Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:22])([O:4][C:5]([N:7]1[CH2:12][CH2:11][C:10]2([C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]([NH2:21])[CH2:13]2)[CH2:9][CH2:8]1)=[O:6])[CH3:3].C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:3][C:2]([CH3:22])([O:4][C:5]([N:7]1[CH2:8][CH2:9][C:10]2([C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]([NH:21][S:31]([CH3:30])(=[O:33])=[O:32])[CH2:13]2)[CH2:11][CH2:12]1)=[O:6])[CH3:1]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(N)c1ccccc12
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(NS(C)(=O)=O)c1ccccc12

Procedure:
A sample of 1'-(1,1-Dimethylethyloxycarbonyl)-3-amino-2,3-dihydrospiro(1H-indene-1,4'-piperidine), prepared by hydrogenation of 500 mg of oxime (1.58 mmole) as in Example 135 Step A, in 3.5 mL methylene chloride containing 475 mg of DMAP (2.46×1.58 mmole), and 550λ of triethylamine (2.51×1.58 mmole), was stirred under nitrogen in an ice bath while adding a solution of 270λ of methanesulfonyl chloride (2.2×1.58 mmole) in 3 mL methylene chloride dropwise over 2-3 minutes. The suspension was stored over night in the refrigerator. It was then washed twice with water, dried with magnesium sulfate and concentrated under reduced pressure to a gum. Preparative TLC on four 8"×8"×1,000 g GF silica gel plates using 1:2 ethyl acetate: hexane afforded the title compound, which crystallized on standing. Yield: 322 mg (54%)
Reaction SMILES: O=[Si]=O.[CH3:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]CC(OCCO)=O>CCCCCCCCCCCC>[CH3:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH3:4]
Reactant: CCCCCCCCC=CCCCCCCCC(=O)OCCO
Agent: O=[Si]=O
Solvent: CCCCCCCCCCCC
Product: CCCCCCCCCCCCCCCC

Procedure:
Results of the gel formation studies are summarized in Table VI. Addition of 1 g CAB-O-SIL® N70-TS to a reheated mixture of 20 wt % paraffin in dodecane did not aid gel formation. Polyethylene glycol monooleate and Zonyl® FSC fluorosurfactant were not miscible with the mixture. Preliminary observations indicated that after reheating a mixture of dodecane and 15 wt % N-14 Epolene® wax to solution point, the gel did not reappear upon cooling. Also, when the gel formed by 15 wt % N-14 wax in 80/20 hexadecane/mineral oil was reheated to solution point, the gel reformed upon cooling, but was easily broken by stirring with a glass rod. Extreme thermal cycling should be avoided.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][OH:12].[H-].[Na+].[NH2:15][C:16]1[C:25](Cl)=[N:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1>O1CCCC1>[NH2:15][C:16]1[C:25]([O:12][CH2:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[N:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1
Reactant: OCc1ccc2ccccc2c1
Reactant: Nc1nc2ccccc2nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1nc2ccccc2nc1OCc1ccc2ccccc2c1
Yield: 82.1 %

Procedure:
According to Step 2 of Reference Example 7-1, by use of 2-naphthalenemethanol (792 mg, 5.01 mmol), 60% sodium hydride (in oil) (200 mg, 5.01 mmol), tetrahydrofuran (6.0 mL) and 2-amino-3-chloroquinoxaline (300 mg, 1.67 mmol), the mixture was stirred and reacted at room temperature for 17 hours. Then, slurry purification was performed using diisopropyl ether, to give 2-amino-3-[(naphthalen-2-yl)methoxy]quinoxaline (Compound BC) (413 mg, yield: 82%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([N+:27]([O-])=O)[CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.Cl>C(O)C.O.[Fe]>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([NH2:27])[CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: O=[N+]([O-])c1ccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c2c1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: Nc1ccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c2c1
Yield: 54 %

Procedure:
N-[3-Chloro-4-(2-pyridylmethoxy)phenyl]-6-nitro-quinazolin-4-amine 4d (4.07 g, 10 mmol) and concentrated hydrochloric acid (2 mL, 24 mmol) were dissolved in 130 mL of the solvent mixture of 95% ethanol and water (V/V=10/3), followed by addition of iron powder (11.17 g, 200 mmol). The reaction mixture was heated to reflux for 2 hours, filtered while hot and the filtrate was concentrated under reduced pressure to remove ethanol. The resulting residue was adjusted to pH>7 with ammonium hydroxide, filtered and the filter cake was dried under vacuum, purified by silica gel column chromatography with elution system A to obtain the title compound N4-[3-chloro-4-(2-pyridylmethoxy)phenyl]quinazoline-4,6-diamine 4e (2.04 g, yield 54.1%) as a white solid.
Reaction SMILES: C([N:4]1[C:9]2[CH:10]=[C:11]([C:14]3[CH:15]([CH3:21])[CH2:16][C:17](=[O:20])[NH:18][N:19]=3)[CH:12]=[CH:13][C:8]=2[O:7][CH2:6][CH2:5]1)(=O)C.CS(N1C2C=C(C3C(C)CC(=O)NN=3)C=CC=2OCC1)(=O)=O.CC1CNC2C=C(C3CCC(=O)NN=3)C=CC=2O1.CC1CNC2C=C(C3C(C)CC(=O)NN=3)C=CC=2O1.O=C1NC2C=C(C3CCC(=O)NN=3)C=CC=2OC1.O=C1NC2C=C(C3C(C)CC(=O)NN=3)C=CC=2OC1>>[O:7]1[C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:15]([CH3:21])[CH2:16][C:17](=[O:20])[NH:18][N:19]=3)=[CH:10][C:9]=2[NH:4][CH2:5][CH2:6]1
Reactant: CC(=O)N1CCOc2ccc(C3=NNC(=O)CC3C)cc21
Agent: CC1CC(=O)NN=C1c1ccc2c(c1)N(S(C)(=O)=O)CCO2
Agent: CC1CC(=O)NN=C1c1ccc2c(c1)NC(=O)CO2
Agent: CC1CNc2cc(C3=NNC(=O)CC3)ccc2O1
Product: CC1CC(=O)NN=C1c1ccc2c(c1)NCCO2

Procedure:
6-(4-acetyl-3,4-dihydro-1,4(2H)-benzoxazin-6-yl)-2,3,4,5-tetrahydro-5-methylpyridazin-3-one; 6-(3,4-dihydro-4-methanesulfonyl-1,4(2H)-benzoxazin-6-yl)-2,3,4,5-tetrahydro-5-methylpyridazin-3-one; 6-(3,4-dihydro-2-methyl-1,4(2H)-benzoxazin-6-yl)-2,3,4,5-tetrahydropyridazin-3-one; 6-(3,4-dihydro-2-methyl-1,4(2H)-benzoxazin-6-yl)-2,3,4,5-tetrahydro-5-methylpyridazin-3-one; 6-(3,4-dihydro-3-oxo-1,4(2H)-benzoxazin-6-yl)-2,3,4,5-tetrahydropyridazin-3-one; 6-(3,4-dihydro-3-oxo-1,4(2H)-benzoxazin-6-yl)-2,3,4,5-tetrahydro-5-methylpyridazin-3-one;
Reaction SMILES: [C:1]1([C:7]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]3[CH:24]=[CH:23][C:22]([CH2:25]Br)=[CH:21][CH:20]=3)=[N:11][N:10]=[N:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:39][C:40]1[N:41]([C:46]2[N:47]=[C:48]([CH2:53][CH2:54][CH3:55])[NH:49][C:50]=2[CH:51]=[O:52])[C:42]([CH3:45])=[CH:43][CH:44]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH3:39][C:40]1[N:41]([C:46]2[N:47]=[C:48]([CH2:53][CH2:54][CH3:55])[N:49]([CH2:25][C:22]3[CH:21]=[CH:20][C:19]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=4[C:12]4[N:8]([C:7]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)([C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=5)[C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)[N:9]=[N:10][N:11]=4)=[CH:24][CH:23]=3)[C:50]=2[CH:51]=[O:52])[C:42]([CH3:45])=[CH:43][CH:44]=1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCc1nc(-n2c(C)ccc2C)c(C=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1nc(-n2c(C)ccc2C)c(C=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of N-(triphenylmethyl)-5-[4'-(bromomethyl)-biphenyl-2-yl]tetrazole (Example 12, 9.66 g, 17.34 mmol), 4-(2,5-dimethyl-1H-pyrrol-1-yl)-2-propyl-1H-imidazole-5-carboxaldehyde (Example 49, 4.0 g, 17.4 mmol), and cesium carbonate (13 g, 40 mmol) in DMF (30 mL) was stirred under an atmosphere of dry nitrogen at room temperature overnight. The reaction mixture was poured over water (750 mL) and the resulting precipitate was collected by filtration. The solid was taken up in ethyl acetate and extracted with water, adjusting the pH of the aqueous layer to pH 8-9 by the addition of sodium bicarbonate. The organic layer was dried over MgSO4 and evaporated to give the crude product as a mixture of regioisomers which were separated by flash chromatography (silica; 3:1 hexane/EtOAc).
Reaction SMILES: C[O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][Cl:16])=[CH:6][CH:5]=1.[OH-].[Na+]>CO>[Cl:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][O:10][C:7]1[CH:6]=[CH:5][C:4]([C:3]([OH:17])=[O:2])=[CH:9][CH:8]=1
Reactant: COC(=O)c1ccc(OCCCCCCl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(OCCCCCCl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(5-Chloropentyloxy)benzoic acid methyl ester (1.14 g. 4.44 mmol) is dissolved in MeOH (15 mL) and 5 N NaOH (10 mL) is added. The reaction mixture is stirred at room temperature overnight. The reaction mixture is concentrated in vacuo and the residue is dissolved in water, acidified with concentrated hydrochloric acid to pH=1.0. This solution is extracted with CH2Cl2, dried over Na2SO4, filtered and evaporated. The resulting material is recrystallized from hexane/CH2Cl2, filtered and dried, to provide 829 mg (77%). NMR (CDCl3): δ 8.05 (d, 2H, J=9 Hz), 6.93 (d, 2H, J=9 Hz), 4.05 (t, 2H, J=6 Hz), 3.57 (t, 2H, J=6 Hz), 4.85 (m, 4H), 1.65 (m, 2H).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][O:5][N:4]([C:7]([C:9]2[C:17]3[C:16](=[O:18])[N:15]([CH3:19])[C:14](=[O:20])[N:13]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:12]=3[S:11][C:10]=2[CH3:25])=[O:8])[CH2:3]1.N1C=CN=C1.[Si:31](Cl)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]>ClCCl>[CH3:35][C:34]([Si:31]([CH3:33])([CH3:32])[O:1][CH:2]1[CH2:6][O:5][N:4]([C:7]([C:9]2[C:17]3[C:16](=[O:18])[N:15]([CH3:19])[C:14](=[O:20])[N:13]([CH2:21][CH:22]([CH3:23])[CH3:24])[C:12]=3[S:11][C:10]=2[CH3:25])=[O:8])[CH2:3]1)([CH3:37])[CH3:36]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1sc2c(c1C(=O)N1CC(O)CO1)c(=O)n(C)c(=O)n2CC(C)C
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: Cc1sc2c(c1C(=O)N1CC(O[Si](C)(C)C(C)(C)C)CO1)c(=O)n(C)c(=O)n2CC(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of the product of step b) (1.2 g) and imidazole (0.24 g) in dichloromethane (20 ml) was added tert-butyldimethylsilyl chloride (0.54 g). After stirring at ambient temperature for 16 h the mixture was washed with water and the organics poured onto a biotage column. Gradient elution with 0 to 5% methanol in dichloromethane gave the sub-title compound as a colourless solid (1.55 g). δ 1HCDCl3 0.09 (3H,s), 0.11 (3H,s), 0.90 (9H,s), 0.99 (6H,d), 2.30 (1H,non), 2.44 (3H,s), 3.36 (3H,s), 3.54 (1H,dd), 3.64 (1H,dd), 3.75 (1H,d), 3.84 (1H,dd), 3.98 (1H,dd), 4.47 (1H,dd), 4.89 (1H,dd).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C1CCN2C(=NCCC2)CC1>C(#N)C>[CH:7]1[C:8]2[C:3](=[C:2]([O:1][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Oc1cccc2cnccc12
Reactant: CCOC(=O)CBr
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCOC(=O)COc1cccc2cnccc12

Procedure:
In 10 ml of acetonitrile, 1.0 g of 5-hydroxyisoquinoline and 1.52 ml of ethyl bromoacetate were added in the presence of 2.07 ml of DBU and the resultant mixture was refluxed for 8 hr. The reaction mixture was evaporated under reduced pressure and the resultant residue was redissolved in 1N-HCl, washed with ethyl acetate. The aqueous layer was made alkaline with sodium hydrogencarbonate and extracted with ethyl acetate. The extract was washed with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The dried solution was evaporated under reduced pressure and subjected to a silica gel column chromatography (chloroform) to give 1.46 g of ethyl 5-isoquinolyloxyacetate. The ester was dissolved in 30 ml of ethanol, mixed with 6.5 ml of 1N-NaOH aqueous solution and stirred for 12 hr. The reaction mixture was evaporated under reduced pressure, neutralized by the addition of 1N-HCl and the precipitated crystals were filtered, washed with water and dried to give 0.68 g of the title compound.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:18]([C:19](O)=[O:20])=[C:17]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:28])[CH:15]=2)[C:10]1=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:33])=O>C1COCC1.CN(C=O)C>[CH2:1]([O:8][N:9]1[C:18]([C:19]([Cl:33])=[O:20])=[C:17]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:28])[CH:15]=2)[C:10]1=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1c(-c2ccccc2)c2cc(Cl)ccc2c(=O)n1OCc1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(Cl)c1c(-c2ccccc2)c2cc(Cl)ccc2c(=O)n1OCc1ccccc1

Procedure:
2-Benzyloxy-6-chloro-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (240 mg) was dissolved in THF (4.8 ml), and oxalyl chloride (100 μl) and DMF (1 drop) were added at 0° C. with stirring. The mixture was stirred at room temperature for 2 hrs. and concentrated under reduced pressure. Toluene was added to the residue and they were boiled together several times to give 2-benzyloxy-6-chloro-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carbonyl chloride.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([O:8][C@@H:9]2[CH:14]3[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]3)[CH2:10]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[NH:30][C:29]([C:34]([F:37])([F:36])[F:35])=[CH:28]3)O1.N>>[F:37][C:34]([F:35])([F:36])[C:29]1[NH:30][C:31]2[C:27]([CH:28]=1)=[CH:26][C:25]([C:2]1[N:7]=[N:6][C:5]([O:8][C@@H:9]3[CH:14]4[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]4)[CH2:10]3)=[CH:4][CH:3]=1)=[CH:33][CH:32]=2
Reactant: Clc1ccc(O[C@H]2CN3CCC2CC3)nn1
Reactant: CC1(C)OB(c2ccc3[nH]c(C(F)(F)F)cc3c2)OC1(C)C
Agent: N
Product: FC(F)(F)c1cc2cc(-c3ccc(O[C@H]4CN5CCC4CC5)nn3)ccc2[nH]1

Procedure:
The product of Example 9A (198 mg, 0.826 mmol) was coupled with the product of Example 48A (345 mg, 1.11 mmol) according to the procedure of Example 26B. The title product was purified by preparative HPLC (column: Xterra™ RP-18, 5 μm, 30×100 mm; eluting solvent, NH4HCO3—NH4OH/H2O (PH=10), (v. 90/10 to 10/90 over 20 min.); flow rate, 40 mL/min.; uv, 254 nm) to provide a solid (79.7 mg, yield, 24.8%). 1H NMR (300 MHz, CD3OD) δ 1.50-1.93 (m, 3H) 1.99-2.15 (m, 1H) 2.29-2.37 (m, 1H) 2.78-3.05 (m, 5H) 3.49 (ddd, J=14.83, 8.39, 1.86 Hz, 1H) 5.27-5.36 (m, 1H) 7.01 (s, 1H) 7.27 (d, J=9.49 Hz, 1H) 7.59 (d, J=8.81 Hz, 1H) 7.94 (dd, J=8.81, 1.70 Hz, 1H) 8.11 (d, J=9.15 Hz, 1H) 8.24 (s, 1H) ppm. MS (DCI/NH3) m/z 389 (M+H)+. Anal. Calculated for C20H19F3N4O: C, 61.85; H, 4.93; N, 14.43. Found: C, 61.62; H, 4.56; N, 13.89.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[N:9]1[N:13]2[C:14]([C@@H:18](O)[CH3:19])=[CH:15][CH:16]=[N:17][C:12]2=[N:11][CH:10]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[Cl-].[Mg+2].[Cl-]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C@@H:18]([C:14]2[N:13]3[N:9]=[CH:10][N:11]=[C:12]3[N:17]=[CH:16][CH:15]=2)[CH3:19])=[CH:4][CH:3]=1
Reactant: C[C@H](O)c1ccnc2ncnn12
Reactant: Oc1ccc(Cl)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: [Cl-]
Agent: [Mg+2]
Solvent: C1CCOC1
Product: C[C@@H](Oc1ccc(Cl)cc1)c1ccnc2ncnn12
Temperature: 7.5 °C
Yield: 37.1 %

Procedure:
A reactor was loaded with 4chlorophenol (2.89 kg), (S)-1-(1,2,4-triazolo[1,5-a]pyrimidin-7-yl)ethanol (3.69 kg), triphenylphosphine (5.9 kg) and tetrahydrofuran (69I). The suspension was cooled to 5-10° C. and diisopropyl azodicarboxylate (4.79 kg) was added over 2 hours. After complete addition of diisopropyl azodicarboxylate the solution was stirred while warming to ambient temperature. Magnesium chloride (anhydrous; 4.3 kg; ˜2 eq) was added and the reaction mixture was heated under reflux for 1 hour. Cooling to 10° C. yielded a suspension which was collected by filtration. The filter pad was washed with tetrahydrofuran (10 I). The mother liquor was refilled into the reactor and tetrahydrofuran replaced with toluene by distillation of inert diluent (100 I) and addition of toluene (100 I) at the same rate. When the inert diluent exchange was complete the solution was cooled to ambient temperature and extracted twice with water. The organic phase was separated, filtered, then charged to the reaction vessel. Toluene (64 I) was distilled off, propan-2ol (128 I) added, and the solvent mixture (123 I) was then distilled off. After this solvent exchange the reaction mixture was slowly cooled to ambient temperature for crystallization of the product. The product was filtered off and washed with propan-2-ol (10 I). (R)-7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine, (2.29 kg) was isolated after drying in vacuo at 40° C. HPLC-analysis: 99.92%; chiral HPLC: ee=100%. No triphenylphosphine oxide was detectable by HPLC analysis.
Reaction SMILES: [CH3:1][C@@H:2]([O:6][C:7]1[CH:8]=[CH:9][C:10]2[CH2:11][N:12](C(OC(C)(C)C)=O)[CH2:13][CH2:14][O:15][C:16]=2[N:17]=1)[CH:3]([CH3:5])[CH3:4].[ClH:25].C(OCC)(=O)C>>[ClH:25].[CH3:1][C@@H:2]([O:6][C:7]1[CH:8]=[CH:9][C:10]2[CH2:11][NH:12][CH2:13][CH2:14][O:15][C:16]=2[N:17]=1)[CH:3]([CH3:4])[CH3:5]
Reactant: CC(C)[C@@H](C)Oc1ccc2c(n1)OCCN(C(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)[C@@H](C)Oc1ccc2c(n1)OCCNC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 78 %

Procedure:
A mixture of the compound obtained in step 1 (0.77 g) and 4N hydrogen chloride/ethyl acetate (10 mL) was stirred at room temperature for 3 hr. The precipitate was collected by filtration, and the aqueous layer was basified and extracted with ethyl acetate and aqueous sodium hydroxide solution. The organic layer was washed with saturated brine and dried, and the solvent was evaporated under reduced pressure. Ethyl acetate was added to the residue, and 4N hydrogen chloride/ethyl acetate was added. The precipitate was collected by filtration and recrystallized twice from ethanol-diisopropyl ether to give the title compound (0.48 g, 78%) as a white powder.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH2:33][CH:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[C:14](=O)[CH2:15][CH:16]([CH3:31])[C:17]([C:19]3[CH:24]=[CH:23][C:22]([CH:25]([OH:30])[C:26]([OH:29])([CH3:28])[CH3:27])=[CH:21][N:20]=3)=O)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.C([O-])(=O)C.[NH4+:44]>C(O)(=O)C.C(OCC)(=O)C>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:14]3[NH:44][C:17]([C:19]4[N:20]=[CH:21][C:22]([CH:25]([OH:30])[C:26]([CH3:27])([OH:29])[CH3:28])=[CH:23][CH:24]=4)=[C:16]([CH3:31])[CH:15]=3)[CH2:33][CH:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: CC(CC(=O)C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1)C(=O)c1ccc(C(O)C(C)(C)O)cn1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1cc(C(CC2CCOCC2)c2ccc(S(=O)(=O)C3CC3)cc2)[nH]c1-c1ccc(C(O)C(C)(C)O)cn1
Temperature: 90 °C
Reaction time: 1 h
Yield: 66.1 %

Procedure:
To a solution of 5-[4-(cyclopropylsulfonyl)phenyl]-1-[5-(1,2-dihydroxy-2-methylpropyl)pyridin-2-yl]-2-methyl-6-(tetrahydro-2H-pyran-4-yl)hexane-1,4-dione (235 mg) in acetic acid (5 mL) was added ammonium acetate (519 mg), and the mixture was stirred at 90° C. for 1 hr. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (150 mg, yield 66%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate. MS: 539 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]([OH:16])=O)=[O:8])=[O:4].[NH2:23][CH2:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[C:31]([NH2:35])=[N:30][CH:29]=[CH:28]2.CN1CCOCC1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:4])[NH:5][C@H:6]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14](=[O:16])[NH:23][CH2:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[C:31]([NH2:35])=[N:30][CH:29]=[CH:28]2)=[O:8]
Reactant: COC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)O)C1CCCCC1
Reactant: NCc1ccc2c(N)nccc2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)NCc1ccc2c(N)nccc2c1)C1CCCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.1 %

Procedure:
A mixture of 1-[(R)-methoxycarbonylamino-cyclohexyl-acetyl]-pyrrolidine-2-(S)-carboxylic acid (0.410 g), 6-aminomethyl-isoquinolin-1-ylamine (0.227 g), N-methyl morpholine (0.58 mL) and 0.423 g of 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) in 10 mL of dry N,N-dimethyl formamide was stirred for 3 h at ambient temperature. The mixture was concentrated and the remaining residue was purified by HPLC (RP-18, H2O/CH3OH 95/5→0/100) to give 0.350 g (58%) of the title compound as a white solid. (+)-APCI-MS: 468 (MH+).
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:18][CH2:19][CH2:20][OH:21])[C:6]2[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[C:8]([C:14]([F:17])([F:16])[F:15])[CH:7]=2)[CH2:3][CH2:2]1.O[C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][CH:24]=1>>[CH:1]1([CH2:4][N:5]([CH2:18][CH2:19][CH2:20][O:21][C:23]2[CH:30]=[CH:29][C:26]([CH2:27][OH:28])=[CH:25][CH:24]=2)[C:6]2[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[C:8]([C:14]([F:16])([F:17])[F:15])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: O=Cc1ccc(O)cc1
Reactant: N#Cc1ccc(N(CCCO)CC2CC2)cc1C(F)(F)F
Product: N#Cc1ccc(N(CCCOc2ccc(CO)cc2)CC2CC2)cc1C(F)(F)F

Procedure:
Synthesized as described in Example 5B from 4-[(cyclopropylmethyl)(3-hydroxypropyl)amino]-2-(trifluoromethyl)benzonitrile and 4-hydroxybenzaldehyde: MS (APCI) m/z 405 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.Br[CH2:10][CH2:11][CH2:12][Cl:13]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:10][CH2:11][CH2:12][Cl:13])=[CH:4][CH:3]=1
Reactant: Sc1ccc(Br)cc1
Reactant: ClCCCBr
Product: ClCCCSc1ccc(Br)cc1

Procedure:
Prepared by Procedure R and Scheme Z using 4-bromobenzenethiol and 1-bromo-3-chloropropane.
Reaction SMILES: C([O-])(=O)C.[K+].C(O)(=O)C.[NH2:10][C:11]1[N:12]=[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])[NH:14][C:15]=1[C:16]#[N:17].CO[CH:24]1[CH2:28][CH2:27][CH:26](OC)O1>ClCCl>[CH2:18]([C:13]1[NH:14][C:15]([C:16]#[N:17])=[C:11]([N:10]2[CH:24]=[CH:28][CH:27]=[CH:26]2)[N:12]=1)[CH2:19][CH2:20][CH3:21]
Reactant: CCCCc1nc(N)c(C#N)[nH]1
Reactant: COC1CCC(OC)O1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCCCc1nc(-n2cccc2)c(C#N)[nH]1
Temperature: 25 °C

Procedure:
A solution of potassium acetate (5.0 g), acetic acid (22 mL) and 4-amino-2-butyl-5-cyanoimidazole (Example 7, 1.45 g) was heated to reflux and treated with 2,5-dimethoxy-tetrahydrofuran (1.25 mL). The reaction was held at reflux for 1 minute then cooled back to room temperature with an ice bath. The majority of the acetic acid was evaporated at reduced pressure then the residue was partitioned between ethyl acetate and 10% aqueous K2CO3 (120 mL) each. The organic layer was dried over MgSO4 and evaporated. The residue was purified by flash chromatography on silica gel, eluting with hexane-ethyl acetate (90:10 to 80:20). Evaporation of solvents gave a gum that was redissolved in dichloromethane and evaporated once again. The residual oil was held under a vacuum overnight to afford a waxy solid. 1H-NMR (CDCl3) δ9.9 (br, 1H), 7.4 (s, 2H), 6.3 (s, 2H), 2.7 (t, 2H), 1.7 (m, 2H), 1.4 (m, 2H), 1.0 (t, 3H).