Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]([O:15]CC)=[O:14])[N:10]=[N:9]2)=[CH:5][CH:4]=1.O[Li].O>CO.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]([OH:15])=[O:14])[N:10]=[N:9]2)=[CH:18][CH:19]=1
Reactant: CCOC(=O)c1cn(Cc2ccc(OC)cc2)nn1
Agent: [Li]O
Solvent: O
Solvent: CO
Product: COc1ccc(Cn2cc(C(=O)O)nn2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
To a mixture of ethyl 1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate (190.0 g, 0.73 mol) and MeOH/H2O (350 mL/100 mL) was added LiOH.H2O (42.0 g, 0.97 mol) in portions at 0° C. and the reaction mixture was stirred at room temperature overnight. The mixture was evaporated, the residue was diluted with water (250 mL), then extracted with Et2O (3×75 mL) to remove neutral impurities. The aqueous layer was adjusted to pH=3-4 with conc. HCl and the precipitate was filtered to afford the title compound (160 g, 94.0%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5](COCC[Si](C)(C)C)[C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([CH2:25][N:26]([CH3:28])[CH3:27])[CH:22]=[C:21]([C:29]#[N:30])[CH:20]=2)[C:12]=1[F:31])=[O:8].[C:40]([OH:46])([C:42]([F:45])([F:44])[F:43])=[O:41]>C(Cl)Cl>[F:43][C:42]([F:45])([F:44])[C:40]([OH:46])=[O:41].[Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([CH2:25][N:26]([CH3:28])[CH3:27])[CH:22]=[C:21]([C:29]#[N:30])[CH:20]=2)[C:12]=1[F:31])=[O:8]
Reactant: CN(C)Cc1cc(C#N)cc(Oc2c(Cl)ccc(CNC(=O)c3c(Cl)ncn3COCC[Si](C)(C)C)c2F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)Cc1cc(C#N)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36 %

Procedure:
To a solution of 4-chloro-N-{[4-chloro-3-({3-cyano-5-[(dimethylamino)methyl]phenyl}oxy)-2-fluorophenyl]methyl}-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (82 mg, 0.138 mmol) in DCM (6.0 ml) was added TFA (2.00 mL) and the reaction mixture was stirred ar RT for one hour. The solvent was removed and the crude material was purified via reverse phase HPLC to give 4-chloro-N-{[4-chloro-3-({3-cyano-5-[(dimethylamino)methyl]phenyl}oxy)-2-fluorophenyl]methyl}-1H-imidazole-5-carboxamide trifluoroacetate (29 mg, 0.050 mmol, 36% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.72 (s, 1H), 7.62 (s, 1H), 7.27-7.49 (m, 4H), 4.63 (s, 2H), 4.35 (s, 2H), 2.85 (s, 6H). LC-MS (ES+) m/z 462.08, [M+H].
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:14])[CH2:6][CH2:5]1.[CH3:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:23]=1[NH:29][C:30](=[O:33])[CH2:31]Cl>>[CH3:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:23]=1[NH:29][C:30]([CH2:31][NH:3][CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:14])[CH2:6][CH2:5]1)=[O:33]
Reactant: NC1CCN(CCCC(=O)c2ccccc2)CC1
Reactant: Cc1cccc(C)c1NC(=O)CCl
Agent: Cl
Product: Cc1cccc(C)c1NC(=O)CNC1CCN(CCCC(=O)c2ccccc2)CC1

Procedure:
4-Amino-1-(4-phenyl-4-oxobutyl) piperidine dihydrochloride (1.75g) was condensed with N-(2,6-dimethylphenyl) chloroacetamide (0.999) in the manner of Example 1 to give the title compound which was converted to the hydrochloride salt (1.85g), m.p. 276.8° Analysis: Found, C, 62.26; H, 7.48; N, 8.68; C25H33N3O2. 2HC1 requires C, 62.25; H, 7.34; N, 8.75%
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH2:12][C@@H:11]([NH:14][C:15](=[O:17])[CH3:16])[CH2:10]2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.N1(/[C:32](/[NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[N:33]\[C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])C=CC=N1>C1COCC1>[C:44]([O:43][C:42](=[O:48])[NH:41]/[C:32](/[NH:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:13][CH2:12][C@@H:11]([NH:14][C:15](=[O:17])[CH3:16])[CH2:10]2)=[CH:7][CH:8]=1)=[N:33]/[C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:47])([CH3:45])[CH3:46]
Reactant: CC(C)(C)OC(=O)/N=C(/NC(=O)OC(C)(C)C)n1cccn1
Reactant: CC(=O)N[C@@H]1CCN(c2ccc(N)cc2)C1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N[C@@H]1CCN(c2ccc(N/C(=N\C(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc2)C1
Yield: 69.8 %

Procedure:
N-[(3R)-1-(4-aminophenyl)pyrrolidin-3-yl]acetamide mono hydrochloride (Method 43; 2.47 g, 9.67 mmol) and Hunigs base (2.02 ml, 1.16 mmol) were reacted with di-tert-butyl [(Z)-1H-pyrazol-1-ylmethylylidene]biscarbamate (2.95 g, 9.5 mmol) in THF (50 ml) at room temperature for 72 hours. After evaporation under reduced pressure, chromatography on silica gel with EtOAc/isohexane (50:50 to 100) gave the title compound as a yellow oil (3.06 g, 69%). NMR: 1.39 (s, 9H), 1.52 (s, 9H), 1.81 (s, 3H), 1.82-1.93 (m, 1H), 2.11-2.24 (m, 1H), 3.00-3.08 (m, 1H), 3.21-3.51 (m, 3H), 4.29-4.40 (m, 1H), 6.50 (d, 2H), 7.29 (d, 2H), 8.12 (d, 1H), 9.74 (s, 1H), 11.49 (s, 1H); m/z 462.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH2:6][CH:7]=O)[CH2:3][CH:4]=O.[NH2:10][C:11]1[S:12][CH:13]=[C:14]([CH3:16])[N:15]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:9])[CH:6]=[CH:7][N:10]([C:11]2[S:12][CH:13]=[C:14]([CH3:16])[N:15]=2)[CH:4]=[CH:3]1
Reactant: Cc1csc(N)n1
Reactant: CC(C)(CC=O)CC=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: Cc1csc(N2C=CC(C)(C)C=C2)n1
Reaction time: 5 h

Procedure:
In 170 ml of benzene, 4.45 l g (0.035 mole) of 3,3-dimethylglutaraldehyde was combined with 3.96 (0.035 mole) of 2-amino-4-methylthiazole under nitrogen. The reaction mixture was brought to reflux and water azeotroped off via a Dean-Stark trap. After 21 hours 0.20 g (0.001 mole) of p-toluenesulfonic acid monohydrate was added to the reaction mixture and heating continued an additional 5 hours after which the solvent was evaporated in vacuo. The crude product was purified by silica gel flash chromatography eluting with a 1% ethyl acetate/hexane solution. The eluate was evaporated in vacuo to yield 2.67 g of the title compound as a clear liquid.
Reaction SMILES: [C:1]1([CH2:7][CH:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:10][CH:11]1[C:15](=[O:16])[C:14]([OH:17])=[C:13]([CH3:18])[O:12]1.B(O)(O)O>>[OH:9][CH:8]([C:13]1([CH3:18])[C:14](=[O:17])[C:15]([OH:16])=[C:11]([CH3:10])[O:12]1)[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=CCc1ccccc1
Reactant: CC1=C(O)C(=O)C(C)O1
Agent: OB(O)O
Product: CC1=C(O)C(=O)C(C)(C(O)Cc2ccccc2)O1
Temperature: 80 °C
Reaction time: 3 h
Yield: 23 %

Procedure:
To a mixture of 6 g (0.05 mole) phenylacetaldehyde and 1.28 g (0.01 mole) of 2.5-dimethyl-4-hydroxy-3-(2H)-furanone was added 60 mg of boric acid and the mixture was stirred at 80°C for 3 hours. After working up the reaction mixture as described earlier, 0.57 g (23%) of the title compound was obtained, with melting point 157.5°-159°C.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([SH:10])[CH2:8][CH3:9].[CH2:11]([N:16]1[CH2:20][C:19]2[CH:21]=[CH:22][CH:23]=[C:24](Cl)[C:18]=2[S:17]1(=[O:27])=[O:26])[CH2:12][CH2:13][CH2:14][CH3:15].O>CN(C)C=O>[CH2:11]([N:16]1[CH2:20][C:19]2[CH:21]=[CH:22][CH:23]=[C:24]([S:10][CH2:7][CH2:8][CH3:9])[C:18]=2[S:17]1(=[O:27])=[O:26])[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCN1Cc2cccc(Cl)c2S1(=O)=O
Reactant: CCCS
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCN1Cc2cccc(SCCC)c2S1(=O)=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5.0 g of potassium-t-butoxide in 40 ml of dry dimethylformamide was added 4.0 ml of propyl mercaptan at -5° C. to 0° C. under an inert atmosphere followed by 11.0 g of 2-pentyl-7-chloro-2,3-dihydro-1,2-benzisothiazole-1,1-dioxide. The mixture was stirred at room temperature for 16 hours, poured into water and extracted with n-butyl chloride. The extract was washed with water and brine, dried over MgSO4 and concentrated to give 10.3 g of the title compound as a yellow oil.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[C:4]1[N:9]=[CH:8][C:7]([C:10]#[N:11])=[CH:6][CH:5]=1.[OH:12][C@H:13]([C:21]1[CH:30]=[CH:29][C:24]2[C:25](=[O:28])[O:26][CH2:27][C:23]=2[C:22]=1[CH3:31])[CH2:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>CCO>[OH:1][CH:2]([C:4]1[N:9]=[CH:8][C:7]([C:10]#[N:11])=[CH:6][CH:5]=1)[CH2:3][N:18]1[CH2:19][CH2:20][N:15]([CH2:14][C@H:13]([OH:12])[C:21]2[CH:30]=[CH:29][C:24]3[C:25](=[O:28])[O:26][CH2:27][C:23]=3[C:22]=2[CH3:31])[CH2:16][CH2:17]1
Reactant: Cc1c([C@@H](O)CN2CCNCC2)ccc2c1COC2=O
Reactant: N#Cc1ccc(C2CO2)nc1
Solvent: CCO
Product: Cc1c([C@@H](O)CN2CCN(CC(O)c3ccc(C#N)cn3)CC2)ccc2c1COC2=O
Temperature: 140 °C

Procedure:
To a microwave tube were added isomer B of 6-(oxiran-2-yl)pyridine-3-carbonitrile (330 mg, 2.26 mmol), 5-[(1R)-1-hydroxy-2-(piperazin-1-yl)ethyl]-4-methyl-2-benzofuran-1(3H)-one (686 mg, 2.48 mmol, as a free base), and EtOH (7.0 mL). The mixture was heated in the microwave for 60 min at 140° C. The solvent was evaporated and the crude product was purified by silica gel MPLC (0->10% CH2CH2:MeOH) to provide 6-(1-Hydroxy-2-{4-[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)pyridine-3-carbonitrile as a single isomer. Further, the product was treated with 1 M HCl in diethyl ether to give the final product as an HCl salt. 1H NMR (500 MHz, DMSO-d6), δ 8.92 (s, 1H), 8.28 (dd, J=1.9 Hz, J=2.0 Hz, 1H), 7.68-7.63 (m, 3H), 5.48 (d, J=4.8 Hz, 1H), 5.37 (d, J=2.2 Hz, 2H), 5.20 (d, J=3.9 Hz, 1H), 5.03 (m, 1H), 4.78 (m, 1H), 2.64 (dd, J=4.1, 1H), 2.55-2.41 (m, 8H), 2.33 (dd, J=3.7 Hz, 1H), 2.24 (s, 3H); LC/MS: (IE, m/z) [(M+1)]+=423.04 (57A). The isomer corresponding to inversion of the benzylic hydroxyl stereocenter was also prepared in a similar fashion starting with isomer A of 6-(oxiran-2-yl)pyridine-3-carbonitrile (57B):
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)=[O:9])[C:5]([CH3:20])=[CH:4][N:3]=1.[F:21][C:22]([F:29])([F:28])[C:23]1[CH:27]=[CH:26][NH:25][N:24]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:20][C:5]1[C:6]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)=[O:9])=[N:7][C:2]([N:25]2[CH:26]=[CH:27][C:23]([C:22]([F:29])([F:28])[F:21])=[N:24]2)=[N:3][CH:4]=1
Reactant: FC(F)(F)c1cc[nH]n1
Reactant: Cc1cnc(Cl)nc1C(=O)c1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cnc(-n2ccc(C(F)(F)F)n2)nc1C(=O)c1cccc(C(F)(F)F)c1
Yield: 16.3 %

Procedure:
The title compound of Step A (0.6 g, 2 mmol), 3-trifluoromethylpyrazole (0.25 g), and potassium carbonate (0.8 g, 6 mmol) were suspended in acetonitrile (15 mL) and heated at reflux for 3 h. The cooled reaction mixture was filtered and the cake washed with acetonitrile. After evaporation of the solvent under reduced pressure, the residue was subjected to silica gel chromatography using hexanes/ethyl acetate (85:15) to give 0.12 g of the title compound of Step B, a compound of the invention, as a white solid. 1H NMR (CDCl3/200 MHz) 2.45 (s, 3H), 6.75 (d, 1H), 7.67 (d, 1H), 7.92 (d, 1H), 8.10 (s, 1H), 8.27 (s, 1H), 8.54 (d, 1H), 8.9 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:16])=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].C([O-])(=O)C.[Na+].[I:22]Cl.S(=O)(O)[O-].[Na+]>O.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([I:22])[C:5]([OH:16])=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8]
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1O
Reactant: ClI
Agent: CC(=O)[O-]
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C(c1ccccc1)c1cc(Cl)cc(I)c1O
Reaction time: 0.08 h

Procedure:
Add 5-chloro-2-hydroxybenzophenone (23.2 g., 0.1 mole) to acetic acid (150 ml.) and sodium acetate (9.3 g., 0.11 mole). Treat the mixture with iodine monochloride (16.5 g., 0.1 mole) and warm in a bath at 70°-85° for one hour. Cool and add 20 ml. of sodium bisulfite solution and then more water. After stirring for five minutes, collect and dry the title compound; m.p. 110°-111° C.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]=1[CH2:15][OH:16].Cl[C:18]1[N:23]=[C:22]([C:24]([O:26][CH3:27])=[O:25])[CH:21]=[CH:20][CH:19]=1.O>O1CCCC1>[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]=1[CH2:15][O:16][C:18]1[N:23]=[C:22]([C:24]([O:26][CH3:27])=[O:25])[CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)c1cccc(Cl)n1
Reactant: Cc1oc(-c2ccccc2)nc1CO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cccc(OCc2nc(-c3ccccc3)oc2C)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 50.8 %

Procedure:
Sodium hydride (60%, oily, 1.80 g) was added to a solution of 5-methyl-2-phenyl-4-oxazolylmethanol (8.51 g) in tetrahydrofuran (100 ml) at 0° C., which was stirred at room temperature for 15 minutes. A solution of methyl 6-chloro-2-pyridinecarboxylate (7.72 g) in tetrahydrofuran (75 ml) was added to the mixture. After being stirred at 40° C. for 5 hours, the reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated to obtain methyl 6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-2-pyridinecarboxylate (7.41 g, yield 51%) as yellow crystals. This was recrystallized from ethyl acetate-hexane. Melting point: 97–98° C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][OH:9])=[CH:4][CH:3]=1.[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>O.C(Cl)Cl>[O:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[O:9][CH2:8][CH2:7][O:6][C:5]1[CH:10]=[CH:11][C:2]([Br:1])=[CH:3][CH:4]=1
Reactant: OCCOc1ccc(Br)cc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: Brc1ccc(OCCOC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a mixture of 12.0 g (55.4 mmol) 2-(4-bromophenoxy)ethanol, 100 ml dry methylene chloride and 5.1 g (60.9 mmol) dihyropyran is added, at RT, 0.42 g (2.2 mmol) p-toluenesulfonic acid.water. The mixture is stirred for 3 days at RT, after which 50 ml methylene chloride, 50 ml water and 10 ml aqueous 15% potassium carbonate are added. The organic phase is separated and washed with water (60 ml) and with saturated aqueous sodium chloride, and is then dried over calcium sulfate. Solvent is removed by rotary evaporation to yield 4-(2-tetrahydropyranyloxyethoxy)bromobenzene.
Reaction SMILES: C([NH:8][C:9]1[C:18]([F:19])=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([Br:20])[CH:10]=1)C1C=CC=CC=1.[H][H]>C(O)(=O)C.[Pd].CO>[NH2:8][C:9]1[C:18]([F:19])=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([Br:20])[CH:10]=1
Reactant: COC(=O)c1cc(F)c(NCc2ccccc2)cc1Br
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1cc(F)c(N)cc1Br
Yield: 73.8 %

Procedure:
A suspension of the methyl 4-(benzylamino)-2-bromo-5-fluorobenzoate (2.4 g, 7.10 mmol) in acetic acid was treated with 10% palladium on charcoal (250 mg) and stirred at room temperature under 2 bar hydrogen for 18 hours. The reaction mixture was then diluted with methanol, filtered through celite and evaporated to low volume. The residue was suspended in water (50 mL) and basified with 5% sodium carbonate solution then was extracted with ethyl acetate (2×). The combined organic phases were dried (sodium sulfate) and evaporated to a sandy solid. This crude solid was dissolved in the methanol and passed down an SCX cartridge. Evaporation of the methanol eluents gave the title compound (1.3 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([N+:11]([O-])=O)[CH:5]=1.O.O.Cl[Sn]Cl>C(O)C>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([NH2:11])[CH:5]=1
Reactant: COC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: COC(=O)c1ccc(Cl)c(N)c1
Temperature: 80 °C

Procedure:
To a solution of 4-Chloro-3-nitro-benzoic acid methyl ester (5.0 g, 23.19 mmol) in 100 ml of ethanol was added SnCl2.2H2O (26.0 g, 115.96 mmol) and the reaction mixture was heated at 80° C. for 2 h. After the completion of the reaction mixture (TLC monitoring), the reaction mixture was evaporated to dryness under reduced pressure. Water (100 mL) was added, basified the reaction mixture with NaOH solution and extracted with hot EtOAc (3×250 mL).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].O1CCCC1.[BH4-].[Na+]>C(O)C>[OH:3][CH:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)[CH3:2]
Reactant: CC(=O)c1ccc(-c2ccc(C(=O)OCc3ccccc3)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(O)c1ccc(-c2ccc(C(=O)OCc3ccccc3)cc2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
33.0 g (0.1 mol) of benzyl 4'-acetyl-4-biphenylcarboxylate, 200 ml of tetrahydrofuran and 50 ml of ethanol were supplied into the same flask as used in Example 9. Then 3.8 g (0.1 mol) of sodium borohydride was added at 15°-25° C. over a period of 10 minutes. After standing at the same temperature for 2 hours, the reaction solution was poured into ice-water and extracted twice with 300 ml of chloroform. The organic layer was washed with water and concentrated under reduced pressure to obtain 32.9 g (99% yield) of benzyl 4'-(1-hydroxyethyl)-4-biphenylcarboxylate (III-15).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[OH:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C:13]2[CH:14]=[CH:15][C:10]([OH:9])=[CH:11][CH:12]=2)=[N:3][CH:4]=1
Reactant: OB(O)c1ccc(O)cc1
Reactant: Clc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Oc1ccc(-c2ccc(Cl)cn2)cc1
Yield: 93 %

Procedure:
Palladium(0),tetrakis(triphenylphosphine) (4.69 g, 4.05 mmol) was added to a stirred suspension of 2,5-dichloropyridine (12.0 g, 81.08 mmol), 4-hydroxybenzene boronic acid (11.2 g, 81.1 mmol) and potassium carbonate (11.2 g, 81.1 mmol) in dioxane (100 mL) and water (100 mL). The mixture was refluxed for 2 hours, then partitioned between diethyl ether (100 mL) and water (100 mL). The organics were washed with brine (100 mL), dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with 4% methanol in dichloromethane, to afford the title compound as an off-white solid (15.5 g, 81%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][NH2:12])=[CH:8][CH:9]=2)[CH:4]=[N:3][CH:2]=1.Br[C:14]1[C:15]([NH2:21])=[N:16][CH:17]=[C:18]([Br:20])[N:19]=1.C(N(C(C)C)CC)(C)C>CCCCO>[Br:20][C:18]1[N:19]=[C:14]([NH:12][CH2:11][C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[N:1]=[CH:2][N:3]=[CH:4]3)[C:15]([NH2:21])=[N:16][CH:17]=1
Reactant: NCc1ccc2ncncc2c1
Reactant: Nc1ncc(Br)nc1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Nc1ncc(Br)nc1NCc1ccc2ncncc2c1
Temperature: 120 °C
Yield: 38.9 %

Procedure:
To the solution of C-quinazolin-6-yl-methylamine (1.2 g, 7.916 mmol) and 2.06 gram of 3,5-dibromo-pyrazin-2-ylamine (2.06 g, 7.916 mmol) in n-BuOH (18 mL) was added diisopropylethylamine (7.0 mL, 40 mmol) at room temperature. The reaction mixture was heated up to 120° C. for two days under nitrogen. The reaction was cooled down, n-BuOH is evaporated directly via rotavapor, followed by purification via a silica gel column to get 5-Bromo-N*3*-quinazolin-6-ylmethyl-pyrazine-2,3-diamine (1.02 g, yield 42%).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[Cl:5][C:6]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:7]=1[CH:8]=[CH:9][S:10]([N:13]=[C:14]([O-])[CH2:15]Cl)(=[O:12])=[O:11]>>[CH:1]1([NH:4][C:14](=[N:13][S:10]([CH:9]=[CH:8][C:7]2[C:18]([Cl:22])=[CH:19][CH:20]=[CH:21][C:6]=2[Cl:5])(=[O:12])=[O:11])[CH3:15])[CH2:3][CH2:2]1
Reactant: O=S(=O)(C=Cc1c(Cl)cccc1Cl)N=C([O-])CCl
Reactant: NC1CC1
Product: CC(=NS(=O)(=O)C=Cc1c(Cl)cccc1Cl)NC1CC1

Procedure:
Reaction of Cyclopropylamine with N-(2,6-dichlorostyrylsulfonyl)chloroacetimidate according to the procedure of Example 32(b) affords N-cyclopropyl-N'-(2,6-dichlorostyrylsulfonyl) acetamidine, m.p. 121°-124° C. when crystallized from benzene.
Reaction SMILES: [Cl:1][C:2]1[C:3](O)=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.C(#N)C.P(Cl)(Cl)([Cl:17])=O>O>[Cl:17][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([N+:8]([O-:10])=[O:9])=[CH:5][N:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cnc(O)c(Cl)c1
Solvent: CC#N
Solvent: O
Product: O=[N+]([O-])c1cnc(Cl)c(Cl)c1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
A mixture of 3-chloro-2-hydroxy-5-nitropyridine (36.0 g), acetonitrile (72 mL), and phosphorus oxychloride (37.5 g) was heated to 80° C. The reaction was then stirred at this temperature for about 15 hours. After cooling the reaction to 40° C., water (27 g) was added, while maintaining the temperature below 70° C. The temperature was adjusted to 45° C. and then more water (189 g) was added slowly. The reaction was then cooled to 23° C., stirred for at least 12 hours, and then filtered. After washing the wet cake with water, the product was dried in a vacuum oven. 1H NMR (400 MHz/CDCl3) δ 9.10 (d, J=2.5 Hz, 1H), 8.56 (d, J=2.4 Hz, 1H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.O.[I:10]I.C(=O)(O)[O-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([I:10])[CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: II
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Oc1ccc(Cl)cc1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 7 %

Procedure:
To a solution of 4-chlorophenol in THF (75 mL), and H2O (75 mL) was added a mixture of crushed iodine (78.7 mmol, 20 g) and sodium bicarbonate (78.7 mmol, 6.6 g). The reaction mixture was stirred at room temperature overnight, then quenched with sufficient 5% sodium thiosulfate solution to turn the color of the reaction mixture from deep violet to light yellow and extracted with ether (2×200 mL). The ether layer was collected, washed with H2O, and the washed ether layer was dried, filtered and the filtrate was evaporated to a crude product, which was purified by distillation to obtain 4-chloro-2-iodo phenol (7%, 1.3 g); mp 79° C.-82° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@@H:9]1[C@@H:14]([OH:37])[C@H:15]([N:23]=[C:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:38][CH:39]([CH3:46])[CH2:40][CH2:41][CH2:42][C:43](O)=[O:44].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.CN(C1C=CC=CN=1)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:43](=[O:44])[CH2:42][CH2:41][CH2:40][CH:39]([CH3:46])[CH3:38])[CH2:10][C@@H:9]1[C@@H:14]([OH:37])[C@H:15]([N:23]=[C:24]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)CCCC(=O)O
Reactant: CC(C)(C)OC(=O)N1CCNC[C@@H]1[C@@H](O)[C@@H](Cc1ccccc1)N=C(c1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)CCCC(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H]([C@@H](O)[C@@H](Cc2ccccc2)N=C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.5 %

Procedure:
Dissolve (2-(R)-[2-(R)-(benzhydrylidene-amino)-1-(S)-hydroxy-3-phenylpropyl]-piperazine-1-carboxylic acid tert-butyl ester (110 mg, 0.22 mmol) in 2.2 ml of dichloromethane and react with 5-methylhexanoic acid (28.6 mg, 0.22 mmol), EDCI (50.6 mg, 0.26 mmol), HOBT (35.6 mg, 0.26 mmol), triethylamine (0.09 ml, 0.66 mmol) and dimethylaminopyridine (2.6 mg, 0.02 mmol). Stir at room temperature overnight. Dilute with CH2Cl2, and wash with 5%NaHCO3 and saturated aqueous sodium chloride. Dry organic layers with MgSO4 and remove the solvent under reduced pressure. Subject residue to silica gel chromatography, eluting with hexanes/ethyl acetate/triethylamine 67:32:1 to obtain 103 mg (76% yield) of the desired product.