Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][C:3]=1[OH:12].C(OCC)(=O)C.C(=O)([O-])O.[Na+].Br[CH:25]([CH2:29][CH2:30][CH2:31][CH3:32])[C:26](Br)=[O:27]>O>[CH2:29]([CH:25]1[C:26](=[O:27])[NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][C:3]=2[O:12]1)[CH2:30][CH2:31][CH3:32]
Reactant: CCCCC(Br)C(=O)Br
Reactant: COC(=O)c1ccc(N)c(O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCC1Oc2cc(C(=O)OC)ccc2NC1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 81.7 %

Procedure:
To a solution of 2-amino-5-methoxycarbonylphenol [Tetrahedron, 4.6 (15), 5177-5186 (1990)] (8.0 g) in a mixed solvent of ethyl acetate (200 ml) and water (200 ml) were added sodium hydrogen carbonate (11.18 g) and 2-bromohexanoyl bromide (12.73 g) and the mixture was stirred at room temperature for 10 minutes. The organic layer was separated and the solvent was distilled off under reduced pressure. The resulting residue was dissolved in dimethylformamide (300 ml), to the solution was added potassium carbonate (6.0 g) and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution and extraction with ethyl acetate was conducted. The solvent was distilled off under reduced pressure and the resulting crystals were recrystallized from ether to give 2-butyl-7-methoxycarbonyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (10.3 g).
Reaction SMILES: C([O:4][CH2:5][C@H:6]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:33])[C:14]=2[NH:18][C:19](=[O:32])[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[C:23]([F:31])[CH:22]=2)[C:9]1=[O:34])[CH3:7])(=O)C.C(=O)([O-])[O-].[K+].[K+].CO>O>[F:31][C:23]1[CH:22]=[C:21]([CH2:20][C:19]([NH:18][C:14]2[C:13]([CH3:33])=[CH:12][CH:11]=[C:10]3[C:15]=2[CH:16]=[CH:17][N:8]([C@H:6]([CH3:7])[CH2:5][OH:4])[C:9]3=[O:34])=[O:32])[CH:26]=[CH:25][C:24]=1[C:27]([F:30])([F:28])[F:29]
Reactant: CC(=O)OC[C@@H](C)n1ccc2c(NC(=O)Cc3ccc(C(F)(F)F)c(F)c3)c(C)ccc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1ccc2c(=O)n([C@H](C)CO)ccc2c1NC(=O)Cc1ccc(C(F)(F)F)c(F)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A round bottom flask was charged with (R)-2-(5-(2-(3-fluoro-4-(trifluoromethyl)phenyl)acetamido)-6-methyl-1-oxoisoquinolin-2(1H)-yl)propyl acetate (300.00 mg, 0.62704 mmol), potassium carbonate (260 mg, 0.0019 mol), methanol (20 mL, 0.4 mol) and 2 drops of water. The reaction was stirred at room temperature for 20 minutes. The reaction was quenched with water and extracted with ethyl acetate, washed with sodium bicarbonate, brine, and dried The solvent was removed under reduced pressure to afford the product as a light yellow solid.
Reaction SMILES: C(OC([N:11]1[C:19]2[C:14](=[C:15]3[O:23][C:22]([CH:24]([CH3:26])[CH3:25])=[C:21]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=4)[C:20](=[O:34])[C:16]3=[CH:17][CH:18]=2)[C:13]([CH3:35])=[CH:12]1)=O)C1C=CC=CC=1>O1CCCC1.C(O)C.Cl.[Pd]>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([C:21]2[C:20](=[O:34])[C:16]3[C:15]([O:23][C:22]=2[CH:24]([CH3:25])[CH3:26])=[C:14]2[C:19](=[CH:18][CH:17]=3)[NH:11][CH:12]=[C:13]2[CH3:35])=[CH:32][CH:31]=1
Reactant: Cc1cn(C(=O)OCc2ccccc2)c2ccc3c(=O)c(-c4ccc(Cl)cc4)c(C(C)C)oc3c12
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c[nH]c2ccc3c(=O)c(-c4ccc(Cl)cc4)c(C(C)C)oc3c12
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A stirred suspension of 3-(4-chlorophenyl)-2-isopropyl-9-methyl-4-oxo-4H-pyrano[2,3-e]indole-7-carboxylic acid benzyl ester and its positional isomer (0.063 g, 0.13 mmol) and 20% Pd on activated carbon (0.013 g) in tetrahydrofuran (1.5 ml), ethanol (1.5 ml) and 5M HCl solution (0.75 ml) is stirred under a hydrogen atmosphere for 3.5 h at room temperature. The catalyst is removed by filtration through Celite filter aid, and the pad of Celite is washed with ethyl acetate and methylene chloride. The combined filtrates are evaporated in vacuo, and the residue is purified by flash chromatography (cyclohexane/ethyl acetate=9:1 to 5:1) to afford the title compound as a pale orange solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([CH:17]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:18]([OH:20])=O)=[C:15]3[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH2:31]([O:33][C:34](=[O:42])[C:35]1[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=1)[CH3:32]>CN(C1C=CN=CC=1)C>[CH2:31]([O:33][C:34](=[O:42])[C:35]1[CH:40]=[CH:39][C:38]([NH:41][C:18](=[O:20])[CH:17]([C:16]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=[C:10]3[C:15]=2[CH:14]=[CH:13][CH:12]=[CH:11]3)[CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]2)=[CH:37][CH:36]=1)[CH3:32]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: O=C(O)C(c1c2ccccc2nn1-c1ccc(Cl)cc1)C1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ccc(NC(=O)C(c2c3ccccc3nn2-c2ccc(Cl)cc2)C2CCCCC2)cc1

Procedure:
In analogy to the procedure described in example 6, [2-(4-chloro-phenyl)-2H-indazol-3-yl]-cyclohexyl-acetic acid was converted into the corresponding acid chloride with thionyl chloride which subsequently reacted with 4-amino-benzoic acid ethyl ester (CAS Reg. No. 94-09-7]) in the presence of DMAP to give the title compound as colorless oil. MS: m/e=516.4 [M+H+].
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][CH2:8][C:9]1[N:10]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:11](=[O:27])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:16][C:15]([CH2:25][NH2:26])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2].[C:33](Cl)(=[O:37])[CH:34]([CH3:36])[CH3:35].C(N(CC)CC)C>O1CCCC1>[C:1]([O:5][C:6](=[O:32])[NH:7][CH2:8][C:9]1[N:10]([CH2:28][CH:29]([CH3:30])[CH3:31])[C:11](=[O:27])[C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[CH:16][C:15]([CH2:25][NH:26][C:33](=[O:37])[CH:34]([CH3:36])[CH3:35])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(CN)ccc2c1=O
Reactant: CC(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(CNC(=O)C(C)C)ccc2c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 592.2 %

Procedure:
To a solution of crude tert-butyl[6-(aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.016 g) (Example 285) in tetrahydrofuran (2 mL) was added isobutyryl chloride (0.038 mL, 0.36 mmol) and triethylamine (0.050 mL, 0.36 mmol), and the mixture was stirred at room temperature for 4 h. The reaction mixture was washed with water (4 mL) and concentrated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1 (v/v)) to give tert-butyl{2-isobutyl-6-[(isobutyrylamino)methyl]-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl}methylcarbamate (0.11 g, 75%) as a pale yellow solid.
Reaction SMILES: COC([C:5]1([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:9][CH2:8][C:7]([CH2:11][Cl:12])([CH3:10])[C:6]1=[O:13])=O.O.C1(C)C(S(O)(=O)=O)=CC=CC=1>O>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][CH:5]2[C:6](=[O:13])[C:7]([CH2:11][Cl:12])([CH3:10])[CH2:8][CH2:9]2)=[CH:20][CH:19]=1
Reactant: COC(=O)C1(Cc2ccc(Cl)cc2)CCC(C)(CCl)C1=O
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: O
Product: CC1(CCl)CCC(Cc2ccc(Cl)cc2)C1=O
Temperature: 120 °C
Reaction time: 1.5 h
Yield: 91.3 %

Procedure:
To 1.00 g of Compound 3-1-3 synthesized in Production Example 4, 0.578 g of toluenesulfonic acid monohydrate and 100 mg of water were added, and the resulting mixture was stirred in an oil bath of 120° C. for 1.5 hours. After the reaction, water was added to the reaction solution thus obtained, and extraction with ethyl acetate was then carried out. The extract was washed with an aqueous solution of sodium hydrogen carbonate and saturated brine. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled away. The residue was purified by silica gel column chromatography to obtain 752 mg of Compound 4-1-3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].Br[C:17]1[CH:27]=[CH:26][CH:25]=[CH:24][C:18]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:17][C:18]=2[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Reactant: CCOC(=O)c1ccccc1Br
Product: CCOC(=O)c1ccccc1-c1cc(OC)c(OC)c(OC)c1

Procedure:
3,4,5-Trimethoxyphenylboronic acid (639 mg) and ethyl 2-bromobenzoate (479 mg) were condensed in the same manner as described in Preparation Example 1 to give the title compound.
Reaction SMILES: [OH:1][CH:2]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:21]=[C:20]([C:22]3[O:26][N:25]=[C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:23]=3[C:33]([F:36])([F:35])[F:34])[O:19][N:18]=2)=[CH:13][CH:12]=1)[C:3]([NH:5][CH2:6][CH2:7][C:8]([OH:10])=O)=[O:4].C[N:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:1][CH:2]([C:11]1[CH:12]=[CH:13][C:14]([C:17]2[N:21]=[C:20]([C:22]3[O:26][N:25]=[C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:23]=3[C:33]([F:35])([F:34])[F:36])[O:19][N:18]=2)=[CH:15][CH:16]=1)[C:3]([NH:5][CH2:6][CH2:7][C:8]([N:38]1[CH2:43][CH:42]([O:41][CH3:40])[CH2:39]1)=[O:10])=[O:4]
Reactant: CN1CCOCC1
Reactant: O=C(O)CCNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COC1CN(C(=O)CCNC(=O)C(O)c2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)cc2)C1
Reaction time: 1 h
Yield: 50 %

Procedure:
(R/S)-3-(2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)propanoic acid (Int-V, 25 mg, 0.050 mmol), 3-methoxyazetidine, HCl (6.15 mg, 0.050 mmol), 4-methylmorpholine (20.13 mg, 0.199 mmol), and HATU (24.60 mg, 0.065 mmol) were added to DMF (3 mL). This was stirred for 1 h before it was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 methanol:water with 10-mM ammonium acetate; Gradient: 35-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give (R/S)-2-hydroxy-N-(3-(3-methoxyazetidin-1-yl)-3-oxopropyl)-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (14.1 mg, 0.025 mmol, 49.6% yield): LCMS=572.2 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.19 (2 H, dd, J=8.41, 1.88 Hz), 7.54-7.77 (7 H, m), 5.11 (1 H, d, J=2.01 Hz), 4.06-4.31 (3 H, m), 3.84-3.98 (1 H, m), 3.69-3.83 (1 H, m), 3.43-3.56 (2 H, m), 3.26 (3 H, d, J=2.76 Hz), 2.29-2.44 (2 H, m); HPLC peak RT=2.4 min (Method E).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][C:11]([O:17][CH3:18])=[CH:12][CH:13]=2)[CH:8]=1)(=O)=O.[CH3:21][N:22](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:18][O:17][C:11]1[CH:10]=[C:9]2[C:14]([CH:15]=[CH:16][C:7]([C:21]#[N:22])=[CH:8]2)=[CH:13][CH:12]=1
Reactant: CN(C)C=O
Reactant: COc1ccc2ccc(OS(=O)(=O)C(F)(F)F)cc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: COc1ccc2ccc(C#N)cc2c1
Temperature: 80 °C
Yield: 80 %

Procedure:
A solution of 7-methoxy-2-naphthyl trifluoromethanesulfonate (4.95 g, 16.1 mmol) in DMF (20 mL) is degassed by repeatedly evacuating the flask then flushing with N2. Zinc cyanide (1.13 g, 9.7 mmol) is added followed by Pd(PPh3)4 (930 mg, 0.81 mmol). The resulting mixture is again degassed and heated to 80° C. for 3 hours. The reaction is allowed to cool, poured into water and washed twice with toluene and once with CH2Cl2. The combined organic extracts are dried (Na2SO4), filtered and concentrated. The resulting material is purified by column chromatography (step gradient, 25–50% CH2Cl2 in hexanes) to give 7-methoxy-2-naphthonitrile as a white solid (2.36 g, 80%). HRMS (EI) calculated for C12H9NO: 183.0684, found 183.0684.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[N:11]=2)=[CH:6][CH:5]=1)([O-])=O.[BH4-].[Na+].[S]>O1CCCC1>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[N:11]=2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(-c2nc(-c3ccccn3)no2)cc1
Agent: [BH4-]
Agent: [Na+]
Agent: [S]
Solvent: C1CCOC1
Product: Nc1ccc(-c2nc(-c3ccccn3)no2)cc1
Yield: 42 %

Procedure:
A solution of 2.5 g (0.01 mole) of 5-(4-nitrophenyl)-3-(2-pyridyl)-1,2,4-oxadiazole in 200 ml of tetrahydrofuran is added slowly to a solution of NaBH2S3 which is prepared by stirring 0.36 g of NaBH4 and 0.96 g of sulfur in 50 ml of tetrahydrofuran for 0.5 hour. The reaction mixture is then refluxed for 24 hours. The mixture is filtered, cooled, and the solvent is evaporated in vacuo to give 1.0 g (42% yield) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1Br.[Mg].II.[CH:14](=[O:20])[C:15]1[O:19][CH:18]=[CH:17][CH:16]=1>O1CCCC1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[CH:14]([C:15]1[O:19][CH:18]=[CH:17][CH:16]=1)[OH:20]
Reactant: Cc1cc(C)c(Br)c(C)c1
Reactant: O=Cc1ccco1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1cc(C)c(C(O)c2ccco2)c(C)c1
Reaction time: 0.42 h

Procedure:
A solution of 2,4,6-trimethyl-1-bromobenzene (30.9 g, 155 mmol) in tetrahydrofuran (100 ml) is added slowly to magnesium turnings (3.77 g, 155 mmol), until the magnesium is just covered. A small quantity of iodine is added and the mixture is allowed to stand at room temperature for 25 minutes and then heated and stirred until the brown colour is lost. The remainder of the aryl bromide solution is added dropwise over a 20 minute period, with occasional heating to maintain the formation of the Grignard reagent solution. The reaction is stirred at room temperature for 1 hour. A solution of furfural (12.8 ml, 155 mmol) in tetrahydrofuran (70 ml) is added dropwise, and once the addition is complete, the reaction is stirred at room temperature for 2 hours. The reaction is quenched by cautious addition of excess saturated ammonium chloride solution, then extracted into ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography on silica gel affords (2,4,6-trimethylphenyl)furan-2-ylmethanol.
Reaction SMILES: [C:1]1([C@H:7]2[CH2:12][CH2:11][C@H:10]([NH:13][CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:23](Cl)Cl.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>CO.O>[CH3:23][N:13]([C@H:10]1[CH2:9][CH2:8][C@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][CH2:11]1)[CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=1
Reactant: ClCCl
Reactant: Oc1ccc(CCN[C@H]2CC[C@H](c3ccccc3)CC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN(CCc1ccc(O)cc1)[C@H]1CC[C@H](c2ccccc2)CC1
Reaction time: 12 h

Procedure:
To a stirred solution of trans-4-[2-(4-phenylcyclohexylamino)ethyl]phenol (380 mg, 1.3 mmol) in MeOH (5 mL), H2O (0.5 mL), and CH2Cl2 (5 mL) was added ρformaldehyde (200 mg, 6.5 mmol). After stirring for 15 minutes NaBH(OAc)3 (340 mg, 1.6 mmol) was added, and the reaction mixture was stirred for 12 hours. Additional NaBH(OAc)3 (138 mg, 0.65 mmol) was added, and the mixture was stirred for 2 days. NaBH(OAc)3 (138 mg, 0.65 mmol) was added, and stirring was continued for 6 hours. Solid NaOH was added to give a clear solution, which was concentrated under reduced pressure. Purification by flash chromatography (silica, 89:10:1 CH2Cl2:MeOH:NH4OH) and formation of the HCl salt gave trans-4-{2-[methyl(4-phenylcyclohexyl)amino]ethyl}phenol (380 mg, 64%), as an off-white solid: mp 97-105° C.; IR (KBr): 2941, 1614, 1517 cm−1; 1H NMR (500 MHz, DMSO-d6) δ 11.05 (s, 1H), 9.42 (s, 1H), 7.35-7.15 (m, 5H), 7.10 (br d, J=8 Hz, 2H), 6.77 (br d, J=8 Hz, 2H), 3.49-2.94 (m, 6H), 2.80-2.70 (m, 2H), 2.56-2.48 (m, 1H), 2.30-2.11 (m, 2H), 1.89 (br d, J=11.5 Hz, 2H), 1.75-1.50 (m, 4H); CI—MS (methane) (m/z): 310 [M+H]+; HPLC: method A, 5.99 minutes (99.4%); method B, 10.68 minutes (99.1%); Anal. Calcd for C21H27NO.HCl.0.25H2O: C, 71.98; H, 8.20; N, 4.00. Found: C, 71.60; H, 8.31; N, 3.86.
Reaction SMILES: C([NH:4][C:5]1[CH:9]=[CH:8][S:7][C:6]=1[S:10][C:11](=O)[CH3:12])(=O)C>C1(C)C=CC=CC=1>[CH3:12][C:11]1[S:10][C:6]2[S:7][CH:8]=[CH:9][C:5]=2[N:4]=1
Reactant: CC(=O)Nc1ccsc1SC(C)=O
Solvent: Cc1ccccc1
Product: Cc1nc2ccsc2s1
Temperature: 205 °C
Yield: 91.4 %

Procedure:
A solution of 660 mg (3.1 mmol) of N-acetyl-2-(acetylthio)-3-thiophenamine in 8 mL of toluene was degassed in a Pyrex robe under high vaccuum. The robe was subsequently sealed under high vaccuum and heated at 205° C. for 5 hr. Chromatographic separation on silica gel using hexane/EtOAc (5:1 ) gave 440 mg (80%) of the title product.
Reaction SMILES: [CH:1]([C@@H:4]1[N:8]([C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[CH:16][C:17]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5[N:28]=[CH:27][N:26](COCC[Si](C)(C)C)[N:25]=5)=[CH:20][CH:19]=4)=[C:11]3[N:10]=2)[C:7](=[O:37])[NH:6][CH2:5]1)([CH3:3])[CH3:2].C([O-])(O)=O.[Na+]>CCO>[NH:26]1[CH:27]=[N:28][C:24]([C:21]2[CH:20]=[CH:19][C:18]([C:17]3[CH:16]=[N:15][N:12]4[CH:13]=[CH:14][C:9]([N:8]5[C@@H:4]([CH:1]([CH3:2])[CH3:3])[CH2:5][NH:6][C:7]5=[O:37])=[N:10][C:11]=34)=[CH:23][CH:22]=2)=[N:25]1
Reactant: CC(C)[C@H]1CNC(=O)N1c1ccn2ncc(-c3ccc(-c4ncn(COCC[Si](C)(C)C)n4)cc3)c2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC(C)[C@H]1CNC(=O)N1c1ccn2ncc(-c3ccc(-c4nc[nH]n4)cc3)c2n1
Yield: 67.2 %

Procedure:
A mixture of (S)-5-isopropyl-1-(3-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)imidazolidin-2-one (Example 25, Step 4, 12 mg, 0.023 mmol) and EtOH/6N aqueous HCl (1:2, 0.5 mL total) was heated at reflux for 3 hours. After cooling, the reaction mixture was neutralized by slow addition of saturated aqueous NaHCO3 solution. The mixture was extracted with dichloromethane, and the combined extracts were washed with brine, dried and concentrated. The residue was purified by column chromatography (12% MeOH in dichloromethane) to give (S)-1-(3-(4-(1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)-5-isopropylimidazolidin-2-one (6 mg, 67%) as a pale yellow solid. LCMS (APCI+) m/z 389 [M+H]+.
Reaction SMILES: Cl.[CH:2]1([NH:8][C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[N:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:25]C1C(CN)=NC=CC=1>>[CH:2]1([NH:8][C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11]([NH:17][CH2:18][C:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=3)[N:10]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: Cc1cccnc1CN
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCCC2)c1C
Agent: Cl
Product: Cc1cccnc1CNc1nc(C)c(C)c(NC2CCCCC2)n1

Procedure:
The titled compound was synthesized according to the general procedure described for preparation of N4-cyclohexyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 1) using [(3-methylpyridin-2-yl)methyl]amine instead of (pyridin-2-ylmethyl)amine. The crude product was purified by crystallization from ethanol (10 mL) to afford the titled compound as the hydrochloride salt as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.10-1.20 (m, 5H), 1.55-1.75 (m, 5H), 1.89 (s, 3H), 2.25 (s, 3H), 2.33 (s, 3H), 3.83 (s, 1H), 4.63 (d, J=5.10 Hz, 2H), 7.15-7.25 (m, 1H), 7.50-7.65 (m, 2H), 7.91 (s, 1H), 8.34 (d, J=4.03 Hz, 1H), 12.62 (s, 1H); MS (ESI) m/z 326.9 (M+1)+.
Reaction SMILES: [C:1]1(C2C=CC=CC=2)[CH:6]=[CH:5][C:4]([CH2:7][C:8]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:15]([O:27][CH2:28]C3C=CC=CC=3)[CH:14]=2)=O)=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:43])=O.[BH4-].[Na+]>C(#N)C.Cl>[ClH:43].[CH2:28]([O:27][C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][C:16]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH:8]([CH2:7][C:4]1[CH:5]=[CH:6][C:1]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:2][CH:3]=1)[NH:10][CH2:11][CH2:12]2)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C(Cc1ccc(-c2ccccc2)cc1)NCCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC#N
Product: c1ccc(COc2cc3c(cc2OCc2ccccc2)C(Cc2ccc(-c4ccccc4)cc2)NCC3)cc1
Reaction time: 8 h

Procedure:
6,7-bis-benzyloxy-1-biphenyl-4-ylmethyl-1,2,3,4-tetrahydro-isoquinoline hydrochloride (2) was prepared as follows: A stirred solution of 3 g (5.69 mmol) of 2-biphenyl-4-yl-N-[2-(3,4-bis-benzyloxy-phenyl)-ethyl]-acetamide and 5.6 ml (60 mmol) of phosphorus oxychloride in 25 ml of anhydrous acetonitrile was refluxed for 20 hours. The reaction solution was evaporated under reduced pressure and the residue was dissolved in 25 ml of methanol. To this stirred solution at 0° C., 2.27 g (60 mmol) of sodium borohydride was added portionwise. The stirred reaction mixture was allowed to reach room temperature overnight and then it was poured in 150 ml of 10% aqueous HCl solution. The precipitate was collected on a glass filter funnel, washed with water (3×50 ml), and air-dried overnight. The solid was recrystallized using ether/methanol mixture to provide 2.56 g (82%) of off-white crystals, mp 187-189° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)([CH2:16][CH2:17][CH2:18][OH:19])[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.Br[C:29]1[CH:34]=[C:33]([CH3:35])[N+:32]([O-:36])=[C:31]([CH3:37])[CH:30]=1>>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C@:13]2([CH2:16][CH2:17][CH2:18][OH:19])[O:12][C:11](=[O:27])[N:10]([C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([C:29]4[CH:34]=[C:33]([CH3:35])[N+:32]([O-:36])=[C:31]([CH3:37])[CH:30]=4)=[CH:3][CH:4]=3)[CH3:9])[CH2:15][CH2:14]2)=[CH:21][CH:22]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Reactant: Cc1cc(Br)cc(C)[n+]1[O-]
Product: Cc1cc(-c2ccc([C@H](C)N3CC[C@](CCCO)(c4ccc(F)cc4)OC3=O)cc2)cc(C)[n+]1[O-]

Procedure:
The title compound was prepared from (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one following procedures analogous to those described in Example 313 Steps 3 and 4 using 4-bromo-2,6-dimethylpyridine-N-oxide in Step 4. LC-MS Method 2 tR=1.092, m/z=479.1; 1H NMR (CDCl3) 1.38 (m, 1H), 1.56 (d, 3H), 1.71 (m, 1H), 1.95 (m, 2H), 2.19-2.31 (m, 3H), 2.58 (s, 3H), 2.61 (s, 3H), 2.95 (m, 1H), 3.58 (m, 1H), 5.71 (m, 1H), 7.05 (m, 4H), 7.21-7.32 (m, 4H), 7.38 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[CH:4][C:3]=1[O:9][CH3:10].[CH2:11]([S-:13])[CH3:12].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:13][CH2:11][CH3:12])=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: CC[S-]
Reactant: COc1cc(F)ccc1Br
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCSc1ccc(Br)c(OC)c1
Reaction time: 72 h
Yield: 17 %

Procedure:
To a room temperature solution of 1-bromo-4-fluoro-2-methoxybenzene (5.00 g, 24.39 mmol) in DMF (15 mL) was added sodium ethanethiolate (2.66 g, 31.71 mmol) and the resulting reaction mixture was stirred for 72 hours. The reaction mixture was partitioned between water (20 mL) and EtOAc (50 mL). The organic layer was separated and the aqueous layer was further extracted with EtOAc (3×50 mL). The organic layers were combined and washed with saturated brine solution (20 mL) then dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography eluting with hexane:EtOAc 98:2 to afford 1-bromo-4-ethylthio-2-methoxybenzene as a colourless liquid in 17% yield, 1.00 g.