Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][CH:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:14]([OH:16])=[O:15])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[OH:23]O>CO>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S@@:12]([C@@H:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:14]([OH:16])=[O:15])=[O:23])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: OO
Reactant: CC#CCOc1ccc(SC(CCCCCC)C(=O)O)cc1
Solvent: CO
Product: CC#CCOc1ccc([S@](=O)[C@@H](CCCCCC)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 24 %

Procedure:
2-(4-But-2-ynyloxy-phenylsulfanyl)-octanoic acid hydroxamide (prepared in Example 6) (1.78 g, 5 mmol) was dissolved in methanol (50 ml) and H2O2 (30%, 10 ml) was added. The reaction mixture was stirred at room temperature for 96 hours and quenched with ice cold solution of NaHSO3 solution. The reaction mixture was concentrated under reduced pressure and the residue was extracted with chloroform. Examination of the reaction mixture showed the formation of two diastereo isomers and they were separated by silica-gel column chromatography by eluting it with 50% ethyl acetate; hexane. 411 g of (S)-2-[(R)-4-but-2-ynyloxy-phenylsulfinyl)-octanoic acid hydroxamide was isolated as a white solid, mp 132.3° C.; Yield 24%; MS: 352.0 (M+H)+; 1H NMR (300 MHz, DMSO-d6): δ0.834 (m, 3H), 1.19 (m, 9H), 1.76 (m, 1H), 1.84(t, 3H), 3.11-3.17 (dd, 2H), 3.33 (t, 3H), 4.81 (d, 2H) 7.15 (d, J=2.8, 2H), 7.36 (d, J=2.3, 2H), 9.00 (s, 1H), 10.56 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([N:6]([CH3:8])[CH3:7])=[CH:4][CH:3]=1.C([Li:15])CCC.CCCCCC>CCOCC>[CH3:7][N:6]([CH3:8])[C:5]1[CH:9]=[CH:10][C:2]([Li:15])=[CH:3][CH:4]=1
Reactant: [Li]CCCC
Reactant: CN(C)c1ccc(Br)cc1
Solvent: CCOCC
Solvent: CCCCCC
Product: [Li]c1ccc(N(C)C)cc1
Reaction time: 4 h

Procedure:
A solution of 20 g (0.1 mol) of p-bromo-N,N-dimethylaniline in 150 mL of anhydrous ether was treated dropwise over 1 h at 0°-5° with a solution of 40 mL of 2.45 M n-butyl lithium in hexane (0.1 mol) in 50 mL of anhydrous diethyl ether. The mixture was stirred at 0.5° for 11/4 h and then allowed to warm to 22°. An additional 1.0 mL of n-butyl lithium solution was added. The mixture was connected to a vacuum line and a distillation receiver bulb cooled in a dry ice bath. The solvents and volatile by-products were removed in vacuo (mechanical pump) at 15°-20°, leaving a pale cream powder of 4-dimethylaminophenyl lithium reagent. The solid was pulverized under argon in the same flask and then further pumped in vacuo at 25° for 20 minutes to remove all volatiles. The lithium reagent was then dissolved in 150 mL of anhydrous ether and treated rapidly with a solution of 5.8 g (5.8 mL×0.03 mol) of di(n-butyl)phosphite in 50 mL of anhydrous ether at 5°-10°. The resulting white slurry was treated with 50 mL of tetrahydrofuran, and the resulting colorless solution was allowed to stir for 12 h at 23°. The mixture was then poured into 200 mL of water and adjusted to neutral pH with a few drops of dilute aqueous sulfuric acid. The organic layer was separated, the aqueous layer was extracted once with 75 mL of diethyl ether, and the combined ether layers were washed (brine) and dried (sodium sulfate) and stripped of solvent to give the crude product as a colorless oil. Addition of 50 mL of fresh ether caused precipitation of 6.6 g (76%) of bis-(4-dimethylaminophenyl)phosphine oxide as a colorless solid, mp 140°-165°. Two recrystallizations from benzene gave 3.1 g (36%) of analytically pure product, mp 150°-170° (in air).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[C:5]12([OH:17])[CH2:14][C:9]3([OH:15])[CH2:10][CH:11]([CH2:13][C:7]([OH:16])([CH2:8]3)[CH2:6]1)[CH2:12]2>CN(C=O)C>[C:1]([O:17][C:5]12[CH2:14][C:9]3([O:15][C:9](=[O:15])[CH3:8])[CH2:10][CH:11]([CH2:13][C:7]([O:16][C:7](=[O:16])[CH3:6])([CH2:8]3)[CH2:6]1)[CH2:12]2)(=[O:3])[CH3:2]
Reactant: OC12CC3CC(O)(C1)CC(O)(C3)C2
Reactant: CC(=O)Cl
Solvent: CN(C)C=O
Product: CC(=O)OC12CC3CC(OC(C)=O)(C1)CC(OC(C)=O)(C3)C2
Temperature: 40 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
In an atmosphere of nitrogen, 10 mmole of 1,3,5-adamantanetriol obtained by the method of Example 32 and 36 mmole of triethylamine were dissolved in 10 mL of DMF. To the mixture, 33 mmole of acetyl chloride was added dropwise over 30 minutes at 40° C. The mixture was stirred for another 3 hours at 40° C. As a result, the conversion of 1,3,5-adamantanetriol was 99%, and 1,3,5-tris(acetyloxy)adamantane (yield 95%) was formed.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1.CC1(C)CC(C)OB([C:28](=[CH2:33])[C:29]([F:32])([F:31])[F:30])O1.O.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.O.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>[F:19][C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:8]2[CH:7]=[C:6]3[C:11](=[CH:10][CH:9]=2)[C:2]([C:28](=[CH2:33])[C:29]([F:32])([F:31])[F:30])=[N:3][N:4]=[CH:5]3)=[CH:14][CH:15]=1
Reactant: Fc1ccc(Nc2ccc3c(Cl)nncc3c2)cc1
Reactant: C=C(B1OC(C)CC(C)(C)O1)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: C=C(c1nncc2cc(Nc3ccc(F)cc3)ccc12)C(F)(F)F
Temperature: 100 °C

Procedure:
A mixture of 1-chloro-N-(4-fluorophenyl)phthalazin-6-amine (0.300 g, 1.1 mmol), 4,4,6-trimethyl-2-(1,1,1-trifluoroprop-2-en-2-yl)-1,3,2-dioxaborinane (0.28 mL, 1.5 mmol), tetrakis(triphenylphosphine)palladium (0.063 g, 0.055 mmol) and sodium carbonate monohydrate (0.41 g, 3.3 mmol) in 6 mL of dioxane/water (3/1) was heated in a microwave at 100° C. for 40 min. Additional 4,4,6-trimethyl-2-(1,1,1-trifluoroprop-2-en-2-yl)-1,3,2-dioxaborinane (0.100 mL) and tetrakis(triphenylphosphine)palladium (0.063 g, 0.055 mmol) was added and the mixture was heated at 100° C. for an additional 30 min. After cooling to RT, water was added and the mixture was extracted with EtOAc (3×). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified on an ISCO column (12 g, 50-80% EtOAc in hexanes) to afford N-(4-fluorophenyl)-1-(1,1,1-trifluoroprop-2-en-2-yl)phthalazin-6-amine as a light yellow solid.
Reaction SMILES: CCN=C=NCCCN(C)C.[CH3:12][O:13][C:14](=[O:30])[CH2:15][O:16][CH2:17][C:18]#[C:19][CH2:20][N:21]1[C:26](=[O:27])[CH2:25][CH2:24][CH2:23][C@@H:22]1[CH2:28][OH:29].CS(C)=O.FC(F)(F)C([O-])=O.[NH+]1C=CC=CC=1>C1C=CC=CC=1>[CH3:12][O:13][C:14](=[O:30])[CH2:15][O:16][CH2:17][C:18]#[C:19][CH2:20][N:21]1[C:26](=[O:27])[CH2:25][CH2:24][CH2:23][C@@H:22]1[CH:28]=[O:29]
Reactant: COC(=O)COCC#CCN1C(=O)CCC[C@@H]1CO
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])C(F)(F)F
Agent: c1cc[nH+]cc1
Solvent: c1ccccc1
Solvent: CS(C)=O
Product: COC(=O)COCC#CCN1C(=O)CCC[C@@H]1C=O
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
EDCI (214 mg, 1.12 mmol) was added to a solution of [4-((R)-2-hydroxymethyl-6-oxo-piperidin-1-yl)-but-2-ynyloxy]-acetic acid methyl ester (100 mg, 0.37 mmol) in benzene (3.5 mL). The reaction mixture was cooled to 0° C. and DMSO (0.11 mL, 1.55 mmol) was added. After 5 min at 0° C., pyridinium trifluoroacetate (79 mg, 0.41 mmol) was added. The reaction was allowed to warm to rt and then was stirred at rt for 3 h. The solution was decanted from the oily residue and the residue was washed with benzene (3×3 mL). The combined benzene phases were concentrated in vacuo to afford crude [4-((R)-2-formyl-6-oxo-piperidin-1-yl)-but-2-ynyloxy]-acetic acid methyl ester, which was used without further purification.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:18][CH2:19][C:20]3([CH3:28])[CH2:27][CH2:26][C:23]4([CH2:25][CH2:24]4)[CH2:22][CH2:21]3)=[CH:6][C:7]([F:17])=[C:8]([CH:16]=2)[C:9]([O:11]C(C)(C)C)=[O:10])[CH2:3][CH2:2]1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([C:4]2[C:5]([O:18][CH2:19][C:20]3([CH3:28])[CH2:27][CH2:26][C:23]4([CH2:24][CH2:25]4)[CH2:22][CH2:21]3)=[CH:6][C:7]([F:17])=[C:8]([CH:16]=2)[C:9]([OH:11])=[O:10])[CH2:2][CH2:3]1
Reactant: CC1(COc2cc(F)c(C(=O)OC(C)(C)C)cc2C2CC2)CCC2(CC1)CC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: COc1ccccc1
Product: CC1(COc2cc(F)c(C(=O)O)cc2C2CC2)CCC2(CC1)CC2
Temperature: 0 °C
Reaction time: 4 h
Yield: 89.9 %

Procedure:
To a cooled (0° C.) solution of tert-butyl 5-cyclopropyl-2-fluoro-4-((6-methylspiro[2.5]octan-6-yl)methoxy)benzoate (0.277 g, 0.713 mmol) and anisole (0.11 mL, 1.07 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (0.75 mL, 9.61 mmol). The reaction mixture was stirred at 0° C. for 4 hours before being quenched with water (5 mL). The reaction was diluted with dichloromethane (20 mL) and washed with water (4×10 mL) until the last wash was neutral as monitored by pH paper. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to afford the title compound (0.213 g, 90%) as a white solid: MS (ES−) m/z 331.3 (M−1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[C:7](=[O:18])[C:6](=[O:19])[NH:5]2.[N+:20]([O-])([O-:22])=[O:21].[K+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:20]([O-:22])=[O:21])[N:8]([CH2:12][CH:13]([CH2:14][CH3:15])[CH2:16][CH3:17])[C:7](=[O:18])[C:6](=[O:19])[NH:5]2
Reactant: O=[N+]([O-])[O-]
Reactant: CCC(CC)Cn1c(=O)c(=O)[nH]c2cc(Cl)ccc21
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCC(CC)Cn1c(=O)c(=O)[nH]c2cc(Cl)c([N+](=O)[O-])cc21
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 89.8 %

Procedure:
30 g (0.106 mol) of 6-chloro-1-(2-ethylbutyl)-2,3(1H,4H)-quinoxalinedione were dissolved in 350 ml of concentrated sulfuric acid and cooled to 0° C. Then, at 0° C., 10.8 g of potassium nitrate were added a little at a time, and the solution was stirred for 1.5 h. The mixture was then poured into ice-water, and the precipitate was filtered off with suction, washed with water and dried to yield 31 g (91%) of the product. Melting point 232°-233° C.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH2:14])(=[O:13])=[O:12])=[C:7]([F:15])[CH:6]=1)(=O)C.[OH-].[Na+].Cl>O>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH2:14])(=[O:12])=[O:13])=[C:7]([F:15])[CH:6]=1
Reactant: CC(=O)Nc1ccc(S(N)(=O)=O)c(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1ccc(S(N)(=O)=O)c(F)c1
Yield: 63.5 %

Procedure:
A mixture of 4-acetamido-2-fluorobenzenesulfonamide (11.15 g, 48 mmol) and sodium hydroxide (11.5 g, 480 mmol) in water (80 mL) was heated at reflux temperature for 3 hours. The mixture was made neutral by addition of 2N-HCl solution, and resulting suspension was filtered to give the subtitle compound (5.8 g, 63.5% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]2)=[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].[CH2:30]([CH2:32][NH2:33])[OH:31].C([BH3-])#N.[Na+].Cl>CO.O1CCOCC1.CCOCC.CO>[ClH:1].[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([NH:33][CH2:32][CH2:30][OH:31])[CH2:25][CH2:24]2)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:9][CH:10]3[CH2:11][CH:12]([CH2:13][CH:14]([CH2:16]3)[CH2:15]1)[CH2:17]2)=[O:5]
Reactant: NCCO
Reactant: O=C1CCN(Cc2ccc(Cl)c(C(=O)NCC34CC5CC(CC(C5)C3)C4)c2)CC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Solvent: CCOCC
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(CN2CCC(NCCO)CC2)ccc1Cl
Reaction time: 48 h

Procedure:
To a solution of 2-chloro-5-[(4-oxo-1-piperidinyl)methyl]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (0.150 g, Example 83a) in methanol (3ml ) at room temperature were added ethanolamine (0.11 ml) and sodium cyanoborohydride (0.068g). The pH was adjusted to 6 by adding a 4N solution of hydrogen chloride in dioxane and the reaction stirred for 48 h. The reaction was acidified with concentrated hydrochloric acid until gas evolution ceased. The precipitate was removed by filtration and the filtrate concentrated under vacuum. The residue was partitioned between ethyl acetate and water. The aqueous layer was basified with 5% aqueous sodium hydroxide and extracted with dichloromethane. The organics were washed with brine and dried over magnesium sulfate. The crude material was purified on silica gel (5% 7N ammonia in methanol/95% dichloromethane) to afford a white foam which was dissolved in ether/methanol and treated with a 4N solution of hydrogen chloride in dioxane to give the title compound (0.135 g).
Reaction SMILES: [C:1]([C:4]1[C:12]2[O:11][CH2:10][CH:9]([C:13]3[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=3)[C:8]=2[C:7]([CH3:22])=[C:6]([NH:23]C=O)[C:5]=1[CH3:26])(=[O:3])[CH3:2].Cl.C(=O)(O)[O-].[Na+]>CO>[C:1]([C:4]1[C:12]2[O:11][CH2:10][CH:9]([C:13]3[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=3)[C:8]=2[C:7]([CH3:22])=[C:6]([NH2:23])[C:5]=1[CH3:26])(=[O:3])[CH3:2]
Reactant: CC(=O)c1c(C)c(NC=O)c(C)c2c1OCC2c1ccc(C(C)C)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CC(=O)c1c(C)c(N)c(C)c2c1OCC2c1ccc(C(C)C)cc1
Temperature: 25 °C

Procedure:
N-(7-Acetyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)formamide obtained in Example 203 (808 mg, 2.3 mmol) was added to a solution of methanol (10 mL) and concentrated hydrochloric acid (5 mL), and the mixture was heated under reflux for 2 hours. The reaction solution was cooled to room temperature and was poured into a cold sodium bicarbonate solution, which was extracted with ethyl acetate. The extract was washed with a saturated brine, dried over sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane ethyl acetate=1:1) to obtain the title compound as an oily matter.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[CH:10]([OH:34])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br.Br[CH2:37][C:38]1[CH:47]=[C:46]2[C:41]([CH:42]=[CH:43][CH:44]=[N:45]2)=[CH:40][CH:39]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[CH:10]([O:34][CH2:37][C:38]2[CH:47]=[C:46]3[C:41]([CH:42]=[CH:43][CH:44]=[N:45]3)=[CH:40][CH:39]=2)[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Reactant: BrCc1ccc2cccnc2c1
Agent: Br
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc3cccnc3c2)cc1

Procedure:
In analogy to the procedure described in example 1(b) the (3RS,4RS)-3-hydroxy-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester was alkylated with 7-bromomethyl-quinoline hydrobromide (1:1) [J. Am. Chem. Soc. 77, 1054(1955)] to yield the (3RS,4RS)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-3-(quinolin-7-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester as an amorphous light yellow solid; MS: 613 (M+H)+.
Reaction SMILES: [Si:1]([O:8][C:9]1[C:10]([CH3:24])=[C:11]([CH3:23])[C:12]2[O:16][CH:15]([CH2:17][CH2:18][CH2:19]Cl)[S:14][C:13]=2[C:21]=1[CH3:22])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[I-:25].[Na+]>CC(C)=O>[Si:1]([O:8][C:9]1[C:10]([CH3:24])=[C:11]([CH3:23])[C:12]2[O:16][CH:15]([CH2:17][CH2:18][CH2:19][I:25])[S:14][C:13]=2[C:21]=1[CH3:22])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: [I-]
Reactant: Cc1c(C)c2c(c(C)c1O[Si](C)(C)C(C)(C)C)SC(CCCCl)O2
Agent: [Na+]
Solvent: CC(C)=O
Product: Cc1c(C)c2c(c(C)c1O[Si](C)(C)C(C)(C)C)SC(CCCI)O2

Procedure:
A mixture of 1.06 g of 5-t-butyldimethylsilyloxy-2-(3-chloropropyl)-4,6,7-trimethyl-1,3-benzoxathiole (prepared as described in Example 78), 4.1 g of sodium iodide and 40 ml of acetone was heated under reflux for 10 hours. The reaction product was then cooled, after which it was treated in the same manner as described in (a) above, to give the title compound having the same Rf value, infrared absorption spectrum and mass spectrum as the product of (a) above.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH3:28])[CH2:14][C:15]2[O:16][C:17]([C:20]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[O:21])=[N:18][N:19]=2)(=[O:12])=[O:11])=[C:5]([CH3:29])[CH:4]=1.[NH2:30][C:31]1[C:36]([CH:37]=O)=[CH:35][CH:34]=[CH:33][N:32]=1.ClCCCl>>[NH2:30][C:31]1[C:36]([CH2:37][N:25]2[CH2:24][CH2:23][N:22]([C:20]([C:17]3[O:16][C:15]([CH2:14][N:13]([CH3:28])[S:10]([C:6]4[C:7]([CH3:9])=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=4[CH3:29])(=[O:11])=[O:12])=[N:19][N:18]=3)=[O:21])[CH2:27][CH2:26]2)=[CH:35][CH:34]=[CH:33][N:32]=1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2nnc(C(=O)N3CCNCC3)o2)c(C)c1
Reactant: Nc1ncccc1C=O
Solvent: ClCCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2nnc(C(=O)N3CCN(Cc4cccnc4N)CC3)o2)c(C)c1

Procedure:
The title compound was prepared according to general procedure CD using 4-methoxy-N,2,6-trimethyl-N-{[5-(piperazin-1-ylcarbonyl)-1,3,4-oxadiazol-2-yl]methyl}benzenesulfonamide (42 mg, 0.10 mmol), 2-aminopyridine-3-carbaldehyde (15 mg, 0.12 mmol), STAB (42 mg, 0.2 mmol) DCE (0.8 mL) and a few 4 Å molecular sieves. The crude product was purified using prep method D.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([F:11])=[CH:4][C:3]=1[CH:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14].C([O-])=O.[NH4+]>C(O)C.[Pd]>[NH2:8][C:6]1[C:5]([F:11])=[CH:4][C:3]([CH:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:2]([F:1])[CH:7]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1cc(F)c([N+](=O)[O-])cc1F
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)C(C(=O)OCC)c1cc(F)c(N)cc1F
Yield: 99.9 %

Procedure:
10% Pd/C (wet paste, 484 mg) was added to a solution of diethyl (2,5-difluoro-4-nitrophenyl)propanedioate (4.84 g, 15.3 mmol) and ammonium formate (5 eq, 4.81 g, 76.34 mmol) in ethanol (100 mL). The reaction mixture was heated to reflux under argon for one hour. The reaction was allowed to cool and then filtered through celite to remove the Pd residues. The filtrate was evaporated to dryness and then partitioned between ethyl acetate (100 mL) and water (100 mL). The organic layer was separated, dried over magnesium sulfate, filtered and then evaporated to dryness to give the title compound as an orange oil (4.39 g) LC/MS Rt=1.07 min, [MH]+ 288.
Reaction SMILES: [CH:1]1([N:4]([C@@H:12]2[CH2:17][CH2:16][NH:15][CH2:14][C@@H:13]2[F:18])C(=O)OC(C)(C)C)[CH2:3][CH2:2]1.Cl[C:20]1[N:25]=[CH:24][C:23]([CH2:26][CH3:27])=[CH:22][N:21]=1>>[CH:1]1([NH:4][C@@H:12]2[CH2:17][CH2:16][N:15]([C:20]3[N:25]=[CH:24][C:23]([CH2:26][CH3:27])=[CH:22][N:21]=3)[CH2:14][C@@H:13]2[F:18])[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N(C1CC1)[C@@H]1CCNC[C@@H]1F
Reactant: CCc1cnc(Cl)nc1
Product: CCc1cnc(N2CC[C@@H](NC3CC3)[C@@H](F)C2)nc1

Procedure:
The title compound is prepared from tert-butyl N-cyclopropyl-N-[(3S,4R)-3-fluoropiperidin-4-yl]carbamate and 2-chloro-5-ethylpyrimidine following a procedure analogous to that described for Intermediate 87. LC (method 20): tR=1.80 min; Mass spectrum (APCI): m/z=265 [M+H]+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([N:6]2[C:14](=[O:15])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]2=[O:16])=[N:2]1.[CH3:17][C:18]1([CH3:35])[O:22][C@H:21]([CH2:23]OS(C2C=CC(Cl)=CC=2)(=O)=O)[CH2:20][O:19]1.CC(C)([O-])C.[Na+].O>O1CCOCC1>[CH3:17][C:18]1([CH3:35])[O:22][C@H:21]([CH2:23][N:1]2[CH:5]=[CH:4][C:3]([N:6]3[C:14](=[O:15])[C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[C:7]3=[O:16])=[N:2]2)[CH2:20][O:19]1
Reactant: O=C1c2ccccc2C(=O)N1c1cc[nH]n1
Reactant: CC1(C)OC[C@@H](COS(=O)(=O)c2ccc(Cl)cc2)O1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC1(C)OC[C@@H](Cn2ccc(N3C(=O)c4ccccc4C3=O)n2)O1
Temperature: 103 °C
Yield: 74 %

Procedure:
A mixture of 2-(1H-pyrazol-3-yl)-isoindole-1,3-dione (5.00 g, 23.5 mmol), 4-chloro-benzenesulfonic acid (S)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl ester (8.00 g, 26.1 mmol), and sodium t-butoxide (2.78 g, 28.9 mmol) in 1,4-dioxane (50 mL) was refluxed (103° C.) for 24 h. Upon cooling to 25° C., water (55 mL) was added. The mixture became cloudy and crystallization was observed. Then, water (50 mL) was slowly added over 30 min. Subsequent filtration, washing with water, and suction drying provided 2-[1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-isoindole-1,3-dione (5.69 g, 74.1%) as an off-white solid: LR-ES-MS m/z calculated for C17H17N3O4 [M]+ 327, observed [M+H]+ 328.
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[N:10]=[C:9]([CH:14]([CH3:29])[CH2:15][C:16]3[CH:28]=[CH:27][C:19]([O:20][CH2:21][C:22]([O:24]CC)=[O:23])=[CH:18][CH:17]=3)[NH:8][C:7]=2[N:6]([CH2:30][CH2:31][CH3:32])[C:5]1=[O:33])[CH2:2][CH3:3].[OH-].[K+]>C(O)C.O>[CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[N:10]=[C:9]([CH:14]([CH3:29])[CH2:15][C:16]3[CH:28]=[CH:27][C:19]([O:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:18][CH:17]=3)[NH:8][C:7]=2[N:6]([CH2:30][CH2:31][CH3:32])[C:5]1=[O:33])[CH2:2][CH3:3]
Reactant: CCCn1c(=O)c2nc(C(C)Cc3ccc(OCC(=O)OCC)cc3)[nH]c2n(CCC)c1=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCn1c(=O)c2nc(C(C)Cc3ccc(OCC(=O)O)cc3)[nH]c2n(CCC)c1=O
Reaction time: 3 h
Yield: 80.7 %

Procedure:
Dissolve (-)-2-[4-[2-(2,3,6,9-tetrahydro-1,3-dipropyl-2,6-dioxo-1H-purin-8-yl)propyl]phenoxy]acetic acid, ethyl ester (0.62 g, 1.36 mmol) in ethanol (15 mL) and treat with a solution of potassium hydroxide (0.091 g, 1.63 mmol) in water (15 mL). Stir for 3 hours, add water (200 mL) and wash with ethyl ether (300 mL). Acidify the aqueous phase with 10% hydrochloric acid and extract into chloroform (4×150 mL). Dry (MgSO4) and evaporate the solvent in vacuo to give the title compound (0.47 g, 81%); [α]d 20 =-79.1° (C=0.537, DMSO).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:13])[C@@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[NH2:6].[C:14](=O)([O-:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17].C(=O)([O-])[O:23]C(C)(C)C.C(N(CC)CC)C>O1CCCC1>[CH3:2][O:3][C:4](=[O:13])[C@H:5]([NH:6][C:14]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:20])[C:7]1[CH:12]=[CH:11][C:10]([OH:23])=[CH:9][CH:8]=1
Reactant: COC(=O)[C@H](N)c1ccccc1
Reactant: CC(C)(C)OC(=O)[O-]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)[C@H](NC(=O)OC(C)(C)C)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(R)-(−)-2-phenylglycine methyl ester hydrochloride (2.17 g, 10 mmol) and di-t-butyl di-carbonate (2.62 g, 12 mmol) were combined in tetrahydrofuran (100 ml). Triethylamine (1.60 ml, 22 mmol) was added to the mixture via syringe at room temperature. The reaction mixture was stirred at room temperature overnight. The THF in reaction mixture was then removed in vacuum. Saturated aqueous NH4Cl and ethyl acetate were added to the mixture in a separatory funnel. The aqueous layer was extracted with ethyl acetate (3×40 ml). The combined organic layer was washed with saturated aqueous NH4Cl, dried over MgSO4, filtered and concentrated to give a white solid (3.08 g, crude product): 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.20 (d, J=8.1 Hz, 2H), 6.77 (m, 2H), 5.73 (br. s., 1H), 5.56 (br. s., 1H), 5.25 (d, J=6.6 Hz, 1H), 3.73 (s, 3H), 1.46 (s, 9H) LCMS (ESI) m/e 282.1 [(M+H)+, calcd for C14H20NO5 282.3].