Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[C:2]([C:6]1[CH:11]=[CH:10][C:9](/[C:12](/[C:31]2[CH:36]=[CH:35][C:34]([S:37][CH3:38])=[C:33]([O:39]C)[N:32]=2)=[CH:13]\[C@@H:14]2[N:18](CC3C=CC(OC)=CC=3OC)[C:17](=[O:30])[CH2:16][CH2:15]2)=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3].O>O1CCOCC1>[C:2]([C:6]1[CH:11]=[CH:10][C:9](/[C:12](/[C:31]2[NH:32][C:33](=[O:39])[C:34]([S:37][CH3:38])=[CH:35][CH:36]=2)=[CH:13]\[C@H:14]2[CH2:15][CH2:16][C:17](=[O:30])[NH:18]2)=[CH:8][CH:7]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: COc1ccc(CN2C(=O)CC[C@@H]2/C=C(\c2ccc(C(C)(C)C)cc2)c2ccc(SC)c(OC)n2)c(OC)c1
Agent: Br
Solvent: O
Solvent: C1COCCO1
Product: CSc1ccc(/C(=C/[C@H]2CCC(=O)N2)c2ccc(C(C)(C)C)cc2)[nH]c1=O
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 27 %

Procedure:
48% hydrobromic acid (1.5 mL) was added to a solution of (5R)-5-{(E)-2-(4-tert-butylphenyl)-2-[6-methoxy-5-(methylsulfanyl)pyridin-2-yl]ethenyl}-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one (53 mg) in 1,4-dioxane (2 mL), and the mixture was stirred at 65° C. for 30 minutes. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. A solution of the residue in trifluoroacetic acid (4 mL) and anisole (2 mL) was stirred at 80° C. for six hours. The solvent was evaporated from the reaction solution under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=100:1→3:1) and preparative HPLC (Waters Sunfire 19×150 mm 5 μm, rate: 20 mL/min, eluent: A=acetonitrile, B=0.1% trifluoroacetic acid solution, gradient: 10 to 90%) and powdered with ethyl acetate-hexane to give the title compound as a colorless powder (10 mg, 27%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:10]2[O:14]CCO2)[CH:7]=[CH:8][CH:9]=1)([CH3:3])=[CH2:2].[CH2:15]1CCCCC1.CCOC(C)=O>>[CH3:15][C:1]1([C:4]2[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=2)[CH:10]=[O:14])[CH2:2][CH2:3]1
Reactant: C1CCCCC1
Reactant: C=C(C)c1cccc(C2OCCO2)c1
Solvent: CCOC(C)=O
Product: CC1(c2cccc(C=O)c2)CC1

Procedure:
The title compound was prepared following a procedure described in J. Am. Chem. Soc. 2007, 127, 12440-12441, starting from 2-(3-isopropenyl-phenyl)-[1,3]dioxolane and was obtained as a light yellow oil: TLC (cyclohexane-EtOAc 80:20) Rf=0.52; HPLC RtG2=1.35 min; 1H NMR (400 MHz, DMSO-d6): δ 9.98 (s, 1H), 7.74 (s, 1H), 7.68 (d, 1H), 7.51 (m, 2H), 1.40 (s, 3H), 0.89 (t, 2H), 0.81 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[NH2:24][CH:25]([CH2:28][OH:29])[CH2:26][OH:27]>>[OH:27][CH2:26][CH:25]([NH:24][C:19](=[O:21])[C:18]1[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:16][CH:17]=1)[CH2:28][OH:29]
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: NC(CO)CO
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NC(CO)CO)cn1
Yield: 87 %

Procedure:
As described for example 191, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.65 mmol) was converted, using 2-amino-1,3-propandiol instead of 2-aminoethyl isopropylether, to the title compound (215 mg, 87%) which was obtained as a colourless oil. MS: m/e=384.0 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)([CH2:7][C:8]#[CH:9])[C:4](=[O:18])[N:3]1[C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([C:27]([F:30])([F:29])[F:28])[CH:20]=1.[CH3:31]N(C=O)C>>[O:1]=[C:2]1[N:6]([CH3:31])[C:5]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)([CH2:7][C:8]#[CH:9])[C:4](=[O:18])[N:3]1[C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([C:27]([F:30])([F:28])[F:29])[CH:20]=1
Reactant: CN(C)C=O
Reactant: C#CCC1(c2ccc(OC)cc2)NC(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Product: C#CCC1(c2ccc(OC)cc2)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1C

Procedure:
Following the procedure of Example 159, a solution of 380 mg of 4-[2,5-dioxo-4-(4-methoxyphenyl)-4-(2-propynyl)imidazolidin-1-yl]-2-trifluoromethylbenzonitrile in 9 mL of DMF is treated to produce 580 mg of crude product which is purified by chromatography over silica while eluting with (90/10 then 85/15) heptane/ethyl acetate mixture. 320 mg of product are obtained in the form of a white solid (Yd=81%).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH2:13]C1C=CC=CC=1)[CH2:8][N:7](CC1C=CC=CC=1)[CH2:6]2>[OH-].[OH-].[Pd+2].C(O)C>[CH3:13][O:12][C:11]1[CH:10]=[C:9]2[C:5]([CH2:6][NH:7][CH2:8]2)=[CH:4][C:3]=1[OH:2]
Reactant: COc1cc2c(cc1OCc1ccccc1)CN(Cc1ccccc1)C2
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: COc1cc2c(cc1O)CNC2
Temperature: 25 °C
Reaction time: 21 h
Yield: 87.4 %

Procedure:
To 35 mL of ethyl alcohol is added 0.5 g of 2,3-dihydro-5-methoxy-6-(phenylmethoxy)-2-(phenylmethyl)-1H-isoindole. The solution is warmed until everything is dissolved. The solution is cooled to room temperature and 0.13 g of 35% palladium hydroxide on carbon is added. The resulting mixture is shaken on a Parr apparatus at 50 pounds per square inch for 21 hours. The solution is filtered through a pad of diatomaceous earth and the pad washed with ethyl alcohol. The volatiles are removed to afford 0.209 g of the desired product as a tan solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8]O)[CH:3]=1.S(Cl)([Cl:12])=O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][Cl:12])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cc(Cl)ccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: ClCc1cc(Cl)ccn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 59.9 %

Procedure:
To a mixture of (4-chloro-pyridine-2-yl)-methanol (146.8 mg, 1.0 mmol) described in Manufacturing Example 51-1-1 and toluene (3 mL) was added thionyl chloride (112 μL, 1.53 mmol) on an ice bath, which was stirred for 1 hour 15 minutes at room temperature. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure and the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=4:1) to obtain the title compound (97 mg, 59%).
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([NH2:16])=[N:14][CH:15]=2)[CH2:5][CH2:4]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N1CCN(C2C=C(N[C:54]([C:56]3[C:57]4[N:58]=[CH:59][CH:60]=[N:61][C:62]=4[C:63]([C:66]4[C:75]5[C:70](=[CH:71][CH:72]=[CH:73][CH:74]=5)[CH:69]=[N:68][CH:67]=4)=[CH:64][CH:65]=3)=[O:55])C=CC=2)CC1)C>C(Cl)Cl.CO>[CH3:2][N:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:54]([C:56]3[C:57]4[N:58]=[CH:59][CH:60]=[N:61][C:62]=4[C:63]([C:66]4[C:75]5[C:70](=[CH:71][CH:72]=[CH:73][CH:74]=5)[CH:69]=[N:68][CH:67]=4)=[CH:64][CH:65]=3)=[O:55])=[N:14][CH:15]=2)[CH2:5][CH2:4]1
Reactant: CCN1CCN(c2cccc(NC(=O)c3ccc(-c4cncc5ccccc45)c4nccnc34)c2)CC1
Reactant: CN1CCN(Cc2ccc(N)nc2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CO
Product: CN1CCN(Cc2ccc(NC(=O)c3ccc(-c4cncc5ccccc45)c4nccnc34)nc2)CC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but stirring the reaction mixture for 17 h at rt, using 2 equiv of 5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-ylamine hydrochloride (Example 31), TBTU (2 equiv) and 8-isoquinolin-4-yl-quinoxaline-5-carboxylic acid (Example 52). Title compound: ESI-MS: 490.0 [M+H]+; tR=2.21 min (System 1); TLC: Rf=0.17 (DCM/MeOH, 9:1).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[CH:12]=[C:11]([C:13]3[CH:36]=[CH:35][C:16]4[N:17]([C:20]5[CH:21]=[C:22]([NH:26][C:27]([NH:29][CH2:30][C:31]([F:34])([F:33])[F:32])=[O:28])[CH:23]=[CH:24][CH:25]=5)[CH:18]=[N:19][C:15]=4[CH:14]=3)[CH:10]=[N:9]2)[CH2:4][CH2:3]1.[CH:37]1([CH2:40][C:41](O)=[O:42])[CH2:39][CH2:38]1>>[CH:37]1([CH2:40][C:41]([N:2]2[CH2:3][CH2:4][CH:5]([N:8]3[CH:12]=[C:11]([C:13]4[CH:36]=[CH:35][C:16]5[N:17]([C:20]6[CH:21]=[C:22]([NH:26][C:27]([NH:29][CH2:30][C:31]([F:33])([F:32])[F:34])=[O:28])[CH:23]=[CH:24][CH:25]=6)[CH:18]=[N:19][C:15]=5[CH:14]=4)[CH:10]=[N:9]3)[CH2:6][CH2:7]2)=[O:42])[CH2:39][CH2:38]1
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-n2cnc3cc(-c4cnn(C5CCNCC5)c4)ccc32)c1
Reactant: O=C(O)CC1CC1
Agent: Cl
Product: O=C(NCC(F)(F)F)Nc1cccc(-n2cnc3cc(-c4cnn(C5CCN(C(=O)CC6CC6)CC5)c4)ccc32)c1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 1 (Step 6) starting from N-{3-[5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]phenyl}-N′-(2,2,2-trifluoroethyl)urea HCl salt and cyclopropylacetic acid, (Alfa aesar, Cat. No. L09416), LCMS (M+H)+: m/z=566.2.
Reaction SMILES: [C:1]([OH:10])(=O)[C@H:2]([C@@H:4]([C:6](O)=[O:7])[OH:5])[OH:3].[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>C1(C)C(C)=CC=CC=1>[CH2:11]([N:18]1[C:6](=[O:7])[C@@H:4]([OH:5])[C@H:2]([OH:3])[C:1]1=[O:10])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Solvent: O
Solvent: Cc1ccccc1C
Product: O=C1[C@@H](O)[C@H](O)C(=O)N1Cc1ccccc1
Yield: 84635.8 %

Procedure:
In xylene (500 ml), D-tartaric acid (25.0 g, 0.17 mol) and benzylamine (19.6 g, 0.18 mmol) were heated under reflux for 18 hours by using a Dean-Stark water separator. After cooling, the reaction mixture was distilled under reduced pressure to remove the solvent, whereby 1-benzyl-(3S,4S)-dihydroxy-2,5-dioxopyrrolidine (33.7 g, 90%) was obtained as a brown solid.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH2:16](O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH:20]1[CH:21]=[CH:22][C:17]([CH2:16][O:6][C:5]([CH2:4][CH2:3][C@H:2]([NH2:1])[C:8]([OH:10])=[O:9])=[O:7])=[CH:18][CH:19]=1
Reactant: OCc1ccccc1
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Agent: O=S(=O)(O)O
Product: N[C@@H](CCC(=O)OCc1ccccc1)C(=O)O
Temperature: 70 °C
Reaction time: 0.75 h
Yield: 45.7 %

Procedure:
1416 grams (g) of L-glutamic acid, 1560 g of 60% sulfuric acid and 1152 g of benzyl alcohol were placed in a 12 liter round bottom flask equipped with a distillation head. The mixture was heated to 70° C. and stirred for 45 minutes. Upon cooling, the resulting solution was stirred and was subjected to a reduced pressure. When the vacuum had stabilized at about 100 millimeters (mm) the reaction temperature was again raised to 70° C. and water was distilled off for about 4.5 hours. Upon standing overnight, the reaction mixture became viscous and was slowly added to a stirred mixture of 1613 g of sodium bicarbonate, 1.2 kilograms (kg) of ice and 12 liters of water. A precipitate formed which was collected by filtration and then washed with about 8 liters of carbon dioxide-free water and 8 liters of acetone and subsequently air-dried. The precipitate was triturated with 2 liters of ether and dried, yielding 1044 g of the desired γ-benzyl L-glutamate, melting point (m.p.) 156°-157° C. Thin layer chromatography detected the presence of unreacted glutamic acid in the crude product. The crude product was recrystallized from 12.5 liters of hot water and filtered through a plug of glass wool suspended in the neck of a heated glass funnel. After cooling, and overnight refrigeration, the recrystallized product was collected, and washed with 2 liters of cold water, then 2 liters of THF. The product was air dried overnight and then dried in vacuo at room temperature for three hours. 693 g of γ-benzyl L-glutamate was recovered as white, shiny plates, m.p. 156.5°-157° C.
Reaction SMILES: [H-].[Na+].[Si:3]([O:20][CH2:21][CH2:22][O:23][CH2:24][C@H:25]([OH:37])[C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][N:30]=1)=[O:27])([C:16]([CH3:19])([CH3:18])[CH3:17])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:39]1[N:44]=[CH:43][N:42]=[C:41]2[N:45]([C:48]3[C:49]([CH3:56])=[C:50]([CH:53]=[CH:54][CH:55]=3)[C:51]#[N:52])[N:46]=[CH:47][C:40]=12.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O.CCOC(C)=O>[Si:3]([O:20][CH2:21][CH2:22][O:23][CH2:24][C@H:25]([O:37][C:39]1[N:44]=[CH:43][N:42]=[C:41]2[N:45]([C:48]3[CH:55]=[CH:54][CH:53]=[C:50]([C:51]#[N:52])[C:49]=3[CH3:56])[N:46]=[CH:47][C:40]=12)[C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][N:30]=1)=[O:27])([C:16]([CH3:17])([CH3:18])[CH3:19])([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Cc1c(C#N)cccc1-n1ncc2c(Cl)ncnc21
Reactant: CC(C)(C)[Si](OCCOC[C@H](O)C(=O)Nc1ccc(C#N)cn1)(c1ccccc1)c1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1c(C#N)cccc1-n1ncc2c(O[C@@H](COCCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C(=O)Nc3ccc(C#N)cn3)ncnc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 35.1 %

Procedure:
Sodium hydride (60% in oil) (87 mg, 2.17 mmol) was added to (S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-N-(5-cyanopyridin-2-yl)-2-hydroxypropanamide (Intermediate AU1) (484 mg, 0.99 mmol) in anhydrous THF (25 ml) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then 3-(4-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-methylbenzonitrile (Intermediate AT2) (267 mg, 0.99 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 4 hours. The reaction mixture was neutralised with 1M citric acid and diluted with water and EtOAc. The organic layer was separated and the aqueous layer re-extracted with EtOAc. The combined organics were washed with saturated brine, dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 0 to 50% EtOAc in isohexane to afford the product (251 mg, 35.1%). m/z (ES+) (M+H)+=723.67; HPLC tR=3.75 min.
Reaction SMILES: [NH2:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:25][CH3:26])[CH:3]=1.[N:27]1[CH:32]=[CH:31][C:30]([CH:33]=O)=[CH:29][CH:28]=1>>[NH2:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][CH2:33][C:30]3[CH:31]=[CH:32][N:27]=[CH:28][CH:29]=3)[CH2:14][CH2:15]2)=[O:7])=[C:4]([O:25][CH3:26])[CH:3]=1
Reactant: O=Cc1ccncc1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCN)CC1
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCNCc2ccncc2)CC1
Yield: 30.7 %

Procedure:
4-Amino-N-(1-(5-aminopentyl)piperidin-4-ylmethyl)-5-chloro-2-methoxybenzamide (3 g) as starting compound and 4-pyridinecarboxaldehyde (0.84 g) were reacted and treated in the same manner as in Example 121 to give 1.14 g of 4-amino-5-chloro-2-methoxy-N-((1-(5-(4-pyridylmethylamino)pentyl)piperidin-4-yl)methyl)benzamide.
Reaction SMILES: C(OC([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]([OH:20])=O)=[CH:15][CH:16]=2)[N:11]([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:10][CH2:9]1)=O)(C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH2:58][C@@H:59]([CH2:73][C:74]1[CH:79]=[C:78]([F:80])[CH:77]=[C:76]([F:81])[CH:75]=1)[C@H:60]([OH:72])[CH2:61][NH:62][CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[C:66]([CH2:70][CH3:71])[CH:65]=1.[ClH:82]>C(Cl)Cl.CO>[ClH:82].[CH2:21]([N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[C:14]([C:18]([NH:58][C@@H:59]([CH2:73][C:74]3[CH:75]=[C:76]([F:81])[CH:77]=[C:78]([F:80])[CH:79]=3)[C@H:60]([OH:72])[CH2:61][NH:62][CH2:63][C:64]3[CH:69]=[CH:68][CH:67]=[C:66]([CH2:70][CH3:71])[CH:65]=3)=[O:20])[CH:13]=2)[NH:8][CH2:9][CH2:10]1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCCN1CCN(C(=O)OC(C)(C)C)c2ccc(C(=O)O)cc21
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: ClCCl
Product: CCCCN1CCNc2ccc(C(=O)N[C@@H](Cc3cc(F)cc(F)c3)[C@H](O)CNCc3cccc(CC)c3)cc21
Reaction time: 8 h
Yield: 21.4 %

Procedure:
A solution of 1-(tert-butoxycarbonyl)-4-butyl-1,2,3,4-tetrahydroquinoxaline-6-carboxylic acid (120 mg), HBTU (204 g), and diisopropylethylamine (100 μL) was stirred in methylene chloride (2.0 mL) for 15 min. A solution of (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol (146 mg) and diisopropylethylamine (100 μL) in methylene chloride (2.0 mL) was added and the mixture was stirred overnight. The mixture was diluted with methylene chloride, washed with 1 N hydrochloric acid (10 mL), saturated sodium bicarbonate (10 mL), and brine. The organic layer was then dried (magnesium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 1:9 methanol/chloroform) provided a clear solid. The solid was dissolved in methanol (1 mL), and treated with hydrochloric acid (0.5 mL, 1.0 M diethyl ether, 0.5 mmol). The resulting precipitate was collected by filtration to provide 45 mg of the title compound: ESI MS m/z 551 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:5]2[O:6][C:7]([CH2:10][CH3:11])([CH3:9])[O:8][C:4]=2[CH:3]=1.[C:14](Cl)(Cl)=[S:15].C(=O)([O-])[O-].[K+].[K+]>O.C(Cl)(Cl)Cl>[CH2:10]([C:7]1([CH3:9])[O:6][C:5]2[CH:12]=[CH:13][C:2]([N:1]=[C:14]=[S:15])=[CH:3][C:4]=2[O:8]1)[CH3:11]
Reactant: S=C(Cl)Cl
Reactant: CCC1(C)Oc2ccc(N)cc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCC1(C)Oc2ccc(N=C=S)cc2O1
Yield: 94.5 %

Procedure:
Using procedures similar to those employed in Step A of Example 8, the reaction of 1.9 g (0.011 mole) of 5-amino-2-ethyl-2-methyl-1,3-benzodioxole with 2.4 g (0.021 mole) of thiophosgene and 6.2 g (0.045 mole) of potassium carbonate in 10 ml of water and 70 ml of chloroform yielded 2.3 g of (2-ethyl-2-methyl-1,3-benzodioxol-5-yl) isothiocyanate as an oil. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[CH:10][C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([S:19]([CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)(=[O:21])=[O:20])[CH:12]=2)=[O:7])CCC.[NH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32].C[O-].[Na+].CO.Cl>O>[CH:22]1([S:19]([C:13]2[CH:12]=[C:11]3[C:16]([C:17]([OH:18])=[C:8]([C:6]([NH:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[O:7])[N:9]=[CH:10]3)=[CH:15][CH:14]=2)(=[O:20])=[O:21])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: NCCC(=O)O
Reactant: CCCCOC(=O)c1ncc2cc(S(=O)(=O)C3CCCCC3)ccc2c1O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C(O)CCNC(=O)c1ncc2cc(S(=O)(=O)C3CCCCC3)ccc2c1O
Yield: 46 %

Procedure:
A mixture of 7-cyclohexanesulfonyl-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester (20 mg, 0.05 mmol) (prepared according to U.S. Pat. No. 7,629,357) and beta-alanine (45 mg, 0.5 mmol) in 0.5 M NaOMe/MeOH (0.8 mL, 0.4 mmol) was microwaved at 120° C. for 30 min. Reaction mixture was diluted with water (50 mL) and acidified by 1 N HCl to pH=3-4. Precipitate was collected, rinsed with water and dried in vacuo to provide the title compound 9.4 mg (0.023 mmol) in 46% yield. LC-MS ESI−: 405.05 (M−1)−.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][O:5][CH2:4][CH:3]1[OH:8].NC1C(O)CCOC1.C(=O)([O-])[O-].[Na+].[Na+].Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>O>[CH2:27]([O:26][C:24](=[O:25])[NH:1][C@H:2]1[CH2:7][CH2:6][O:5][CH2:4][C@@H:3]1[OH:8])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NC1CCOCC1O
Agent: NC1COCCC1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(N[C@H]1CCOC[C@@H]1O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a crude 5:1 mixture of rac-(3R,4S)-4-aminotetrahydro-2H-pyran-3-ol and rac-(3R,4S)-3-aminotetrahydro-2H-pyran-4-ol (see Example 8, 3.50 g, 29.9 mmol) in 150 mL of water at 0° C. was added sodium carbonate (3.80 g, 35.9 mmol) followed by benzyl chloroformate (5.12 mL, 35.9 mmol) dropwise. After 30 min, the mixture was warmed to rt, and after 4 h, a solid precipitate was collected via filtration and recrystallized from ethyl acetate/hexanes to provide benzyl[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]carbamate that gave a proton NMR spectra consistent with theory. The filtrate was concentrated and the resultant residue was subjected to purification via silica gel chromatography, eluting with 30-70% ethyl acetate in hexanes to provide a mixture of benzyl[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]carbamate and benzyl [(3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl]carbamate. The two enantiomers were separated via chiral chromatography to provide pure benzyl[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]carbamate and benzyl[(3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl]carbamate. The semi-preparative separation was performed on a 5 cm id by 50 cm length, 20 μm, AD column run at 85 mL/min in a mixture of 60% ethanol/40% heptane with 0.1% DEA added to both components.
Reaction SMILES: [Cl:1][C:2]1[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][C:5]1[C:6]([O:21][CH3:22])=[N:7][NH:8][C:9]=1[N:10]1C(=O)C2C(=CC=CC=2)C1=O.O.NN>C1COCC1>[Cl:1][C:2]1[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][C:5]1[C:9]([NH2:10])=[N:8][NH:7][C:6]=1[O:21][CH3:22]
Reactant: COc1n[nH]c(N2C(=O)c3ccccc3C2=O)c1Cc1cccc(Cl)c1Cl
Agent: NN
Solvent: O
Solvent: C1CCOC1
Product: COc1[nH]nc(N)c1Cc1cccc(Cl)c1Cl
Temperature: 25 °C
Yield: 71.8 %

Procedure:
To a solution of 2-(4-(2,3-dichlorobenzyl)-3-methoxy-1H-pyrazol-5-yl)isoindoline-1,3-dione (620 mg, 1.54 mmol) in THF (20 mL) was added hydrazine hydrate (1.0 g, 20 mmol) dropwise with stirring at room temperature. Then, the mixture was stirred at room temperature for 2 hours and 50° C. for another 2 hours. Then the reaction mixture was concentrated under vacuo and the residue was purified by silica gel chromatography eluted with EA to give the titled compound (301 mg, 72%) as a colorless viscous liquid. LC/MS: MS (ES+) m/e 272 (MH+); 1H NMR (300 MHz, CDCl3) δ ppm 3.71 (s, 2H), 3.86 (s, 3H), 7.07-7.14 (m, 2H), 7.29-7.32 (m, 1H).