Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][N:6]([CH:8]2[CH2:11][O:10][CH2:9]2)[C@H:5]([CH3:12])[CH2:4][N:3]1[C:13]1[CH:14]=[CH:15][C:16]([NH:19][C:20]2[C:25](=[O:26])[N:24]([CH3:27])[CH:23]=[C:22]([C:28]3[C:33]([CH:34]=[O:35])=[C:32]([N:36]4[CH:48]=[CH:47][N:39]5[C:40]6[CH2:41][CH2:42][CH2:43][CH2:44][C:45]=6[CH:46]=[C:38]5[C:37]4=[O:49])[N:31]=[CH:30][CH:29]=3)[CH:21]=2)=[N:17][CH:18]=1.[BH4-].[Na+]>CO>[CH3:1][C@H:2]1[CH2:7][N:6]([CH:8]2[CH2:11][O:10][CH2:9]2)[C@H:5]([CH3:12])[CH2:4][N:3]1[C:13]1[CH:14]=[CH:15][C:16]([NH:19][C:20]2[C:25](=[O:26])[N:24]([CH3:27])[CH:23]=[C:22]([C:28]3[CH:29]=[CH:30][N:31]=[C:32]([N:36]4[CH:48]=[CH:47][N:39]5[C:40]6[CH2:41][CH2:42][CH2:43][CH2:44][C:45]=6[CH:46]=[C:38]5[C:37]4=[O:49])[C:33]=3[CH2:34][OH:35])[CH:21]=2)=[N:17][CH:18]=1
Reactant: C[C@@H]1CN(c2ccc(Nc3cc(-c4ccnc(-n5ccn6c7c(cc6c5=O)CCCC7)c4C=O)cn(C)c3=O)nc2)[C@@H](C)CN1C1COC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C[C@@H]1CN(c2ccc(Nc3cc(-c4ccnc(-n5ccn6c7c(cc6c5=O)CCCC7)c4CO)cn(C)c3=O)nc2)[C@@H](C)CN1C1COC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.3 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer was charged with 160a (80 mg, 0.12 mmol), NaBH4 (23 mg, 0.60 mmol), and methanol (10 mL). The mixture was stirred at room temperature for 1 h. It was quenched with water (1 mL) and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 160 (44 mg, 55%). MS-ESI: [M+H]+ 663.3. 1H NMR (500 MHz, CDCl3) δ 8.72-8.70 (m, 1H), 8.57 (d, J=5.0 Hz, 1H), 8.03 (d, J=2.5 Hz, 1H), 7.89-7.87 (m, 2H), 7.50 (d, J=5.0 Hz, 1H), 7.37-7.35 (m, 1H), 7.06 (s, 1H), 6.97 (d, J=6.0 Hz, 1H), 6.81 (d, J=9.0 Hz, 1H), 6.68 (d, J=6.0 Hz, 1H), 5.10-5.08 (m, 1H), 4.76-4.32 (m, 6H), 3.76-3.72 (m, 4H), 3.20-3.17 (m, 1H), 2.93-2.90 (m, 1H), 2.76-2.69 (m, 6H), 2.49-2.46 (m, 1H), 1.97-1.94 (m, 3H), 1.87-1.84 (m, 2H), 0.89 (t, J=6.5 Hz, 6H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([N+:11]([O-:13])=[O:12])=[CH:6][CH:5]=2.[Cl-].[CH:15](=[N+:22]([CH3:24])[CH3:23])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH3:23][N:22]([CH3:24])[CH:15]([C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[CH:8]=2)[NH:3][C:2]=1[CH3:1])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C[N+](C)=Cc1ccccc1
Reactant: Cc1cc2cc([N+](=O)[O-])ccc2[nH]1
Agent: [Cl-]
Product: Cc1[nH]c2ccc([N+](=O)[O-])cc2c1C(c1ccccc1)N(C)C

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 2-methyl-5-nitro-1H-indole and benzylidene-dimethyl-ammonium chloride, which had been prepared in accordance with example 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[N:7][C:6]2=[S:20].[CH3:21][I:22]>>[I-:22].[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N+:9]([CH3:13])=[C:8]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[N:7]=[C:6]2[S:20][CH3:21]
Reactant: COc1ccc2c(c1)c(=S)nc(-c1ccccc1)n2C
Reactant: CI
Product: COc1ccc2c(c1)c(SC)nc(-c1ccccc1)[n+]2C
Product: [I-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.00 g (3.54 mmol) 6-Methoxy-1-methyl-2-phenyl-1H-quinazolin-4-thione was slowly added to 5 ml (80 mmol) methyl iodide at 0° C. and stirred for 1 h at room temperature. The solution was filtrated and the residue washed with ethyl ether and dichloromethane.
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][S:11]2(=[O:17])=[O:16])[CH:7]=[C:6]([C:18](=[O:20])[CH3:19])[CH:5]=1.CO.O.[Li+].[OH-]>C1COCC1>[C:18]([C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][S:11]2(=[O:16])=[O:17])[CH:7]=1)[C:3]([OH:21])=[O:2])(=[O:20])[CH3:19]
Reactant: COC(=O)c1cc(C(C)=O)cc(N2CCCCS2(=O)=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1cc(C(=O)O)cc(N2CCCCS2(=O)=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.7 %

Procedure:
To a solution of 3-acetyl-5-(1,1-dioxo-1λ6-[1,2]thiazinan-2-yl)-benzoic acid methyl ester (100 mg, 0.32 mmol) in a mixture of THF (0.3 mL), MeOH (0.6 mL) and H2O (1.5 mL) was added LiOH (23.1 mg, 0.96 mmol) and the mixture was stirred at room temperature for 1 h. The mixture was concentrated and partitioned between ethyl acetate and H2O. The aqueous layer was washed with ethyl acetate twice and acidified with 1N HCl solution to pH around 2˜3. The aqueous layer was extracted with ethyl acetate 3 times and the combined organic layers were dried over sodium sulfate and concentrated under vacuum to give the title compound (93 mg): 1H NMR (CD3OD, 500 MHz) δ ppm 1.93-1.99 (2H, m), 2.31-2.37 (2H, m), 2.67 (3H, s), 3.27-3.30 (2H, m), 3.83 (2H, t, J=5 Hz), 8.13 (1H, m), 8.20 (1H, m), 8.52 (1H, m). HPLC retention time: 1.292 min (method A). MS (ESI) (M+Na)+ 320.14.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][C:7]1[N:11]([C:12]2[CH:13]=[CH:14][C:15]([C:20]([F:23])([F:22])[F:21])=[C:16]([CH:19]=2)[C:17]#[N:18])[N:10]=[N:9][N:8]=1>C1(C)C=CC=CC=1.CCOC(C)=O>[Cl:3][CH2:6][C:7]1[N:11]([C:12]2[CH:13]=[CH:14][C:15]([C:20]([F:23])([F:22])[F:21])=[C:16]([CH:19]=2)[C:17]#[N:18])[N:10]=[N:9][N:8]=1
Reactant: O=S(Cl)Cl
Reactant: N#Cc1cc(-n2nnnc2CO)ccc1C(F)(F)F
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: N#Cc1cc(-n2nnnc2CCl)ccc1C(F)(F)F
Temperature: 25 °C
Yield: 521 %

Procedure:
Thionyl chloride (4.25 g, 3.57 mmol) was added dropwise to a solution of 5-[5-(hydroxymethyl)-1H-tetrazol-1-yl]-2-(trifluoromethyl)benzonitrile (Intermediate 40, 8.0 g, 29.7 mmol) in toluene (200 mL) at 0° C. The reaction mixture was allowed to warm to room temperature and then heated to reflux for 4 hr. The mixture was diluted with EtOAc and washed with ice-water, and saturated NaHCO3, dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford the crude product. This was purified by column chromatography (100-200 mesh silica gel), eluting with 20%-40% ethyl acetate/pet ether to give the title compound (5.35 g) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([S:11][CH:12]([CH2:17][CH2:18][CH2:19][CH3:20])[C:13](OC)=[O:14])[N:4]=1.[H-].[Li+].[Al+3].[H-].[H-].[H-]>O1CCCC1>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([S:11][CH:12]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][OH:14])[N:6]=1
Reactant: CCCCC(Sc1nc(OC)cc(OC)n1)C(=O)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCC(CO)Sc1nc(OC)cc(OC)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.1 %

Procedure:
A tetrahydrofuran solution of methyl 2-(4,6-dimethoxy-2-Pyrimidinylthio)-hexanoate (3.2 g) was added dropwise to a tetrahydrofuran suspension of aluminum lithium hydride (0.7 g) under ice-cooling, followed by 30 minutes stirring at room temperature, addition thereto of water and removal therefrom of precipitates by filtration. Then tetrahydrofuran was distilled off form the reaction liquid under reduced pressure and the resulting residue was subjected to silica gel column chromatography, to obtain the desired 2-(4,6-dimethoxy-2-pyrimidinylthio)hexanol (2.7 g). nD 1.5303.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]2[CH2:13][CH2:12][CH2:11][S:10]2=[O:14])=[CH:4][N:3]=1.I.[N-:16]=[N+]=[N-].[Na+]>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][CH:9]2[CH2:13][CH2:12][CH2:11][S:10]2(=[O:14])=[NH:16])=[CH:6][CH:7]=1
Reactant: O=S1CCCC1Cc1ccc(Cl)nc1
Reactant: [N-]=[N+]=[N-]
Agent: I
Agent: [Na+]
Product: N=S1(=O)CCCC1Cc1ccc(Cl)nc1

Procedure:
2-[(6-Chloropyridin-3-yl)methyl]tetrahydro-1H-1λ4-thiophen-1-imine-1-oxide was prepared from 2-chloro-5-[(1-oxidotetrahydrothien-2-yl)methyl]-pyridine by the method as described in Example I-H using NaN3 as the iminating agent.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[CH2:11]([O:13][C:14]1[C:19]([C:20]2([OH:33])[C:28]3[C:23](=[CH:24][C:25]([F:31])=[C:26]([C:29]#[N:30])[CH:27]=3)[NH:22][C:21]2=[O:32])=[CH:18][CH:17]=[CH:16][N:15]=1)[CH3:12]>N1C=CC=CC=1.ClCCl>[C:29]([C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][C:25]=1[F:31])[N:22]([C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3])[C:21](=[O:32])[C:20]2([C:19]1[C:14]([O:13][CH2:11][CH3:12])=[N:15][CH:16]=[CH:17][CH:18]=1)[O:33][C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3])#[N:30]
Reactant: CCOc1ncccc1C1(O)C(=O)Nc2cc(F)c(C#N)cc21
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOc1ncccc1C1(OC(=O)Oc2ccccc2)C(=O)N(C(=O)Oc2ccccc2)c2cc(F)c(C#N)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.7 %

Procedure:
330 μl (2.62 mmol) of phenyl chloroformate were slowly added dropwise to a solution, cooled to 0° C., of 342 mg (0.66 mmol; 60% purity) of 3-(2-ethoxypyridin-3-yl)-6-fluoro-3-hydroxy-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile (mother liquor from example a.2) in 8 ml of pyridine, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and extracted with water. The organic phase was washed with water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (Redisep cartridge, mobile phase gradient from 0 to 5% methanol in dichloromethane). 291 mg of the title compound were obtained.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:34]=[CH:33][C:11]3[NH:12][C:13]([C:15]4[C:23]5[C:18](=[CH:19][CH:20]=[C:21]([N+:24]([O-])=O)[CH:22]=5)[N:17]([CH:27]5[CH2:32][CH2:31][CH2:30][CH2:29][O:28]5)[N:16]=4)=[N:14][C:10]=3[CH:9]=2)[CH2:4][CH2:3]1.[H][H]>C(O)C.[Pd]>[CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:34]=[CH:33][C:11]3[NH:12][C:13]([C:15]4[C:23]5[C:18](=[CH:19][CH:20]=[C:21]([NH2:24])[CH:22]=5)[N:17]([CH:27]5[CH2:32][CH2:31][CH2:30][CH2:29][O:28]5)[N:16]=4)=[N:14][C:10]=3[CH:9]=2)[CH2:4][CH2:3]1
Reactant: CC1CCN(c2ccc3[nH]c(-c4nn(C5CCCCO5)c5ccc([N+](=O)[O-])cc45)nc3c2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC1CCN(c2ccc3[nH]c(-c4nn(C5CCCCO5)c5ccc(N)cc45)nc3c2)CC1
Yield: 80.3 %

Procedure:
3-(5-(4-Methylpiperidin-1-yl)-1H-benzo[d]imidazol-2-yl)-5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (100 mg, 0.217 mmol) was added to 10% Pd/C (2.302 mg, 0.022 mmol) in ethanol (25 mL) and then hydrogen gas (60 psi) was applied for 8 h at room temperature. The reaction mixture was filtered through Celite, and the solvent was removed in vacuo. Purification by flash chromatography (5% CH3OH/CH2Cl2) afforded the title compound (75 mg) as a solid. 1H NMR: (400 MHz, CD3OD): δ 7.66 (d, 1H, J=2.0 Hz), 7.51 (m, 2H), 7.17 (bs, 1H), 7.05-7.00 (m, 2H), 5.78 (dd, 1H, J=2.4 & 9.2 Hz), 3.98 (m, 1H), 3.78 (m, 1H), 3.56 (m, 2H), 2.67 (m, 3H), 2.14-2.03 (m, 2H), 1.76 (m, 3H), 1.65 (m, 2H), 1.40 (m, 3H), 0.98 (d, 3H, J=6.0 Hz); ESI-MS [M+H]+: 431.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:8]=[C:9]([C:14]([OH:16])=O)[S:10][C:11]=1[O:12][CH3:13].[NH2:18][C@@H:19]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=1)[CH2:20][N:21]1[C:29](=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]1=[O:31].CC(OC(N[C@H](C(O)=O)CC1C=CC=CC=1C(F)(F)F)=O)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:8]=[C:9]([C:14]([NH:18][C@@H:19]([CH2:32][C:33]2[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=2)[CH2:20][N:21]2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]2=[O:31])=[O:16])[S:10][C:11]=1[O:12][CH3:13]
Reactant: COc1sc(C(=O)O)cc1-c1c(Cl)cnn1C
Reactant: N[C@@H](Cc1ccc(F)cc1)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C(F)(F)F)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1sc(C(=O)N[C@@H](Cc2ccc(F)cc2)CN2C(=O)c3ccccc3C2=O)cc1-c1c(Cl)cnn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.6 %

Procedure:
To a 50 mL round-bottomed flask was added 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-(methyloxy)-2-thiophenecarboxylic acid (208 mg, 0.76 mmol) [prepared according to the procedure of Example 188], 2-[(2S)-2-amino-3-(4-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (257 mg, 0.77 mmol) [prepared according to the procedure of Preparation 6, except substituting N-{[(1,1-dimethylethyl)oxy]carbonyl}-4-fluoro-L-phenylalanine (4.95 g, 17.5 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (435 mg, 0.93 mmol) in chloroform (7.6 mL). DIEA (670 μL, 3.84 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (238 mg, 0.43 mmol, 56%): LC-MS (ES) m/z=553 (M+H)+.
Reaction SMILES: C(C1C=C(C2ON=C(C3C=C(C)C(OCC(O)CNC(=O)CO)=C(C)C=3)N=2)C=CC=1)=O.[CH:32]([C:34]1[CH:35]=[C:36]([CH:40]=[C:41]([CH2:43][CH3:44])[CH:42]=1)[C:37]([OH:39])=O)=[O:33].[CH2:45]([C:47]1[CH:62]=[C:61]([C:63](=[NH:66])[NH:64]O)[CH:60]=[C:59]([CH3:67])[C:48]=1[O:49][CH2:50][C@@H:51]([OH:58])[CH2:52][NH:53][C:54](=[O:57])[CH2:55][OH:56])[CH3:46]>>[CH2:45]([C:47]1[CH:62]=[C:61]([C:63]2[N:66]=[C:37]([C:36]3[CH:40]=[C:41]([CH2:43][CH3:44])[CH:42]=[C:34]([CH:32]=[O:33])[CH:35]=3)[O:39][N:64]=2)[CH:60]=[C:59]([CH3:67])[C:48]=1[O:49][CH2:50][C@@H:51]([OH:58])[CH2:52][NH:53][C:54](=[O:57])[CH2:55][OH:56])[CH3:46]
Reactant: CCc1cc(C(=N)NO)cc(C)c1OC[C@@H](O)CNC(=O)CO
Reactant: CCc1cc(C=O)cc(C(=O)O)c1
Agent: Cc1cc(-c2noc(-c3cccc(C=O)c3)n2)cc(C)c1OCC(O)CNC(=O)CO
Product: CCc1cc(C=O)cc(-c2nc(-c3cc(C)c(OC[C@@H](O)CNC(=O)CO)c(CC)c3)no2)c1
Yield: 34.1 %

Procedure:
The title compound (538 mg) was prepared in analogy to rac-N-(3-{4-[5-(3-formyl-phenyl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-2-hydroxy-propyl)-2-hydroxy-acetamide, starting from 3-formyl-5-ethyl-benzoic acid (600 mg, 3.37 mmol) and N—((S)-3-[2-ethyl-4-(N-hydroxycarbamimidoyl)-6-methyl-phenoxy]-2-hydroxy-propyl)-2-hydroxy-acetamide (1096 mg, 3.37 mmol). LC-MS**: tR=0.74 min; [M+1]+=468.26; 1H NMR (D6-DMSO): δ 1.24 (t, J=7.5 Hz, 3H), 1.30 (t, J=7.5 Hz, 3H), 2.36 (s, 3H), 2.71-2.78 (m, 5H), 2.88 (q, J=7.8 Hz, 2H), 2.90 (s, 3H), 3.21-3.28 (m, 1H), 3.41-3.48 (m, 1H), 3.72-3.82 (m, 2H), 3.84 (s, 2H), 3.94-4.01 (m, 1H), 5.31 (br s, 1H), 5.55 (br s, 1H), 7.70 (t, J=6.0 Hz, 1H), 7.83 (s, 2H), 7.96 (s, 1H), 8.10 (s, 1H), 8.35 (s, 1H), 8.52 (s, 1H), 10.16 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.[C:12]1(OB(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].C(OC(=O)C)C.Cl>O>[C:12]1([C:2]2[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)c1cc(Br)ccc1O
Reactant: OB(O)Oc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)c1cc(-c2ccccc2)ccc1O
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 89.2 %

Procedure:
In 400 ml of water, 21.7 g of 5-bromosalicylic acid, 13.41 g of phenylboric acid and 15.28 g of potassium carbonate were dissolved. The solution was stirred at room temperature for 40 minutes. After the completion of the reaction was confirmed with TLC, the reaction liquid was poured into a mixed medium of diluted hydrochloric acidethyl acetate. The mixture was extracted, and the organic phase was collected and washed with saturated sodium chloride aqueous solution. After dried with magnesium sulfate, the liquid was concentrated to form a crude product. The product was recrystallized from acetonitrile to obtain 18.58 g of 5-phenylsalicylic acid in the form of colorless crystallites. The yield was 87%. The product was confirmed with NMR and mass spectroscopy.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].C(N(CC)CC)C.[S:12]1(=[O:18])(=[O:17])[CH:16]=[CH:15][CH2:14][CH2:13]1>C(O)C>[OH:4][CH2:3][CH2:2][NH:1][CH:14]1[CH2:15][CH2:16][S:12](=[O:18])(=[O:17])[CH2:13]1
Reactant: NCCO
Reactant: O=S1(=O)C=CCC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=S1(=O)CCC(NCCO)C1
Temperature: 78 °C

Procedure:
A mixture of 2-aminoethanol (310 mg, 5.08 mmol), triethylamine (514 mg, 5.08 mmol) and 2,3-dihydrothiophene 1,1-dioxide (200 mg, 1.693 mmol) in ethanol (3 mL) was heated up at 78° C. for 16 hours. TLC indicated the starting material was consumed and desired product was formed (30% methanol/ethyl acetate). The reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel chromatography with 0-35% methanol/ethyl acetate to provide the title compound as a colorless oil (260 mg, 86%). 1H NMR (400 MHz, CHLOROFORM-d) δ 3.78-3.56 (m, 3H), 3.38-3.21 (m, 2H), 3.14-3.00 (m, 1H), 2.94 (dd, J=13.3, 6.0 Hz, 1H), 2.85-2.68 (m, 2H), 2.53-2.34 (m, 1H), 2.22-2.03 (m, 1H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@H:8]1[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]1.[C:14]1(O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[O:13]([C@H:10]1[CH2:11][CH2:12][C@H:8]([O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)[CH2:9]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O[C@@H]1CC[C@H](OC2CCCCO2)C1
Reactant: Oc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1ccc(O[C@H]2CC[C@H](OC3CCCCO3)C2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.9 %

Procedure:
To a stirred solution of (1R,3S)-3-tetrahydropyranyloxycyclopentanol (2.00 g, 10.7 mmol), phenol (1.20 g, 12.0 mmol) and triphenylphosphine (3.20 g, 12.0 mmol) in dry THF (40 ml) cooled to 0° C. was added dropwise a solution of diethyl azodicarboxylate (2.60 g, 15.0 mmol) in dry THF (10 ml). The mixture was stirred for 1 h at room temperature and then the volatiles removed under reduced pressure. Chromatographic purification of the residue {SiO2, 150 g; hexane/ethyl acetate (20:1)} provided 2.16 g (77 %) of the title compound as a colorless oil: 1H NMR δ7.33-7.22 (m, 2H), 6.99-6.83 (m, 3H), 4.98-4.81 (m, 1H), 4.70-4.60 (m, 1H), 4.55-4.41 (m, 1H), 4.00-3.85 (m, 1H), 3.58-3.47 (m, 1H), 2.30-1.45 (m, 12H).
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]3([CH2:20][OH:21])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH:11]=[CH:10][C:9]=2[NH:22][C:23]([C:25]2[NH:26][CH:27]=[C:28]([C:30]#[N:31])[N:29]=2)=[O:24])=[CH:4][CH2:3]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>>[CH3:1][C:2]1([CH3:32])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]3([CH:20]=[O:21])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH:11]=[CH:10][C:9]=2[NH:22][C:23]([C:25]2[NH:26][CH:27]=[C:28]([C:30]#[N:31])[N:29]=2)=[O:24])=[CH:4][CH2:3]1
Reactant: CC1(C)CC=C(c2cc(C3(CO)CCOCC3)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Product: CC1(C)CC=C(c2cc(C3(C=O)CCOCC3)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Yield: 100.4 %

Procedure:
The title compound was prepared by the procedure of Example 21, step (a) using 4-cyano-1H-imidazole-2-carboxylic acid [2-(4,4-dimethyl-cyclohex-1-enyl)-4-(4-hydroxymethyl-tetrahydro-pyran-4-yl)-phenyl]-amide (as prepared in Example 25, 40.0 mg, 0.0921 mmol) and Dess-Martin periodinane (80.5 mg, 0.184 mmol). The title compound (40 mg, 100%) was obtained as a white solid and used in the next step without further purification. Mass spectrum (ESI, m/z): Calcd. for C25H28N4O3, 433.2 (M+H). found 433.4.
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][NH:8][C:9]2[CH:19]=[CH:18][C:12]([C:13]([O:15]CC)=[O:14])=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[K+].Cl>C(O)C.O>[CH:1]1([CH2:6][CH2:7][NH:8][C:9]2[CH:19]=[CH:18][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1ccc(NCCC2CCCC2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(NCCC2CCCC2)cc1

Procedure:
A solution of 2 g. of ethyl p-[2-(cyclopentyl)ethylamino]benzoate in 50 ml. of ethanol:water (9:1) containing 2 g. of potassium hydroxide is stirred at the reflux temperature under argon atmosphere for 3 hours. The chilled solution is acidified with concentrated hydrochloric acid, diluted with 45 ml. of water, and filtered to furnish 1.52 g. of white crystals. Recrystallization from ethanol/hexane provided product as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][N:10]=[C:11]3[CH:16]=[CH:15][C:14]([C:17]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=4)([C:19]4[N:23]([CH3:24])[CH:22]=[N:21][CH:20]=4)O)=[CH:13][C:12]=23)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+]>O.C1COCC1>[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([C:25]2[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=2)[C:19]2[N:23]([CH3:24])[CH:22]=[N:21][CH:20]=2)=[CH:13][C:12]=1[CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[OH:9]
Reactant: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2noc(-c3cccc(Cl)c3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cn1cncc1C(c1ccc(Cl)cc1)c1ccc(N)c(C(O)c2cccc(Cl)c2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 20.6 %

Procedure:
TiCl3 15% in water (35 ml) was added slowly to a mixture of (±)-3-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-2,1-benzisoxazole-5-methanol (prepared as described in WO 97/21701) (0.0111 mol) in THF (50 ml). The mixture was stirred at room temperature for 24 hours, basified with NaOH 3N, extracted with DCM, filtered over celite and pasted up with DCM. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated till dryness. The residue (4.4 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 96/4/0.1; 20–45 μm). Two pure fractions were collected and their solvents were evaporated, yielding 1.6 g F1 (34%) and 1 g of 2-amino-α-(3-chlorophenyl)-5-[(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-benzene methanol (21%). F1 was crystallized from acetonitrile and DIPE. The precipitate was filtered off, washed with diethyl ether and dried, yielding 0.8 g (16.5%) of [2-amino-5-[(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]phenyl](3-chlorophenyl)-methanone (intermediate 16), mp. 179° C.
Reaction SMILES: [CH3:1][C@H:2]1[O:7][CH2:6][C@@H:5]([CH3:8])[NH:4][CH2:3]1.[Cl:9][C:10]1[CH:15]=[C:14](Cl)[N:13]=[C:12]([NH:17][CH3:18])[N:11]=1.CCN(C(C)C)C(C)C>CC#N>[Cl:9][C:10]1[CH:15]=[C:14]([N:4]2[C@H:5]([CH3:8])[CH2:6][O:7][C@H:2]([CH3:1])[CH2:3]2)[N:13]=[C:12]([NH:17][CH3:18])[N:11]=1
Reactant: C[C@@H]1CO[C@H](C)CN1
Reactant: CNc1nc(Cl)cc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CNc1nc(Cl)cc(N2C[C@@H](C)OC[C@H]2C)n1

Procedure:
To a solution of (2R,5R)-2,5-dimethylmorpholine (400 mg, 3.47 mmol) and 4,6-dichloro-N-methyl-2-pyrimidinamine (742 mg, 4.17 mmol) in CH3CN (5 mL) stirred at room temperature was added Hunig's base (1.213 mL, 6.95 mmol). The reaction vessel was sealed and heated in Biotage Initiator using initial normal to 120° C. for 1 hour. After cooling the reaction, the mixture was concentrated under reduced pressure and the residue was added to a silica gel column and was eluted with Hex/EtOAc (10:1 to 3:1). Collected fractions:the first fraction was the starting material 4,6-dichloro-N-methyl-2-pyrimidinamine (300 mg), and the second fraction was the title compound (460 mg) as a light yellow solid. LC-MS (ES) m/z=257 [M+H]+.