Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:2]([C:7](OCC1C=CC=CC=1)=[O:8])[CH2:3][C:4](=O)O.Cl.[N+:25]([C:28]1[CH:36]=[CH:35][C:31]([CH2:32][CH2:33][NH2:34])=[CH:30][CH:29]=1)([O-:27])=[O:26].C(N(CC)CC)C.C([BH3-])#N.[Na+].[OH-].[Na+]>CO.O>[C:20]([O:19][C:17](=[O:18])[NH:1][C@H:2]1[CH2:3][CH2:4][N:34]([CH2:33][CH2:32][C:31]2[CH:30]=[CH:29][C:28]([N+:25]([O-:27])=[O:26])=[CH:36][CH:35]=2)[C:7]1=[O:8])([CH3:21])([CH3:22])[CH3:23]
Reactant: NCCc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)C(=O)OCc1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H]1CCN(CCc2ccc([N+](=O)[O-])cc2)C1=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 39.1 %

Procedure:
To a solution of Boc-L-Asp(H)-OBn (3.3 g, 10.7 mmol) dissolved in methanol (50 mL) is added 4 Å molecular sieves, 4-nitrophenethylamine hydrochloride (4.35 g, 21.5 mmol) and triethylamine (2.25 g, 22.2 mmol). The solution is stirred at room temperature for 45 minutes and then the mixture is treated with sodium cyanoborohydride (0.72 g, 11.5 mmol). The reaction mixture is stirred at room temperature for 16 hours. After this time,1 N NaOH (10 mL) followed by water (25 mL) is added. The resulting mixture is stirred for 30 minutes and then concentrated in vacuo to a smaller volume. The solution is diluted with EtOAc (250 mL), filtered through a pad of Celite and washed with water and EtOAc. The solution is poured into a separatory funnel and the layers are separated. The aqueous layer is extracted with EtOAc. The combined organic layers are washed with 1N HCl, H2O, saturated NaHCO3 solution and saturated NaCl. The organic phase is dried over MgSO4, filtered and concentrated. The crude residue is purified by column chromatography eluting with 50% EtOAc/CH2Cl2 to afford the title compound (1.46 g, 4.18 mmol) as a pale yellow solid.
Reaction SMILES: C(OC([N:8]=[C:9]([NH:40]C(OC(C)(C)C)=O)[NH:10][C:11]1[CH:12]=[C:13]([CH:17]([O:21][P:22]([C@@H:25]([NH:29][S:30]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)(=[O:32])=[O:31])[CH:26]([CH3:28])[CH3:27])([OH:24])=[O:23])[C:18]([OH:20])=[O:19])[CH:14]=[CH:15][CH:16]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:10]([C:11]1[CH:12]=[C:13]([CH:17]([O:21][P:22]([CH:25]([NH:29][S:30]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)(=[O:31])=[O:32])[CH:26]([CH3:28])[CH3:27])([OH:24])=[O:23])[C:18]([OH:20])=[O:19])[CH:14]=[CH:15][CH:16]=1)[C:9]([NH2:40])=[NH:8]
Reactant: CC(C)[C@H](NS(=O)(=O)Cc1ccccc1)P(=O)(O)OC(C(=O)O)c1cccc(NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C(NS(=O)(=O)Cc1ccccc1)P(=O)(O)OC(C(=O)O)c1cccc(NC(=N)N)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 12.5 %

Procedure:
To a solution of 2-(3-(N′,N″-di(t-butoxycarbonyl)guanidino)phenyl)-2-((1R)-(1-(benzylsulfonyl)amino-2-methylpropyl)(hydroxy)phosphinoyloxy)ethanoic acid (0.53 mmol) in 3 mL of methylene chloride was added TFA (3 mL, 39 mmol). After stirring for 1.5 hours at ambient temperature, the solution was concentrated. Purification by HPLC provided 33.0 mg (12%, 4 steps) of 2-(3-guanidinophenyl)-2-((1-(benzylsulfonyl)amino-2-methylpropyl)(hydroxy)phosphinoyloxy)ethanoic acid as white fluffy solid; NMR (DMSO-d6) 0.92 (m, 6), 2.01 (m, 1), 3.5 (m, 2), 4.54-4.26 (overlapping AB q, 2), 5.74 (overlapping doublets, 1), 7.22 (m, 1), 7.29-7.46 (m, 14), 9.78 (m, 1).
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:8]=[C:9]([CH:24]=[CH:25][CH:26]=1)[CH2:10][CH:11]1[CH:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)[O:14]C(=O)[NH:12]1)[C:2]([CH3:5])([CH3:4])[CH3:3].[OH-].[Na+]>C(O)C.O>[NH2:12][CH:11]([CH2:10][C:9]1[CH:24]=[CH:25][CH:26]=[C:7]([O:6][CH2:1][C:2]([CH3:5])([CH3:4])[CH3:3])[CH:8]=1)[CH:15]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=1)[OH:14]
Reactant: CC(C)(C)COc1cccc(CC2NC(=O)OC2c2cccc(Cl)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)COc1cccc(CC(N)C(O)c2cccc(Cl)c2)c1
Yield: 79.3 %

Procedure:
To a solution of (4RS,5SR)-4-[3-(neopentyloxy)benzyl]-5-(3-chlorophenyl)-1,3-oxazolidin-2-one (4.0 g, 10.7 mmol) in ethanol (80 ml) was added 8N aqueous sodium hydroxide solution (6.7 ml, 53.5 mmol), and the mixture was heated under reflux for 5 hrs. After completion of the reaction, the mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by recrystallization (hexane-ethyl acetate) to give (1RS,2SR)-2-amino-3-[3-(neopentyloxy)phenyl]-1-(3-chlorophenyl)-1-propanol (2.95 g, 79%) as colorless crystals.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:2]=1>C(O)C.[Rh]>[NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:13])([CH3:12])[CH3:14])[CH2:2]1
Reactant: CC(C)(C)OC(=O)NCc1cccnc1
Agent: [Rh]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCC1CCCNC1
Reaction time: 27 h

Procedure:
A mixture of tert-butyl 3-pyridinylmethylcarbamate (4.3 g) and 5% rhodium on carbon (400 mg) in ethanol (50 mL) at 25° C. in a paar apparatus was stirred under hydrogen at 60 pounds per square inch for 27 hours, filtered through diatomaceous earth (Celite®), and concentrated. 1H NMR (300 MHz, CDCl3) δ 4.55 (b, 1H), 2.99 (m, 4H), 2.56 (t, 1H), 2.33 (t, 1H), 1.74 (m, 1H), 1.66 (m, 2H), 1.44 (s, 9H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[O:11][C:12]1[CH:23]=[CH:22][C:15]([O:16][CH:17]([CH3:21])[C:18](O)=[O:19])=[CH:14][CH:13]=1.S(Cl)(Cl)=O>ClCCCC>[CH2:2]([N:1]([CH2:10][CH3:9])[C:18](=[O:19])[CH:17]([O:16][C:15]1[CH:22]=[CH:23][C:12]([O:11][C:2]2[CH:3]=[N:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)=[CH:13][CH:14]=1)[CH3:21])[CH3:3]
Reactant: CC(Oc1ccc(Oc2cnc3ccccc3n2)cc1)C(=O)O
Solvent: O=S(Cl)Cl
Solvent: CCCCCl
Product: CCN(CC)C(=O)C(C)Oc1ccc(Oc2cnc3ccccc3n2)cc1

Procedure:
The title compound can be prepared by interaction of 2-[4-(2-quinoxalinyloxy)phenoxy]propionic acid with thionyl chloride in a suitable solvent such as chlorobutane. Add a solution of 3.3 g (0.01 mole) 2-[4-(2-quinoxalinyloxy)phenoxy]propionyl chloride in 30 cc methylene chloride to a cold (5° C.) solution of 1.8 g (0.025 mole) diethylamine in 30 cc methylene chloride. Stir the mixture at room temperature overnight. Wash the methylene chloride solution with water and dry over magnesium sulfate. Remove the methylene chloride under vacuum to yield N,N-diethyl-2-[4-(quinoxalinyloxy)phenoxy]propanamide.
Reaction SMILES: Cl.[CH:2]1([N:6]2[CH2:11][CH2:10][CH:9]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([Cl:19])=[O:18])=[CH:15][CH:14]=3)[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3]1.CC[N:24]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:25]C.C=CC1C=CC=CC=1.C=CC1C=CC(C=C)=CC=1.C1C2C(=CC=CC=2)CN1>C(Cl)Cl>[ClH:19].[CH:2]1([N:6]2[CH2:11][CH2:10][CH:9]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([N:24]4[CH2:25][C:29]5[C:28](=[CH:33][CH:32]=[CH:31][CH:30]=5)[CH2:27]4)=[O:18])=[CH:15][CH:14]=3)[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3]1
Reactant: CCN(CC)Cc1ccccc1
Reactant: O=C(Cl)c1ccc(OC2CCN(C3CCC3)CC2)cc1
Agent: C=Cc1ccc(C=C)cc1
Agent: Cl
Agent: c1ccc2c(c1)CNC2
Solvent: C=Cc1ccccc1
Solvent: ClCCl
Product: O=C(c1ccc(OC2CCN(C3CCC3)CC2)cc1)N1Cc2ccccc2C1
Reaction time: 16 h
Yield: 70.4 %

Procedure:
A stirred mixture of 4-[(1-cyclobutyl-4-piperidinyl)oxy]benzoyl chloride hydrochloride (D25) (0.25 g) and diethylaminomethyl polystyrene (3.2 mmol/g, 1.13 g) in DCM (10 ml) at rt was treated with isoindoline (0.098 g) and stirred for 16 h. The reaction mixture was chromatographed directly [silica gel, step gradient 0-10% MeOH (containing 10% 0.880 ammonia solution) in DCM)]. Fractions containing the required product were evaporated, redissolved in DCM, treated with excess hydrogen chloride (1M solution in diethyl ether) and then concentrated. The residue was crystallised from acetone to yield the title compound (E59) as a white powder (220 mg). MS electrospray (+ion) 377 (MH+). 1H NMR δ (DMSO-d6): 10.62 (1H, s), 7.62 (2H, m), 7.40-7.25 (4H, m), 7.08 (2H, m) 4.82 (4H, m), 4.64 (1H, m), 3.81-3.58. (1H, m), 3.45-3.20 (2H, m), 2.95 (2H, m), 2.38-1.62 (10H, m).
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.P([O-])([O-])([O-])=O.C(=O)([O-])[O-].[Na+].[Na+].S([O-])([O-])(=O)=O.[Mg+2]>C1C=[N+]([C@@H]2O[C@H](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](O)[C@@H]3O)(O)=O)(O)=O)[C@@H](O)[C@H]2O)C=C(C(N)=O)C=1.C(OCC)(=O)C.C(OCCCC)(=O)C>[OH:1][CH:2]([CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(=O)CCc1ccccc1
Agent: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: O=C([O-])[O-]
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: CCCCOC(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(O)CCc1ccccc1
Temperature: 30 °C
Reaction time: 9 h
Yield: 99 %

Procedure:
3.0 g of ethyl 2-oxo-4-phenylbutyrate, 0.49 g of the above-mentioned wet cell, 3.0 mg of NAD+, 4.5 g of glucose, 30 ml of 100 mM phosphate buffering solution (pH 7.0) and 6 ml of butyl acetate were mixed and stirred at 30° C. for 9 hours. During stirring, 2M sodium carbonate aqueous solution was added gradually so that the reaction solution had a pH of 7.0. Thereafter, to the reaction liquid was added 50 ml of ethyl acetate, then, centrifugal separation was performed to obtain an organic layer. This organic layer was dehydrated over magnesium sulfate, and ethyl acetate was distilled off, to obtain 3.0 g of ethyl 2-hydroxy-4-phenylbutyrate. The optical purity of the resulting ethyl 2-hydroxy-4-phenylbutyrate was measured, to find 100% e.e. for (R) configuration.
Reaction SMILES: Cl[C:2]([O:4][C@H:5]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:31])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:22])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:6]1)=[O:3].[CH3:32][N:33]([CH3:37])[CH2:34][CH2:35][NH2:36].II>C(Cl)(Cl)Cl>[CH3:22][C@@H:15]([C@@H:14]1[C@@:23]2([CH3:31])[CH2:24][CH2:25][C@@H:26]3[C@@:27]4([CH3:30])[CH2:28][CH2:29][C@H:5]([O:4][C:2]([NH:36][CH2:35][CH2:34][N:33]([CH3:37])[CH3:32])=[O:3])[CH2:6][C:7]4=[CH:8][CH2:9][C@H:10]3[C@@H:11]2[CH2:12][CH2:13]1)[CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20]
Reactant: CN(C)CCN
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(=O)Cl)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: II
Solvent: ClC(Cl)Cl
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(=O)NCCN(C)C)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
Compound XIV was synthesized by mixing a-solution of cholesterol chloroformate (0.5 mmol) in chloroform with a solution of N,N-dimethylethylenediamine (9.1 mmol) in chloroform in a dry ice-ethanol bath. The solvent and the unreacted amine were removed in vacuo. Compound XIV was purified by two successive recrystallizations in ethanol. (Yield, 65%) TLC (chloroform:methanol=65:35) showed a single spot (Rf=0.37) when developed with iodine. The product was characterized by proton NMR.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]C(C)(C)C)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C1(S)C=CC=CC=1>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([SH:11])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)Sc1ccc(C(C)(C)C)cc1
Agent: Sc1ccccc1
Product: CC(C)(C)c1ccc(S)cc1
Temperature: 90 °C
Reaction time: 4 h
Yield: 129.6 %

Procedure:
A mixture of 1285 grams (5.8 moles) of tert-butyl 4-(tert-butyl)phenyl sulfide (from replicates of EXAMPLE III) 1040 grams (9.5 moles) of thiophenol, and 350 grams of boron trifluoride-phosphoric acid complex was heated slowly to 90° C. The reaction mixture was stirred at 90° C. for four hours, cooled to 25° C., the organic layer was separated from the lower catalyst layer and added to 500 ml of toluene. This toluene solution was washed five times with 1000-ml portions of water, dried with magnesium sulfate, and then concentrated in vacuo. The residue was distilled through a 10-tray column to give 1250 grams (65% yield) of p-(tert-butyl)thiophenol, b.p. 58°-60°/1.0 mm. The nmr spectrum supported the proposed structure. A residue of 285 grams of 4-(tert-butyl)phenyl tert-butyl sulfide was obtained.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([F:24])[CH:22]=3)[N:17]=[C:16]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[OH:31])[N:15]=2)[CH2:10]1.Cl[C:33]([O:35][CH2:36][CH:37]([CH3:39])[CH3:38])=[O:34]>C(Cl)Cl>[F:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][CH:20]=1)[N:17]=[C:16]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[OH:31])[N:15]=[C:14]2[N:11]1[CH2:12][CH2:13][C@@H:9]([NH:8][C:33](=[O:34])[O:35][CH2:36][CH:37]([CH3:39])[CH3:38])[CH2:10]1
Reactant: CC(C)COC(=O)Cl
Reactant: N[C@@H]1CCN(c2nc(-c3ccccc3O)nc3ccc(F)cc23)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)COC(=O)N[C@@H]1CCN(c2nc(-c3ccccc3O)nc3ccc(F)cc23)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.7 %

Procedure:
At −70° C., triethylamine (215 μL, 1.54 mmol) was added to a solution of (R)-2-(4-(3-aminopyrrolidin-1-yl)-6-fluoroquinazolin-2-yl)phenol (250 mg, 0.77 mmol) in CH2Cl2 (2.5 mL), followed by the dropwise addition of isobutyl chloroformate (100 μL, 0.77 mmol). The reaction was stirred for 30 minutes and warmed to RT. The mixture was quenched with H2O and extracted with CH2Cl2. The combined organic extracts were dried over MgSO4, filtered, and concentrated. Purification via silica gel chromatography using 2.5-10% EtOAc in a 1:1 mixture of CH2Cl2 and hexanes gave (R)-isobutyl 1-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)pyrrolidin-3-ylcarbamate (compound 15) (195 mg, 60%). 1H NMR (400 MHz, acetic acid-d4) δ 8.43 (m, 1H), 8.01 (m, 1H), 7.90 (m, 1H), 7.76 (m, 1H), 7.58 (d, J=5.6 Hz, 1H), 7.37 (m, 1H), 6.93 (m, 2H), 4.07 (m, 5H), 3.75 (d, J=6.2 Hz, 2H), 2.23 (m, 1H), 2.03 (m, 1H), 1.83 (m, 1H), 0.88 (d, J=6.5 Hz, 6H) ppm. LC/MS: m/z 425.3 (M+H)+ at 2.77 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [CH3:1][N:2]([S:21]([C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)(=[O:23])=[O:22])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18]([OH:20])=O)[CH2:15][N:16]=1)=[CH:8]2.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)C(C)C)C.[NH:60]1[CH2:65][CH2:64][O:63][CH2:62][CH2:61]1>CN(C)C=O.O>[CH3:1][N:2]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18]([N:60]3[CH2:65][CH2:64][O:63][CH2:62][CH2:61]3)=[O:20])[CH2:15][N:16]=1)=[CH:8]2)[S:21]([C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)(=[O:22])=[O:23]
Reactant: C1COCCN1
Reactant: CN(c1cccc2cc(C3=NCC(CC(=O)O)S3)[nH]c12)S(=O)(=O)c1cccs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CN(c1cccc2cc(C3=NCC(CC(=O)N4CCOCC4)S3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 20 h
Yield: 57 %

Procedure:
To a solution of (2-{7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetic acid (0.150 g) in N,N-dimethylformamide (6 mL) were added 1H-1,2,3-benzotriazol-1-ol (0.063 g), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.079 g), N-ethyldiisopropylamine (0.12 mL) and morpholine (0.06 mL), and the mixture was stirred at room temperature for 20 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:methanol=50:50-0:100), and recrystallized from hexane-ethyl acetate to give the title compound (0.099 g, yield 57%) as colorless crystals. melting point 173-174° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:15])=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[O:18]([C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl.N1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(OCCO)C.O>[Cl:15][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:29][C:28]3[CH:27]=[CH:26][C:25]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:31][CH:30]=3)=[C:3]([C:16]#[N:17])[CH:4]=[N:5]2)=[CH:10][C:9]=1[N+:12]([O-:14])=[O:13]
Reactant: Nc1ccc(Oc2ccccc2)cc1
Reactant: N#Cc1cnc2cc(Cl)c([N+](=O)[O-])cc2c1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOCCO
Solvent: O
Product: N#Cc1cnc2cc(Cl)c([N+](=O)[O-])cc2c1Nc1ccc(Oc2ccccc2)cc1
Temperature: 115 °C
Yield: 73.8 %

Procedure:
A mixture of 722.7 mg (2.70 mmol) of 4,7-dichloro-6-nitro-3-quinolinecarbonitrile, 100.1 mg (2.70 mmol) of 4-phenoxyaniline and 312.1 mg (2.70 mmol) of pyridine hydrochloride in 30 mL of 2-ethoxyethanol is heated at 110-120° C. for 3 hours. After cooling, the mixture is diluted with water, neutralized with an aqueous solution of saturated sodium carbonate, and extracted with ethyl acetate. The separated organic layer is washed with brine and dried over sodium sulfate. Removal of the solvent yields a solid residue which is purified by flash chromatography (elution with 99:1 methylene chloride/methanol), giving 831.0 mg (73.9%) of the product as a deep yellow solid, mp 220-222° C.
Reaction SMILES: CC([CH:5]1[CH2:10][N:9]([CH2:11][CH:12]2[C:21]3[C:16](=[C:17]([C:22]#[N:23])[CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14][O:13]2)[CH2:8][CH2:7][N:6]1C([O-])=O)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[N:9]1([CH2:11][CH:12]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([C:22]#[N:23])[C:16]=3[CH2:15][CH2:14][O:13]2)[CH2:10][CH2:5][NH:6][CH2:7][CH2:8]1
Reactant: CC(C)(C)C1CN(CC2OCCc3c(C#N)cccc32)CCN1C(=O)[O-]
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: N#Cc1cccc2c1CCOC2CN1CCNCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1,1-dimethylethyl-4-[(5-cyano-3,4-dihydro-1H-isochromen-1-yl)methyl]piperazine-1-carboxylate (150 mg, 0.42 mmol) in 10 mL of DCM was added 5 mL of 4N HCl/dioxane, and the mixture was stirred at room temperature for 2 hours. The solvents was removed off under vacuum to afford 1-(piperazin-1-ylmethyl)-3,4-dihydro-1H-isochromene-5-carbonitrile.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[N:13][N:14]=[C:10]3[CH2:9][CH:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[C:6]=2[CH:23]=1.N([O-])=O.[Na+].C(=O)([O-])O.[Na+].[BrH:33]>CS(O)(=O)=O.O.[Cu]Br>[Br:33][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[N:13][N:14]=[C:10]3[CH2:9][CH:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[C:6]=2[CH:23]=1
Reactant: Cc1nnc2n1-c1ccc(N)cc1C(c1ccccc1Cl)=CC2
Reactant: Br
Agent: [Cu]Br
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Solvent: O
Product: Cc1nnc2n1-c1ccc(Br)cc1C(c1ccccc1Cl)=CC2
Reaction time: 0.08 h

Procedure:
A solution of 155 mg of 8-amino-6-(2-chlorophenyl)-1-methyl-4H-s-triazolo[4,3-a][1]benzazepine in 1 ml of 2N methanesulphonic acid is cooled to 0° and treated with a solution of 44 mg of sodium nitrite in 0.2 ml of water. The mixture is stirred at 5° for 5 minutes and then added to a solution of 206 mg of copper (I) bromide in 2.4 ml of 48% hydrobromic acid. The mixture is stirred at room temperature for a further 10 minutes, whereupon it is neutralized with sodium hydrogen carbonate solution and extracted with chloroform. The chloroform extracts are dried and then evaporated. The residue is dissolved in chloroform and chromatographed on 5 g of silica gel. Impurities are eluted with chloroform and the desired product is eluted with chloroform/ethanol (19:1). After crystallization from ethyl acetate/ether, there is obtained 8-bromo-6-(2-chlorophenyl)-1-methyl-4H-s-triazolo[4,3-a][1] benzazepine of melting point 250°-252°.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[N:5]=[C:4]([C:14]2[CH:67]=[CH:66][C:17](OCC3C=CC(C4SC(N5CCC6C(=C(C(=O)N(C7SC8C=CC=CC=8N=7)COCC[Si](C)(C)C)C=CC=6)C5)=NC=4C(OCC)=O)=CC=3)=[CH:16][CH:15]=2)[C:3]=1[C:68]#[N:69].NC1N(C(OC(C)(C)C)=O)N=C(C2C=CC(O)=CC=2)C=1C#N.[S:92]1[C:96]2[CH:97]=[CH:98][CH:99]=[CH:100][C:95]=2[N:94]=[C:93]1[N:101]([CH2:128][O:129][CH2:130][CH2:131][Si:132]([CH3:135])([CH3:134])[CH3:133])[C:102]([C:104]1[CH:105]=[CH:106][CH:107]=[C:108]2[C:113]=1[CH2:112][N:111]([C:114]1[S:115][C:116]([C:124]#[C:125][CH2:126][OH:127])=[C:117]([C:119]([O:121][CH2:122][CH3:123])=[O:120])[N:118]=1)[CH2:110][CH2:109]2)=[O:103].NC1N(C(OC(C)(C)C)=O)N=C(C2C=CC=C(O)C=2)C=1C#N>>[NH2:1][C:2]1[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[N:5]=[C:4]([C:14]2[CH:15]=[C:16]([CH:17]=[CH:66][CH:67]=2)[O:127][CH2:126][C:125]#[C:124][C:116]2[S:115][C:114]([N:111]3[CH2:110][CH2:109][C:108]4[C:113](=[C:104]([C:102](=[O:103])[N:101]([C:93]5[S:92][C:96]6[CH:97]=[CH:98][CH:99]=[CH:100][C:95]=6[N:94]=5)[CH2:128][O:129][CH2:130][CH2:131][Si:132]([CH3:135])([CH3:133])[CH3:134])[CH:105]=[CH:106][CH:107]=4)[CH2:112]3)=[N:118][C:117]=2[C:119]([O:121][CH2:122][CH3:123])=[O:120])[C:3]=1[C:68]#[N:69]
Reactant: CCOC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1C#CCO
Reactant: CCOC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1-c1ccc(COc2ccc(-c3nn(C(=O)OC(C)(C)C)c(N)c3C#N)cc2)cc1
Agent: CC(C)(C)OC(=O)n1nc(-c2ccc(O)cc2)c(C#N)c1N
Agent: CC(C)(C)OC(=O)n1nc(-c2cccc(O)c2)c(C#N)c1N
Product: CCOC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1C#CCOc1cccc(-c2nn(C(=O)OC(C)(C)C)c(N)c2C#N)c1

Procedure:
Compound 36C was prepared in a similar manner to the synthesis of compound 35A by substituting compound 34D and compound 31F with compound 36B and compound 36A, respectively as a mixture of two inseparable isomers: MS (ESI(+)): m/z 932 (M+H).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[Cl:28][C:29]1[CH:30]=[C:31]([C:36]2[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[N:39]3[N:46]=[C:47]([C:49](O)=[O:50])[CH:48]=[C:38]3[N:37]=2)[CH:32]=[CH:33][C:34]=1[Cl:35].[CH2:52]([NH2:59])[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1.C(N(CC)CC)C>O1CCCC1.C(OCC)C>[CH2:52]([NH:59][C:49]([C:47]1[CH:48]=[C:38]2[N:37]=[C:36]([C:31]3[CH:32]=[CH:33][C:34]([Cl:35])=[C:29]([Cl:28])[CH:30]=3)[CH:41]=[C:40]([C:42]([F:45])([F:43])[F:44])[N:39]2[N:46]=1)=[O:50])[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1
Reactant: O=C(O)c1cc2nc(-c3ccc(Cl)c(Cl)c3)cc(C(F)(F)F)n2n1
Reactant: NCc1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NCc1ccccc1)c1cc2nc(-c3ccc(Cl)c(Cl)c3)cc(C(F)(F)F)n2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.9 %

Procedure:
Benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate (BOP) (0.845 g, 1.91 mmol) was added to a suspension of 5-(3,4-dichloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (0.600 g, 1.59 mmol) and benzylamine (0.209 mL, 1.91 mmol) in tetrahydrofuran (25 ml) containing triethylamine (0.665 mL, 4.77 mmol). The reaction mixture was stirred overnight at room temperature, diluted with ethyl ether (25 mL) and washed with a saturated aqueous solution of sodium bicarbonate (50 mL). The organic layer was collected, concentrated under reduced pressure and the crude product was purified by column chromatography on silica gel to give 5-(3,4-dichloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid benzylamide (0.665 g, 89%).