1H), 6.93 (d, J=8.8, 2H), 7.17 (dd, J=17.0, 10.4, 1H), 7.95 (d, J=8.8, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16](=[O:17])[C:15]2[C@@H:14]3[C:18]([CH3:20])([CH3:19])[C@@:11]([CH3:21])([CH2:12][CH2:13]3)[C:10]=2[NH:9]1.I[CH2:23][CH2:24][CH3:25]>CN(C)C=O.C(=O)(O)[O-].[Na+]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16](=[O:17])[C:15]2[C@@H:14]3[C:18]([CH3:20])([CH3:19])[C@@:11]([CH3:21])([CH2:12][CH2:13]3)[C:10]=2[N:9]1[CH2:23][CH2:24][CH3:25]
Reactant: CCCI
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccccc3F)c(=O)c12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCn1c2c(c(=O)n1-c1ccccc1F)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 100 °C
Reaction time: 18 h
Yield: 35 %

Procedure:
A mixture of a (4S,7R)-2-(2-fluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 12; 150 mg, 0.52 mmol) and 1-iodopropane (103 μL, 1.05 mmol) in N,N-dimethylformamide (2 mL) in a microwave reaction tube was heated to 100° C. and stirred for 18 h. The reaction mixture was allowed to cool, diluted with saturated sodium bicarbonate, and extracted twice with ethyl acetate. The organic extracts were combined, washed with water and brine, dried (magnesium sulfate), filtered, evaporated, and purified using an ISCO CombiFlash® Sg100c chromatography system with an Isco 12 g column, eluting with 25-100% ethyl acetate/hexanes to give (4S,7R)-2-(2-fluoro-phenyl)-7,8,8-trimethyl-1-propyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (59.7 mg, 35%) as an orange oil. ES(+)-MS (M+H) 329.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]([N:15]1[C:24]2[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=2[CH:18]=[C:17]([CH2:25][OH:26])[C:16]1=[O:27])[CH2:12][CH2:13][CH3:14].C(N(CC)CC)C.Cl>C(Cl)Cl>[CH2:11]([N:15]1[C:24]2[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=2[CH:18]=[C:17]([CH:25]=[O:26])[C:16]1=[O:27])[CH2:12][CH2:13][CH3:14]
Reactant: CCCCn1c2c(cc(CO)c1=O)CCCC2
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCCCn1c2c(cc(C=O)c1=O)CCCC2
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 56.1 %

Procedure:
DMSO (0.54 mL, 7.64 mmol) was dissolved in methylene chloride (27 mL) and the solvent was cooled at −78° C. To the solvent were added dropwise oxalyl chloride (0.4 mL, 4.58 mL), a solution of 1-butyl-3-hydroxymethyl-5,6,7,8-tetrahydro-1H-quinoline-2-one (1-015-03) (0.9 g, 3.82 mmol) in methylene chloride (20 mL) and triethylamine (1.33 mL, 9.55 mmol), and then the reaction mixture was stirred at −78° C. for 5 min. The reaction mixture was gradually warmed to room temperature, and stirred at room temperature for 20 min. To the reaction mixture was added 1 mol/L diluted hydrochloric acid (50 mL), and the reaction mixture was extracted with ethyl acetate (200 mL), washed with aqueous saturated sodium hydrogen carbonate solution (50 mL) and brine (50 mL), dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (toluene/ethyl acetate) to give 1-butyl-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboaldehyde (1-015-04) (0.5 g, 56%) as a pale yellow bubbly substance.
Reaction SMILES: [CH2:1]([S:5][CH:6]1[CH2:11][O:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)=[N:8][N:7]1[C:22]([NH:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=1)=[O:23])[CH2:2][CH2:3][CH3:4].C(=O)(O)[O-:36].[Na+].ClC1C=CC=C(C(OO)=O)C=1>ClCCl>[CH2:1]([S:5]([CH:6]1[CH2:11][O:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:19])([F:21])[F:20])[CH:13]=2)=[N:8][N:7]1[C:22]([NH:24][C:25]1[CH:26]=[CH:27][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=1)=[O:23])=[O:36])[CH2:2][CH2:3][CH3:4]
Reactant: O=C([O-])O
Reactant: CCCCSC1COC(c2cccc(C(F)(F)F)c2)=NN1C(=O)Nc1ccc(C(F)(F)F)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: CCCCS(=O)C1COC(c2cccc(C(F)(F)F)c2)=NN1C(=O)Nc1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To an ice-cooled mixture of 1.1 g 5-(butylthio)-5,6-dihydro-2-[3-(trifluoromethyl)phenyl]-N-[4-(trifluoro-methyl)phenyl]-4H-1,3,4-oxadiazine-4-carboxamide (Compound 14) and 1.8 g sodium bicarbonate in 15 ml dichloromethane was added dropwise a solution of 0.52 g 3-chloroperbenzoic acid in 4 ml dichloromethane. After stirring for 30 min the mixture was filtered. The filtrate was washed with 2M sodium sulfite and saturated sodium bicarbonate and then dried over sodium sulfate and concentrated under vacuum to produce 5-(butylsulfinyl)-5,6-dihydro-2-[3-(trifluoromethyl)phenyl]-N-[4-(trifluoromethyl)phenyl]-4H-1,3,4-oxadiazine-4-carboxamide. The structure was confirmed by 1H NMR.
Reaction SMILES: N#N.[CH3:3][C:4]1[O:5][C:6]([C:12]2[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=2)=[C:7]([C:9](O)=[O:10])[N:8]=1.CN(C=O)C.C(Cl)(=O)C([Cl:27])=O>C1(C)C=CC=CC=1>[CH3:3][C:4]1[O:5][C:6]([C:12]2[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=2)=[C:7]([C:9]([Cl:27])=[O:10])[N:8]=1
Reactant: Cc1cccc(-c2oc(C)nc2C(=O)O)c1
Reactant: O=C(Cl)C(=O)Cl
Agent: N#N
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Cc1cccc(-c2oc(C)nc2C(=O)Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a suspension of 2-methyl-5-m-tolyl-oxazole-4-carboxylic acid (74 mg, 0.34 mmol) in toluene (2.0 mL) was treated with a drop of DMF followed by oxalyl chloride (0.10 mL, 1.18 mmol) and the resulting yellow solution was stirred at rt for 1 h. The solvent was then removed under reduced pressure (coevaporation with toluene) to give 2-methyl-5-m-tolyl-oxazole-4-carbonyl chloride.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH2:7])[NH:4][N:3]=1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]2[C@:17]3([C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]([CH2:26][C:27]4[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=4)[C:30](O)=[O:31])[C:18]3=[O:36])[CH2:16]2)=[CH:11][CH:10]=1>>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]2[C@:17]3([C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]([CH2:26][C:27]4[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=4)[C:30]([NH:7][C:5]4[NH:4][N:3]=[C:2]([CH3:1])[CH:6]=4)=[O:31])[C:18]3=[O:36])[CH2:16]2)=[CH:11][CH:10]=1
Reactant: O=C(O)c1cccc(CN2C(=O)[C@]3(C[C@@H]3c3ccc(Cl)cc3)c3ccccc32)c1
Reactant: Cc1cc(N)[nH]n1
Product: Cc1cc(NC(=O)c2cccc(CN3C(=O)[C@]4(C[C@@H]4c4ccc(Cl)cc4)c4ccccc43)c2)[nH]n1

Procedure:
The title compound was prepared in analogy to Example 60 starting from 3-methyl-1 H-pyrazol-5-amine, (3-bromomethyl)-benzoate (commercially available), racemic (1R,2S) and (1S,2R)-3-((2-(4-chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzoic acid prepared as in Scheme 1. LC/MS m/e calcd. for C28H23ClN4O2: 482, observed (M+H)+: 483.21H NMR (400 MHz, MeOD-d4) δppm 2.23 (d, J=8.59 Hz, 2 H) 2.55 (s, 3 H) 3.26-3.32 (m, 1 H) 5.08-5.23 (m, 2 H) 5.85 (d, J=1.01 Hz, 1 H) 6.08 (d, J=7.07 Hz, 1 H) 6.73 (t, J=7.58 Hz, 1 H) 6.94 (d, J=7.83 Hz, 1 H) 7.07-7.14 (m, 1 H) 7.19 (d, J=8.08 Hz, 2 H) 7.30 (d, J=8.59 Hz, 2 H) 7.48 (t, J=7.71 Hz, 1 H) 7.58 (d, J=8.34 Hz, 1 H) 7.80 (d, J=7.83 Hz, 1 H) 7.85 (s, 1 H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([OH:17])=[C:14]([C:18]#[N:19])[C:13](=[O:20])[NH:12][C:11]=3[S:10][CH:9]=2)=[CH:4][CH:3]=1.[S:21]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22]1.OC1C=CC(B(O)O)=CC=1>>[OH:17][C:15]1[C:16]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([C:23]4[CH:24]=[CH:25][S:21][CH:22]=4)=[CH:3][CH:4]=3)=[CH:9][S:10][C:11]=2[NH:12][C:13](=[O:20])[C:14]=1[C:18]#[N:19]
Reactant: N#Cc1c(O)c2c(-c3ccc(Br)cc3)csc2[nH]c1=O
Reactant: OB(O)c1ccsc1
Agent: OB(O)c1ccc(O)cc1
Product: N#Cc1c(O)c2c(-c3ccc(-c4ccsc4)cc3)csc2[nH]c1=O

Procedure:
Example 109 was prepared from 3-(4-Bromo-phenyl)-4-hydroxy-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carbonitrile (Example 9) using the same procedure as described for Example 189 substituting 3-thiopheneboronic acid for 4-hydroxyphenyl boronic acid. MS (ESI) m/z 350.9 (M+H+); 1H NMR (300 MHz, DMSO-d6) δ ppm 7.91 (dd, 1H), 7.71 (d, 2H), 7.65 (dd, 1H), 7.60 (dd, 1H), 7.45 (d, 1H).
Reaction SMILES: [CH3:1][C@@:2]1([C:14]([O:16][CH3:17])=[O:15])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].C(OCC)(=[O:20])C>O>[CH3:1][C@@:2]1([C:14]([O:16][CH3:17])=[O:15])[CH2:6][CH2:5][C:4](=[O:20])[N:3]1[C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8]
Reactant: CCOC(C)=O
Reactant: COC(=O)[C@]1(C)CCCN1C(=O)OC(C)(C)C
Solvent: O
Product: COC(=O)[C@]1(C)CCC(=O)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a vigorously stirred solution of (S)-1-tert-butyl 2-methyl 2-methylpyrrolidine-1,2-dicarboxylate 106B (1 g, 4.11 mmol) in ethyl acetate (40 ml) was added a solution of NaIO4 (3.52 g, 16.46 mmol) and RuCl3 (10 mg, 0.04 mmol) in water (40 ml). The reaction mixture was stirred at room temperature overnight and quenched with isopropanol. The reaction mixture was stirred at room temperature for 20 min and concentrated. The residue was dissolved in ethyl acetate, washed with water and brine, and dried over Na2SO4. The crude product was purified by flash chromatography (20-50% EtOAc/hexane) to give (S)-1-tert-butyl 2-methyl 2-methyl-5-oxopyrrolidine-1,2-dicarboxylate 106C (1.02 g, 100%) as an oil. 1H NMR (CDCl3, 400 MHz) δ 3.74 (s, 3H), 2.51-2.64 (m, 2H), 2.16-2.21 (m, 1H), 1.97-2.02 (m, 3H), 1.65 (s, 3H), 1.46 (s, 9H).
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[C@@H:3]([NH:20]C(=O)OCC1C=CC=CC=1)[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][C:13]2=[O:19])[CH2:8][CH2:7]1)=[O:5]>C(O)C.[C].[Pd]>[NH2:20][C@H:3]([C:2]([CH3:32])([CH3:31])[CH3:1])[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][C:13]2=[O:19])[CH2:8][CH2:7]1)=[O:5]
Reactant: CN1CCN(C2CCN(C(=O)[C@H](NC(=O)OCc3ccccc3)C(C)(C)C)CC2)C(=O)C1
Agent: [Pd]
Solvent: CCO
Product: CN1CCN(C2CCN(C(=O)[C@H](N)C(C)(C)C)CC2)C(=O)C1
Yield: 95.5 %

Procedure:
Benzyl(1R)-2,2-dimethyl-1-((4-(4-methyl-2-oxo-1-piperazinyl)-1-piperidinyl)carbonyl)propylcarbamate (0.18 g) obtained in Example 103c) was dissolved in ethanol (10 ml), 10% palladium carbon (50% water content; 20 mg) was added thereto, and mixed under hydrogen atmosphere at room temperature for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound as a colorless oil (0.12 g, 91%).
Reaction SMILES: [CH2:1]([C:3]1[O:8][C:7](=[O:9])[C:6]([C:10](=[O:13])[CH2:11][CH3:12])=[C:5]([OH:14])[CH:4]=1)[CH3:2].[Li+].CC([N-]C(C)C)C.Br[CH2:24][CH2:25][CH2:26][O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29].CN(P(N(C)C)(N(C)C)=O)C>C1COCC1>[Si:28]([O:27][CH2:26][CH2:25][CH2:24][CH:1]([C:3]1[O:8][C:7](=[O:9])[C:6]([C:10](=[O:13])[CH2:11][CH3:12])=[C:5]([OH:14])[CH:4]=1)[CH3:2])([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]
Reactant: CCC(=O)c1c(O)cc(CC)oc1=O
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CCC(=O)c1c(O)cc(C(C)CCCO[Si](C)(C)C(C)(C)C)oc1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
6-Ethyl-4-hydroxy-3-propionyl-2-H-pyran-2-one (III in Scheme 1; Example 1.2; 0.5 g; 2.56 mmol) was dissolved in 20 ml anhydrous THF and cooled to 0° C. under argon. To the cooled solution, was added LDA (5.12 ml of 1.5 M solution in cyclohexane; 7.68 mmol; Aldrich) and the reaction mixture was stirred for 30 min. To the cooled reaction mixture, was added 3-bromopropoxy-t-butyldimethylsilane (0.77 g; 3.07 mmol; Aldrich) and 1 ml HMPA (Aldrich). The reaction mixture was stirred for 30 min at 0° C., quenched with saturated NH4Cl, extracted with 3×20 ml EtOAc, dried with anhydrous Na2SO4, and evaporated to an oil. The product was purified via silica chromatography (10% EtOAc in hexanes).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)[C@@H:10]([C@H:21]([OH:31])[CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:32][C:33]1[CH:34]=[CH:35][C:36](O)=[N:37][CH:38]=1>>[CH2:1]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)[C@@H:10]([C@@H:21]([O:31][C:36]2[CH:35]=[CH:34][C:33]([Cl:32])=[CH:38][N:37]=2)[CH2:22][O:23][Si:24]([C:27]([CH3:28])([CH3:30])[CH3:29])([CH3:26])[CH3:25])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H](O)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(F)c(F)c1
Reactant: Oc1ccc(Cl)cn1
Product: CC(C)(C)[Si](C)(C)OC[C@H](Oc1ccc(Cl)cn1)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(F)c(F)c1

Procedure:
The titled compound was prepared following the general procedure for Mitsunobu reaction using (S)-1-[(3R,4S)-1-benzyl-4-(3,4-difluoro-phenyl)-pyrrolidin-3-yl]-2-(tert-butyl-dimethyl-silanyloxy)-ethanol and 5-Chloro-pyridin-2-ol. ES-MS m/e: 559.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:42])[C:6]=1[C:7]1[CH:8]=[C:9]([C:15]([NH:17][C@@H:18]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:38]([F:41])([F:40])[F:39])[CH2:19][N:20]2C(=O)C3C(=CC=CC=3)C2=O)=[O:16])[S:10][C:11]=1[CH2:12][CH2:13][CH3:14].NN>O1CCCC1.CO>[NH2:20][CH2:19][C@@H:18]([NH:17][C:15]([C:9]1[S:10][C:11]([CH2:12][CH2:13][CH3:14])=[C:7]([C:6]2[N:5]([CH3:42])[N:4]=[CH:3][C:2]=2[Cl:1])[CH:8]=1)=[O:16])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]([F:41])([F:40])[F:39]
Reactant: CCCc1sc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cc1-c1c(Cl)cnn1C
Agent: NN
Solvent: CO
Solvent: C1CCOC1
Product: CCCc1sc(C(=O)N[C@H](CN)Cc2ccccc2C(F)(F)F)cc1-c1c(Cl)cnn1C
Reaction time: 12 h
Yield: 80 %

Procedure:
To a solution of 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-propyl-2-thiophenecarboxamide (245 mg, 0.40 mmol) in tetrahydrofuran (2.4 ml) and methanol (2.4 ml) at 25° C. was added hydrazine (0.12 ml, 3.98 mmol) dropwise. After 12 h, the solution was concentrated, dry loaded onto silica and purified by column chromatography (5% MeOH in DCM (1% NH4OH)). The free base was transferred to the HCl salt by addition of excess 4M HCl in dioxane (1 ml) to the residue in MeOH (2 ml) affording the HCl salt of N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-propyl-2-thiophenecarboxamide (178 mg, 0.32 mmol, 80% yield) as a yellow solid: LCMS (ES) m/z=485, 487 (M, M+2)+, 1H NMR (400 MHz, DMSO-d6) δ ppm 8.96 (br. s., 1H) 8.13 (br. s., 3H) 7.93 (s, 1H) 7.66-7.73 (m, 2H) 7.62 (br. s., 1H) 7.55 (t, J=7.45 Hz, 1H) 7.42 (t, J=7.45 Hz, 1H) 4.48 (br. s., 1H) 3.71 (s, 3H) 2.99-3.08 (m, 4H) 2.63 (t, J=7.20 Hz, 2H) 1.53-1.57 (m, 2H) 0.83 (t, J=7.33 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[C:11](=[O:22])[C:12](=[O:21])[C:13]=2[NH:14][CH:15]([CH3:20])[C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.[CH3:30][N:31](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:21]=[C:12]1[C:11](=[O:22])[C:10](/[CH:9]=[CH:8]/[C:5]2[CH:6]=[CH:7][C:2]([C:30]#[N:31])=[CH:3][CH:4]=2)=[C:13]1[NH:14][CH:15]([CH3:20])[C:16]([CH3:19])([CH3:18])[CH3:17]
Reactant: CN(C)C=O
Reactant: CC(Nc1c(/C=C/c2ccc(Br)cc2)c(=O)c1=O)C(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: Cc1ccccc1
Product: CC(Nc1c(/C=C/c2ccc(C#N)cc2)c(=O)c1=O)C(C)(C)C
Temperature: 100 °C
Reaction time: 18 h
Yield: 73 %

Procedure:
The title compound was prepared via cyano-debromination (Tschaen, Synth. Comm. 1994, 24, 887) of the title compound of Example 26. To a mixture of 3-[(E)-2-(4-bromo-phenyl)-vinyl]-4-(1,2,2-trimethyl-propylamino)-cyclobut-3-ene-1,2-dione (400 mg, 1.10 mmol) and zinc (II) cyanide (77.8 mg, 0.662 mmol) in DMF (1.20 mL) was added tetrakis(triphenylphosphine)palladium (0) (76.6 mg, 0.0662) under an atmosphere of Argon. The reaction mixture was heated to 100° C., stirred 18 hours, then worked up by dilution with toluene (150 mL), followed by consecutive extraction with ammonium hydroxide (3×50 mL) and brine (50 mL). The organic phase was further diluted with ethyl acetate (300 mL), dried over MgSO4, filtered through a short pad of diatomaceous earth, and then concentrated onto silica gel. Submission to flash chromatography (multiple gradient elution with ether-petroleum ether) afforded a yellow solid which was triturated with ether-hexanes. Drying under high vacuum at 60° C. yielded the title compound (248 mg, 73%) as a hydroscopic yellow solid (1H NMR in DMSO-d6 suggested the presence of amide rotamers in a ratio of approximately 4:1): m.p. 240.2-241.0° C.; 1H NMR (DMSO-d6) δ 8.96(d,1H), 7.83(m,4H), 7.64(d,1H), 7.48(d,1H), 4.03(dq,1H), 1.20(d,3H), 0.90(s,9H); IR (KBr) 3450, 3250, 3290, 2960, 1770, 1725, 1620, 1600, 1500, 1480, 1440, 1405, 1170, 1140, 1080, 980, 825, 755; MS (m/z) 309 [(M+H)+], 331 [(M+Na)+].
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-])=O)=[C:10]([NH:15][CH2:16][C:17]2[O:21][N:20]=[C:19]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH:18]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1>[Pt].C(#N)C>[Cl:1][C:2]1[C:11]([NH2:12])=[C:10]([NH:15][CH2:16][C:17]2[O:21][N:20]=[C:19]([C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)[CH:18]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=[N+]([O-])c1c(Cl)nc2ccccc2c1NCc1cc(-c2ccc(F)cc2)no1
Agent: [Pt]
Solvent: CC#N
Product: Nc1c(Cl)nc2ccccc2c1NCc1cc(-c2ccc(F)cc2)no1
Yield: 98.8 %

Procedure:
Under a nitrogen atmosphere, acetonitrile (2 L) was added to a Parr vessel containing 5% platinum on carbon (2.0 g) and 2-chloro-N-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-3-nitroquinolin-4-amine (36.12 g, 90.58 mmol). The vessel was sealed, purged with nitrogen, and placed under hydrogen pressure (30 psi, 2.1×105 Pa) for 17 hours at room temperature. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting semi-solid was treated with diethyl ether, which was removed under reduced pressure to provide 33 g of 2-chloro-N4-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}quinoline-3,4-diamine as a yellow-orange solid. A portion of the material was purified by column chromatography on silica gel (6 g, eluting with 10% ethyl acetate in hexane) to provide 0.0298 g of an analytically pure sample as pale yellow crystals, mp 127-128.0° C.
Reaction SMILES: Cl[CH:2]1[CH2:7][CH:6]([CH2:8][CH:9]([CH3:11])[CH3:10])[O:5][C:3]1=[O:4].C(=O)([O-])[O-:13].[K+].[K+]>Cl>[OH:13][CH:2]1[CH2:7][CH:6]([CH2:8][CH:9]([CH3:11])[CH3:10])[O:5][C:3]1=[O:4]
Reactant: CC(C)CC1CC(Cl)C(=O)O1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Product: CC(C)CC1CC(O)C(=O)O1
Temperature: 25 °C
Reaction time: 40 h
Yield: 99 %

Procedure:
In a 50 ml flask with a cooling column, 1.77 g (10 mmole) of α-chloro-γ-isobutyl-γ-butyrolactone and 12 ml of 2N aqueous potassium carbonate were kept at 80 C. for 40 hours under stirring. The reaction mixture was cooled to room temperature and poured into 10 ml of 12N hydrochloric acid. The reaction product was extracted with ether and the ether extract was dried with anhydrous sodium sulfate. After removal of ether, distillation of the residue under reduced pressure gave α-hydroxy-γ-isobutyl-γ-butyrolactone. (yield 99%).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][Sn:5]([C:14]1[S:18][C:17]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[N:16][CH:15]=1)([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9].[H-].[Na+].I[CH2:30][CH2:31][CH3:32]>CN(C=O)C.O>[CH2:30]([N:19]([C:17]1[S:18][C:14]([Sn:5]([CH2:6][CH2:7][CH2:8][CH3:9])([CH2:4][CH2:3][CH2:2][CH3:1])[CH2:10][CH2:11][CH2:12][CH3:13])=[CH:15][N:16]=1)[C:20](=[O:21])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:31][CH3:32]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc(NC(=O)OC(C)(C)C)s1
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCC[Sn](CCCC)(CCCC)c1cnc(N(CCC)C(=O)OC(C)(C)C)s1
Temperature: 60 °C
Reaction time: 8 h
Yield: 71.3 %

Procedure:
To a solution of 2-(N-BOC)-5-(tributylstannyl)thiazole (200 mg, 0.409 mmole) in DMF (2 mL) was added NaH (60% dispersion in mineral oil, 20 mg, 0.500 mmole) at RT. After gas evolution had ceased 1-iodopropane (0.048 mL, 0.490 mmole) was added and the mixture was heated to 60° C. After stirring overnight the mixture was cooled to RT, diluted with H2O, and extracted with EtOAc (3×). The combined organic layers were washed with H2O and brine, dried (MgSO4), filtered, and concentrated. Flash column chromatography (Biotage-SNAP-25 g SiO2, 0-10% EtOAc/hexanes) gave the title compound (155 mg, 71%) as a clear oil. 1H NMR (400 MHz, CDCl3): δ 7.33 (s, 1 H); 4.11-4.03 (m, 2 H); 1.79-1.69 (m, 1 H); 1.62-1.52 (m, 18 H); 1.38-1.28 (m, 7 H); 1.13-1.05 (m, 7 H); 0.95 (m, 3 H); 0.93-0.84 (m, 9 H).