Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][C:11]([CH:13]=O)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH:15]1[CH:19]=[C:18]([CH2:20][CH2:21][N:22]2[C:26](=[O:27])[CH2:25][NH:24][C:23]2=[S:28])[N:17]=[CH:16]1.N1CCCCC1>ClCCl>[NH:15]1[CH:19]=[C:18]([CH2:20][CH2:21][N:22]2[C:26](=[O:27])/[C:25](=[CH:13]/[C:11]3[O:12][C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([I:1])[CH:3]=4)=[CH:9][CH:10]=3)/[NH:24][C:23]2=[S:28])[N:17]=[CH:16]1
Reactant: O=Cc1ccc(-c2cccc(I)c2)o1
Reactant: O=C1CNC(=S)N1CCc1c[nH]cn1
Solvent: C1CCNCC1
Solvent: ClCCl
Product: O=C1/C(=C/c2ccc(-c3cccc(I)c3)o2)NC(=S)N1CCc1c[nH]cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 51 %

Procedure:
5-(3-Iodophenyl)furan-2-carbaldehyde (30 mg, 0.1 mmol) synthesized by the same method as in Example 1 and 3-(2-(1H-imidazol-4-yl)ethyl)-2-thioxoimidazolidin-4-one (21 mg, 0.1 mmol) were dissolved in dichloromethane (7 mL), piperidine (20 μL) was added thereto, and the mixture was stirred at room temperature (25° C.) for 3 hours. After the reaction was completed the solvent was removed by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography using chloroform/methanol (9/1 (volume ratio)) as an eluent, to give compound 3 in a yield of 25 mg (yield 51.0%).
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[NH2:7][C:8]1[CH:9]=[C:10]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:12]>N1C=CC=CC=1>[CH2:1]([S:3]([NH:7][C:8]1[CH:9]=[C:10]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:12])(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)Cl
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Solvent: c1ccncc1
Product: CCS(=O)(=O)Nc1cc(C(=O)Nc2ccccc2)ccc1OC
Yield: 90.4 %

Procedure:
Prepared according to the procedure described for Example 121 using ethanesulfonyl chloride (1.5 mL, 15.8 mmol), 3-amino-4-methoxy-N-phenyl-benzamide (2.43 g. 10 mmol) and pyridine (25 mL) to afford the product (3.023 g); m.p. 175-177° C. after trituration in hexanes/ethyl acetate (1:1).
Reaction SMILES: C([C:3]1[CH:4]=[C:5]([N:16]2[CH2:20][C@H:19]([CH2:21][NH:22][C:23](=[O:25])[CH3:24])[O:18][C:17]2=[O:26])[CH:6]=[CH:7][C:8]=1[C:9]1[CH2:14][CH2:13]S[C:11](=[O:15])[CH:10]=1)C.C(N)(=[O:29])C>>[O:29]=[C:11]1[CH:10]=[C:9]([C:8]2[CH:3]=[CH:4][C:5]([N:16]3[CH2:20][C@H:19]([CH2:21][NH:22][C:23](=[O:25])[CH3:24])[O:18][C:17]3=[O:26])=[CH:6][CH:7]=2)[CH2:14][CH2:13][O:15]1
Reactant: CC(N)=O
Reactant: CCc1cc(N2C[C@H](CNC(C)=O)OC2=O)ccc1C1=CC(=O)SCC1
Product: CC(=O)NC[C@H]1CN(c2ccc(C3=CC(=O)OCC3)cc2)C(=O)O1

Procedure:
N-((5S)-3-(3-ethyl-4-(2-oxo-5,6-dihydrothiapyran-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide and N-(5S)-3-(3-hydroxy-4-(2-oxo-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide are excluded.
Reaction SMILES: [C:1]([O:4][C@H:5]([CH3:25])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:15](=[O:16])[C:14]2[C:17](=[O:22])[CH:18]=[C:19]([CH3:21])[NH:20][C:13]=2[N:12]([CH3:23])[C:11]1=[O:24])(=[O:3])[CH3:2].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([O:4][C@H:5]([CH3:25])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:15](=[O:16])[C:14]2[C:17](=[O:22])[CH:18]=[C:19]([CH3:21])[N:20]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:13]=2[N:12]([CH3:23])[C:11]1=[O:24])(=[O:3])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(=O)cc(C)[nH]c2n(C)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(=O)cc(C)n(Cc3ccccc3)c2n(C)c1=O
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A mixture of (R)-3-(5-acetoxyhexyl)-1,7-dimethylpyrido[2,3-d]pyrimidine-2,4,5(1H,3H,8H)-trione (1.84 g, 5.27 mmol), acetonitrile (20 ml), benzyl bromide (0.95 ml, 7.91 mmol) and potassium carbonate (2.19 g, 15.8 mmol) was stirred at 50° C. for 2 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was treated with water (50 ml) and extracted with ethyl acetate (50 ml). The organic extract was concentrated under reduced pressure to afford crude (R)-3-(5-acetoxyhexyl)-8-benzyl-1,7-dimethylpyrido[2,3-d]pyrimidine-2,4,5(1H,3H,8H)-trione.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)[CH2:6][NH:7][CH2:8][CH3:9].F[C:20]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:21]=1[CH:22]=[O:23].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.[Cl-].[Na+].O>[F:1][C:2]([F:17])([F:18])[C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)[CH2:6][N:7]([CH2:8][CH3:9])[C:20]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:21]=1[CH:22]=[O:23]
Reactant: CCNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=Cc1cc(C(F)(F)F)ccc1F
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccc(C(F)(F)F)cc1C=O
Temperature: 90 °C
Reaction time: 8 h
Yield: 16.7 %

Procedure:
(3,5-Bis-trifluoromethyl-benzyl)-ethyl-amine (1.03 g) is dissolved in N,N-dimethylformamide (10 ml), and thereto are added 2-fluoro-5-trifluoromethyl-benzaldehyde (1.45 g) and potassium carbonate (1.48 g), and the mixture is stirred under nitrogen atmosphere at 90° C. for 3 hours and at room temperature overnight. To reaction mixture is added a saturated brine and water, and the mixture is extracted five times with ethyl acetate and the organic layer is washed twice with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to give 2-[(3,5-bis-trifluoromethyl-benzyl)-ethyl-amino]-5-trifluoromethyl-benzaldehyde (282 mg). MS (m/z): 444 [M+H]+
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][CH:13]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[O:22][CH3:23])[CH2:15][CH2:14]1)[CH:6]=[CH:5]2.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[N:26]=1>>[CH3:23][O:22][C:20]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:21]=1[CH:13]([NH:12][C:7]1[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([NH:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[N:26]=4)[CH:3]=3)[N:8]=1)[CH2:14][CH2:15]2
Reactant: Cc1cccc(N)n1
Reactant: COc1cccc2c1C(Nc1ccc3cc(Br)ccc3n1)CC2
Product: COc1cccc2c1C(Nc1ccc3cc(Nc4cccc(C)n4)ccc3n1)CC2

Procedure:
The title compound, yellow foam, MS: m/e=397.3 (M+H+), was prepared in accordance with the general method of example 66 from rac-(6-bromo-quinolin-2-yl)-(7-methoxy-indan-1-yl)-amine (see example 91, step A) and commercially available 2-amino-6-methyl-pyridine.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[SH:6].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([S:21]([NH:24][CH:25]([CH2:30][CH:31]3[O:33][CH2:32]3)[C:26]([O:28]C)=[O:27])(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1>>[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]([S:21]([NH:24][CH:25]([CH2:30][CH:31]([OH:33])[CH2:32][S:6][C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)[C:26]([OH:28])=[O:27])(=[O:22])=[O:23])=[CH:19][CH:20]=2)=[CH:13][CH:14]=1
Reactant: COC(=O)C(CC1CO1)NS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1
Reactant: Sc1cccs1
Product: COc1ccc(-c2ccc(S(=O)(=O)NC(CC(O)CSc3cccs3)C(=O)O)cc2)cc1

Procedure:
Example 34 is prepared from 2-thiophenethiol and 1d using the procedure described for compound 20.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[C:16]([OH:18])=O.[CH2:19]([N:26]1[CH2:31][CH2:30][CH2:29][CH:28]([NH2:32])[CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[C:16]([NH:32][CH:28]1[CH2:29][CH2:30][CH2:31][N:26]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:27]1)=[O:18]
Reactant: NC1CCCN(Cc2ccccc2)C1
Reactant: O=C(O)[C@@H]1CCCCN1c1nc2ccccc2o1
Product: O=C(NC1CCCN(Cc2ccccc2)C1)[C@@H]1CCCCN1c1nc2ccccc2o1

Procedure:
The title compound was prepared by a similar method to Example 1 from (2S)-1-(1,3-benzoxazol-2-yl)-2-piperidinecarboxylic acid [see Preparation 3] and 1-benzyl-3-piperidinylamine [see J. Med. Chem. (1980), 23(8), 848-851]. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 90:10 changing to 40:60, by volume, hexane:ethyl acetate in 10% increments, to afford (2S)-1-(1,3-benzoxazol-2-yl)-N2-(1-benzyl-3-piperidinyl)hexahydro-2-pyridinecarboxamide as a yellow gum.
Reaction SMILES: [O:1]1[C@@:5]2([CH:10]3[CH2:11][CH2:12][N:7]([CH2:8][CH2:9]3)[CH2:6]2)[CH2:4][NH:3][C:2]1=[O:13].Br[C:15]1[CH:16]=[C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[S:18][CH:19]=1>>[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:17]1[S:18][CH:19]=[C:15]([N:3]2[CH2:4][C@:5]3([CH:10]4[CH2:11][CH2:12][N:7]([CH2:8][CH2:9]4)[CH2:6]3)[O:1][C:2]2=[O:13])[CH:16]=1
Reactant: Brc1csc(-c2ccccn2)c1
Reactant: O=C1NC[C@@]2(CN3CCC2CC3)O1
Product: O=C1O[C@]2(CN3CCC2CC3)CN1c1csc(-c2ccccn2)c1

Procedure:
The title compound was prepared by a method analogous to that described in Preparation 3 from (S)-spiro[1-azabicyclo[2.2.2]octan-3,5′-oxazolidin]-2′-one and 4-bromo-2-(2-pyridyl)thiophene. The title compound (140 mg) was obtained as a pale-yellow solid, m/z 342 (MH+).
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:18])([CH3:17])[C:8]1[CH:9]=[C:10]([CH2:15]O)[CH:11]=[C:12]([CH3:14])[CH:13]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:19]([N:21](CC)CC)C.CS(Cl)(=O)=O.[C-]#N.[Na+]>ClCCl>[C:1]([SiH2:5][O:6][C:7]([CH3:18])([CH3:17])[C:8]1[CH:9]=[C:10]([CH2:15][C:19]#[N:21])[CH:11]=[C:12]([CH3:14])[CH:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(CO)cc(C(C)(C)O[SiH2]C(C)(C)C)c1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Agent: [C-]#N
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(CC#N)cc(C(C)(C)O[SiH2]C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.8 %

Procedure:
To a stirred solution of [3-(tert-butyl-dimethyl-silanyloxymethyl)-5-methyl-phenyl]-methanol (11.1 g, 41.67 mmol) in dichloromethane (80 ml) at 0° C. (ice bath), was added triethylamine (8.78 ml, 62.5 mmol) followed by methanesulfonyl chloride (3.87 ml, 50 mmol). After stirring for 2 hr, the reaction mixture was washed with aqueous saturated sodium bicarbonate solution, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The crude product was then dissolved in anhydrous DMF (80 ml) and sodium cyanide (6.28 g, 128 mmol) was added into the mixture. The mixture was stirred in an oil bath (60° C.) for 2 hr. After cooling to room temperature, the mixture was partitioned between ether and water. The ether layer was taken, washed with water twice, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent, EA: hexanes (from 1:20 to 1:10)) to afford 8.36 g (73%) of a white solid. m.p. 52-54° C.; 1H NMR (200 MHz, CDCl3) δ 0.12 (6H, s), 0.95 (9H, s), 4.2.35 (3H, s), 3.71 (2H, s), 4.71 (2H, s), 7.03 (1H, s), 7.08 (2H, s).
Reaction SMILES: [F:1][CH:2]([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][N:5]=1.C(O)(=O)C>CO.[Pd]>[F:13][CH:2]([F:1])[O:3][C:4]1[N:5]=[CH:6][C:7]([NH2:10])=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(OC(F)F)nc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: Nc1ccc(OC(F)F)nc1
Reaction time: 1 h
Yield: 104.9 %

Procedure:
To 2-(difluoromethoxy)-5-nitropyridine (4.7 g, 24.7 mmol) in degassed methanol (100 mL) was added 10% palladium on carbon (500 mg, 0.47 mmol) and the reaction was hydrogenated at atmospheric pressure for 1 hour. To this was added acetic acid (2.83 mL, 49.4 mmol) and the reaction was filtered through Celite and concentrated in vacuo to afford 6-(difluoromethoxy)pyridin-3-amine (6.33 g, 25.9 mmol, 105% yield) as an olive green liquid. 1H NMR (400 MHz, MeOD-d4) δ ppm 7.60 (d, J=2.76 Hz, 1H), 7.37 (s, 0.5H), 7.15 (dd, J=8.66, 2.89 Hz, 1H), 7.00 (s, 0.5H), 6.71 (d, J=8.78 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[O:14][CH2:13]3)[C:7]=1[CH:8]=[O:9].[BH4-].[Na+]>CO>[F:1][C:2]1[C:7]([CH2:8][OH:9])=[C:6]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[O:14][CH2:13]3)[CH:5]=[N:4][CH:3]=1
Reactant: O=Cc1c(F)cncc1-c1ccc2c(c1)COC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=C1OCc2cc(-c3cncc(F)c3CO)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 3-fluoro-5-(1-oxo-1,3-dihydro-isobenzofuran-5-yl)-pyridine-4-carbaldehyde (180 mg, 0.700 mmol) in MeOH (7 mL) at 0° C. was added sodium borohydride (39.7 mg, 1.050 mmol). The reaction mixture was stirred at room temperature for 30 min. The reaction was quenched with water and extracted with DCM twice. The organic layer was dried over sodium sulfate and concentrated in vacuo. The crude was dissolved in MeOH (10 mL) and purified on HPLC using RP18 column and gradient 0.1% aqueous NH4OH in acetonitrile to afford 5-(5-fluoro-4-hydroxymethyl-pyridin-3-yl)-3H-isobenzofuran-1-one. 1H NMR (400 MHz, MeOD) δ ppm 4.62 (d, J=1.5 Hz, 2H), 5.51 (s, 2H), 7.78 (d, J=7.8 Hz, 1H), 7.82 (s, 1H), 8.04 (d, J=7.8 Hz, 1H), 8.46 (s, 1H), 8.59 (d, J=1.5 Hz, 1H); HRMS: (ESI) m/z 260.0735 [(M+H)+ Calcd for C14H10FNO3 260.0723].
Reaction SMILES: C([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])C.[CH3:8][C:9]1[CH:26]=[CH:25][CH:24]=[CH:23][C:10]=1[C:11]([NH:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1)=[O:12]>ClCCl>[CH:16]1[C:7]2[CH2:23][CH2:24][C:25]3[CH:26]=[CH:9][CH:10]=[CH:11][C:5]=3[CH2:4][N:3]([C:18]([C:17]3[CH:21]=[CH:22][C:14]([NH:13][C:11](=[O:12])[C:10]4[CH:23]=[CH:24][CH:25]=[CH:26][C:9]=4[CH3:8])=[CH:15][CH:16]=3)=[O:19])[C:6]=2[CH:22]=[CH:14][CH:15]=1
Reactant: CCN(CC)CC
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3ccccc3CCc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.4 %

Procedure:
To a mixture of 0.245 g (1 mmol) of 5,6,-12-tetrahydrodibenz[b,f]azocine hydrochloride and 30 μl (2.2 mmol) of triethylamine in 2 ml of dichloromethane is added a solution of 0.281 g (1.1 mmol) of 4-[(2-methylbenzoyl)amino]benzoyl chloride in 4 ml of dichloromethane. The mixture is stirred overnight at room temperature, washed with water 2N HCl (3×2 ml) and 1N sodium bicarbonate (3×2 ml). The organic layer is dried (MgSO4) and filtered through a thin pad of hydrous magnesium silicate (pad washed with 3 volumes of CH2Cl2). The filtrate is concentrated to give 200 mg of a foam; Mass Spec.-FAB 447 (M+H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]=[C:21]3[C:17]([N:18]=[CH:19][N:20]3[C@@H:23]3[CH2:27][C@H:26]([NH:28][C:29](=[O:39])[CH2:30][O:31]CC4C=CC=CC=4)[C@@H:25]([OH:40])[C@H:24]3[OH:41])=[C:16]([NH:42][CH2:43][CH:44]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[N:15]=2)[CH2:10]1>C(O)C.[OH-].[OH-].[Pd+2]>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]=[C:21]3[C:17]([N:18]=[CH:19][N:20]3[C@@H:23]3[CH2:27][C@H:26]([NH:28][C:29](=[O:39])[CH2:30][OH:31])[C@@H:25]([OH:40])[C@H:24]3[OH:41])=[C:16]([NH:42][CH2:43][CH:44]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:51]3[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=3)[N:15]=2)[CH2:10]1
Reactant: N[C@@H]1CCN(c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](NC(=O)COCc5ccccc5)[C@@H](O)[C@H]4O)c3n2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H]1CCN(c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](NC(=O)CO)[C@@H](O)[C@H]4O)c3n2)C1
Temperature: 25 °C
Reaction time: 30 h

Procedure:
A solution of N-{(1S,2R,3S,4R)-4-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-2-benzyloxy-acetamide trifluoroacetate (0.022 g, 0.03 mmol) in ethanol (2 ml) under an atmosphere of Argon is treated with palladium hydroxide on carbon (0.05 g, 20% w/w carbon). The reaction mixture is placed under an atmosphere of hydrogen and stirred at room temperature for 30 hours and then filtered through Celite™. The filtrate is concentrated in vacuo and purification of the crude by reverse phase column chromatography (Isolute™ C18, 0-100% acetonitrile in water −0.1% TFA) yields the title product. (MH+ 573.4)
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([NH:6][CH2:7][C:8]2[CH:22]=[CH:21][C:11]([O:12][C:13]([CH3:20])([CH3:19])[C:14](OCC)=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[NH4+]>CCOCC>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([NH:6][CH2:7][C:8]2[CH:22]=[CH:21][C:11]([O:12][C:13]([CH3:20])([CH3:19])[CH2:14][OH:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CNc2ccc(Cl)cc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOCC
Product: CC(C)(CO)Oc1ccc(CNc2ccc(Cl)cc2)cc1
Yield: 79.6 %

Procedure:
A solution of 5 g of ethyl 2-[4-(4-chloroanilinomethyl)phenoxy]-2-methylpropionate in 50 ml of ether is dropwise added to a suspension of 775 mg of lithium aluminum hydride in 50 ml of anhydrous ether under 10° C. with stirring and the mixture is stirred for 2 hours at the same temperature. To the resultant mixture is dropwise added 60 ml of 10% ammonium chloride aqueous solution at 5° to 10° C. An insoluble material is filtered off and the ether layer is separated. The aqueous layer is further extracted with ether and both of the ether layers are combined. The combined ether solution is washed with a saturated sodium chloride aqueous solution and dried. The solvent is distilled off and the residue is washed with diisopropyl ether and dried to give 3.5 g of 2-[4-(4-chloroanilinomethyl)phenoxy]-2-methylpropanol, mp 84° to 91° C. This material is recrystallized from diisopropyl ether to give pure compound, mp 92° to 93° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH2:21][CH:22]3[CH2:24][CH2:23]3)[C:11](=[O:25])[C@@H:10]([CH2:26][C:27](OC)=[O:28])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[NH3:31].CO.[C-]#N.[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[N:12]([CH2:21][CH:22]3[CH2:23][CH2:24]3)[C:11](=[O:25])[C@@H:10]([CH2:26][C:27]([NH2:31])=[O:28])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: N
Reactant: COC(=O)C[C@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(CC2CC2)C1=O
Agent: [C-]#N
Agent: [Na+]
Solvent: CO
Product: NC(=O)C[C@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(CC2CC2)C1=O
Temperature: 50 °C
Reaction time: 72 h

Procedure:
In a sealed tube, 60 mg (134 μmol) of methyl 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiperidin-3-yl)acetate (Example 47) and 4.8 mL of a solution of ammonia in methanol (7N, 3.4 mmol) were stirred at 25° C. for 5 days. Then NaCN (3 mg) was added and the resulting solution was stirred at 50° C. for 3 days. Excess NH3 and MeOH were removed under reduced pressure. Separation by reversed phase HPLC (10 to 90% AcCN/H2O in 45 min) provided the title compound as a a white solid.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=O)C=1.[CH2:12]([C:14]1[N:15]([CH2:27][C:28]([CH3:35])([CH3:34])[C:29]([O:31][CH2:32]C)=[O:30])[C:16]2[C:25]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:19]=[CH:18][C:17]=2[N:26]=1)[CH3:13].ClC(Cl)(Cl)C([N:40]=C=O)=O>ClCCl>[NH2:40][C:18]1[C:17]2[N:26]=[C:14]([CH2:12][CH3:13])[N:15]([CH2:27][C:28]([CH3:35])([CH3:34])[C:29]([O:31][CH3:32])=[O:30])[C:16]=2[C:25]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N:19]=1
Reactant: CCOC(=O)C(C)(C)Cn1c(CC)nc2cnc3ccccc3c21
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)C(=O)OC
Temperature: 0 °C
Reaction time: 3 h
Yield: 33.4 %

Procedure:
mCPBA (4.8 g of 75%, 22 mmol) was added over a period of several minutes to a solution of ethyl 3-(2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)-2,2-dimethylpropanoate (3.6 g, 11 mmol) in dichloromethane (100 mL), which had been cooled to approximately 0° C. The reaction mixture was stirred cold for ten minutes and then for three hours at ambient temperature. The reaction mixture was then washed twice with a mixture of saturated aqueous sodium bicarbonate (34 mL) and 25% aqueous sodium hydroxide (1 mL), dried over potassium carbonate, filtered, and then cooled to 0° C. Trichloroacetyl isocyanate (1.7 mL, 14 mmol) was added, and the reaction was stirred cold for 15 minutes, warmed to ambient temperature, and stirred for one hour. The solvent was removed under reduced pressure, and the residue was dissolved in methanol (50 mL). Sodium methoxide (6.5 mL of a 25% solution in methanol, 30 mmol) was added to the resulting solution, and the reaction was stirred at ambient temperature overnight and cooled to approximately 0° C. for 30 minutes. A precipitate formed and was isolated by filtration to provide 1.2 g of methyl 3-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)-2,2-dimethylpropanoate.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C.[Fe]>[CH2:1]([NH:8][C:9]1[C:10]([NH2:15])=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccccc1NCc1ccccc1
Agent: [Fe]
Solvent: CC(=O)O
Product: Nc1ccccc1NCc1ccccc1
Temperature: 40 °C

Procedure:
To a solution of Benzyl-(2-nitro-phenyl)-amine (230 mg, 1 mmol) in 3 ml acetic acid, was added iron (70 mg, 1.24 mmol). The reaction mixture was heated to 40° C. under argon for 2 hours. The mixture was cooled to ambient temperature and filtered through celite and the filtrate was concentrated. The resulting solid was dissolved in ethyl acetate. The organic layer was washed with saturated NaHCO3, dried over MgSO4, filtered and the filtrate was concentrated in vacuo to yield crude product that was used in step Example 5c.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[CH3:9][N:10](C=O)C>ClCCl>[C:9]([C:2]1[N:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1)#[N:10]
Reactant: Cc1ccc(Br)nc1
Reactant: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc(C#N)nc1
Yield: 78 %

Procedure:
A mixture of 6-bromo-3-picoline (3 g, 17.4 mmol) and cuprous cyanide (2.3 g, 26.1 mmol) in DMF (60 mL) was heated at reflux for 1.5 h. The reaction mixture was diluted with dichloromethane, washed with aqueous ammonia, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by column chromatography (EtOAc:n-hexane, 1:9) to give the title compound (1.6 g, 78%).
Reaction SMILES: [NH2:1][C:2]([CH3:19])([CH2:5][N:6]1[C:14]([O:15][CH3:16])=[C:13]2[C:8]([C:9]([Cl:18])=[CH:10][C:11]([Cl:17])=[CH:12]2)=[N:7]1)[C:3]#[N:4].[F:20][C:21]([F:32])([F:31])[C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[S:27])=[CH:24][CH:23]=1>>[C:3]([C:2]([NH:1][C:26](=[S:27])[C:25]1[CH:24]=[CH:23][C:22]([C:21]([F:20])([F:31])[F:32])=[CH:30][CH:29]=1)([CH3:19])[CH2:5][N:6]1[C:14]([O:15][CH3:16])=[C:13]2[C:8]([C:9]([Cl:18])=[CH:10][C:11]([Cl:17])=[CH:12]2)=[N:7]1)#[N:4]
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Reactant: COc1c2cc(Cl)cc(Cl)c2nn1CC(C)(N)C#N
Product: COc1c2cc(Cl)cc(Cl)c2nn1CC(C)(C#N)NC(=S)c1ccc(C(F)(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-3-(5,7-dichloro-3-methoxy-2H-indazol-2-yl)-2-methylpropionitrile (181 mg, described in Example 114) and 4-trifluoromethylthiobenzoyl chloride, the title compound was isolated as a white solid (161 mg, 51%). MS (ES): M/Z [M+H]=503. 1H NMR: (400 MHz, CHLOROFORM-d): 1.96 (s, 3H), 4.42 (s, 3H), 4.53 (d, J=14.2 Hz, 1H), 4.88 (d, J=14.2 Hz, 1H), 7.35 (d, J=1.7 Hz, 1H), 7.68 (d, J=1.7 Hz, 1H), 7.75 (d, J=8.2 Hz, 2H), 8.02-8.09 (m, 2H) and 9.21 (s, 1H). 19F NMR (376 MHz, CHLOROFORM-d): −42.4 (s, 3F).