Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:12]=[C:11]([O:13][CH2:14][CH3:15])[O:10][C:9](=[O:16])[C:8]=2[C:17]=1[CH3:18])([O-])=O>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[N:12]=[C:11]([O:13][CH2:14][CH3:15])[O:10][C:9](=[O:16])[C:8]=2[C:17]=1[CH3:18]
Reactant: CCOc1nc2ccc([N+](=O)[O-])c(C)c2c(=O)o1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOc1nc2ccc(N)c(C)c2c(=O)o1
Reaction time: 5 h
Yield: 71 %

Procedure:
A solution of 4.0 g (16 mmoles) of 6-nitro-5-methyl-2-ethoxy-3,1-benzoxazin-4-one in 65 mL ethyl acetate was transferred to a Parr bottle. 1.0 g (0.94 mmoles) 10% Pd/C catalyst (obtained from Matheson, Coleman & Bell) was added. The sample was hydrogenated on a Parr shaker at ambient room temperature and 1 atm pressure for 5 hours. The catalyst was removed by filtration through a pad of Celite. The filtrate was concentrated in vacuo to produce a bright yellow solid. There was obtained 2.5 g (71% yield) of 6-amino-5-methyl-2-ethoxy-3,1-benzoxazin-4-one. NMR (DMSO-d6): 1.33(t,3H,J=6.9 Hz), 2.46(s,3H), 4.36(q,2H,J=6.9 Hz), 5.24(bs,2H), 7.05(d,1H,J=8.4 Hz), 7.14(d,1H,J=8.4 Hz). IR(nujol): 1743 cm-1 (lactone carbonyl). MS(m/z): 220(M+).
Reaction SMILES: [SH:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].C(ON=O)CC(C)C.[Cl:16][C:17]1[CH:22]=[CH:21][C:20](N)=[C:19]([O:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][C:26]=2[Cl:35])[CH:18]=1>C(#N)C.O>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:19]([O:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:32])=[O:33])=[CH:27][C:26]=2[Cl:35])[CH:18]=1
Reactant: CCOC(=O)CS
Reactant: CS(=O)(=O)c1ccc(Oc2cc(Cl)ccc2N)c(Cl)c1
Agent: CC(C)CCON=O
Solvent: O
Solvent: CC#N
Product: CCOC(=O)CSc1ccc(Cl)cc1Oc1ccc(S(C)(=O)=O)cc1Cl
Temperature: 60 °C

Procedure:
Ethyl mercaptoacetate (0.11 ml) followed by isoamylnitrite (0.16 ml) were added to a solution of the product from example 15 step (i) (0.5 g) in dry acetonitrile (20 ml) and heated at 60° C. for 10 h. The mixture was diluted with water, extracted with diethylether, the organics dried and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with dichloromethane, yield 0.60 g.
Reaction SMILES: [NH2:1][C@@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].N[C@H](C(O)=O)CC(=O)N.N[C@@H](C(O)=O)CC(=O)N.N[C@H](C(O)=O)CCC(=O)O.N[C@@H](C(O)=O)CCC(=O)O.N[C@H](C(O)=O)CC(=O)O>>[NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6]
Reactant: NC(=O)CC[C@@H](N)C(=O)O
Agent: NC(=O)C[C@@H](N)C(=O)O
Agent: NC(=O)C[C@H](N)C(=O)O
Agent: N[C@@H](CC(=O)O)C(=O)O
Product: NC(=O)CC[C@H](N)C(=O)O

Procedure:
D-Gln, Asn, D-Asn, Glu, D-Glu, Asp, D-As
Reaction SMILES: C(N(CC)C(C1C=CC=CC=1S([C:14]1[C@H:15]([CH3:45])[C@@H:16]2[C@@H:33]([C@H:34]([O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[CH3:35])[C:32](=[O:44])[N:17]2[C:18]=1[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:20])=O)=O)C.[N+:48]([C:51]1[CH:64]=[CH:63][C:54]([CH2:55][O:56][C:57]([NH:59][CH2:60][CH2:61][SH:62])=[O:58])=[CH:53][CH:52]=1)([O-:50])=[O:49]>>[Si:37]([O:36][C@@H:34]([C@H:33]1[C:32](=[O:44])[N:17]2[C:18]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=3)=[O:20])=[C:14]([S:62][CH2:61][CH2:60][NH:59][C:57]([O:56][CH2:55][C:54]3[CH:63]=[CH:64][C:51]([N+:48]([O-:50])=[O:49])=[CH:52][CH:53]=3)=[O:58])[C@H:15]([CH3:45])[C@H:16]12)[CH3:35])([C:40]([CH3:41])([CH3:42])[CH3:43])([CH3:39])[CH3:38]
Reactant: O=C(NCCS)OCc1ccc([N+](=O)[O-])cc1
Reactant: CCN(CC)C(=O)c1ccccc1S(=O)C1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)[C@H]2[C@H]1C
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SCCNC(=O)OCc3ccc([N+](=O)[O-])cc3)[C@H](C)[C@H]12
Yield: 83 %

Procedure:
Following a procedure similar to that described in Example 21(b), but using 4-nitrobenzyl (1R,5S,6S)-2-(2-diethylcarbamoylphenylsulfinyl)-1-methyl-6-[1(R)-t-butyldimethylsilyloxyethyl]-1-carbapen-2-em-3-carboxylate (prepared as described in Example 39) and 2-(4-nitrobenzyloxycarbonyl)aminoethylmercaptan as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained in a yield of 83%.
Reaction SMILES: Cl[C:2]1[C:3]([C:12]([F:15])([F:14])[F:13])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].[Cl:22][C:23]1[CH:24]=[C:25]([OH:30])[CH:26]=[CH:27][C:28]=1[Cl:29]>CC(N(C)C)=O>[Cl:22][C:23]1[CH:24]=[C:25]([CH:26]=[CH:27][C:28]=1[Cl:29])[O:30][C:2]1[C:3]([C:12]([F:15])([F:14])[F:13])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: Nc1cc(Cl)c(C(F)(F)F)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Nc1cc(Oc2ccc(Cl)c(Cl)c2)c(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 85 °C
Yield: 98.9 %

Procedure:
To a mixture of 5-chloro-2-nitro-4-trifluoromethyl-phenylamine (1.00 g, 4.16 mmol) and DMA (21 mL) was added K2CO3 (1.15 g, 8.32 mmol) and 3,4-dichloro-phenol (1.36 g, 8.32 mmol). The mixture was heated to 85° C. for 18 h. The mixture was cooled to 23° C. and poured into ice water. The precipitate was collected, dissolved in EtOAc (150 mL) and washed with brine (2×30 mL). The organic layers were combined, dried, filtered, and concentrated under reduced pressure to yield the titled compound (1.51 g, 99%). 1H NMR (500 MHz, CDCl3): 8.52 (s, 1H), 7.53 (d, J=8.7 Hz, 1H), 7.26 (d, J=3.2 Hz, 1H), 7.00 (dd, J=8.7, 2.7 Hz, 1H), 6.37 (s, 2H), 6.06 (s, 1H).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2].[BH4-].[Na+]>C(O)C>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:16]=[CH:15][C:12]([CH2:13][OH:14])=[CH:11][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCN(c2ccc(C=O)cc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCN1CCN(c2ccc(CO)cc2)CC1

Procedure:
This compound was prepared in the manner of Step A, Example 5, using 0.4 gram (0.019 mole) of [4-(4-ethylpiperazinyl)benzaldehyde and 0.4 gram (0.01 mole) of sodium borohydride in 40 mL of absolute ethanol (available from J. T. Baker Inc.) The yield of the title compound was 0.3 gram. The NMR Spectrum was consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[NH:15][NH2:16].[C:17]([CH2:19][C:20](Cl)=[O:21])#[N:18]>O1CCCC1>[NH2:18][C:17]1[N:15]([C:3]2[CH:4]=[C:5]([S:9][CH2:10][C:11]([F:13])([F:14])[F:12])[C:6]([CH3:8])=[CH:7][C:2]=2[F:1])[N:16]=[C:20]([OH:21])[CH:19]=1
Reactant: N#CCC(=O)Cl
Reactant: Cc1cc(F)c(NN)cc1SCC(F)(F)F
Solvent: C1CCOC1
Product: Cc1cc(F)c(-n2nc(O)cc2N)cc1SCC(F)(F)F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 58.1 %

Procedure:
27.5 g of 2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenylhydrazine was dissolved in 300 mL of tetrahydrofuran, and to this solution, 14 g of cyanoacetyl chloride was added, followed by stirring at room temperature for 5 minutes. Then, the solvent was distilled off under reduced pressure, the residue was dissolved in 300 mL of 1-propanol, and 10.6 g of methanesulfonic acid was added, followed by reflux with heating for 3 hours. After cooling to room temperature, the solvent was distilled off under reduced pressure, the reaction solution was neutralized to pH=7 with sodium hydrogen carbonate, and extraction with ethyl acetate was carried out. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane:acetic acid=50:50:1) to obtain 20.2 g of 5-amino-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-hydroxypyrazole in the form of brown crystals (melting point: 110-113° C.).
Reaction SMILES: [CH:1]1[CH:6]=[N:5][C:4](Cl)=[C:3]([C:8]#[N:9])[CH:2]=1.[CH2:10]([NH2:14])[CH2:11][CH2:12][CH3:13]>C(O)(C)C>[CH2:10]([NH:14][C:4]1[C:3]([C:8]#[N:9])=[CH:2][CH:1]=[CH:6][N:5]=1)[CH2:11][CH2:12][CH3:13]
Reactant: CCCCN
Reactant: N#Cc1cccnc1Cl
Solvent: CC(C)O
Product: CCCCNc1ncccc1C#N

Procedure:
2-Chloronicotinitrile (1.30 g, 9.60 mmol) was refluxed with 3 mL of n-butylamine and 10 mL of isopropyl alcohol overnight. The solvents were removed in vacuo and the residue obtained chromatographed on silica gel eluting with 2:1 hexane/ethyl acetate to give 1.6 g of the title compound.
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].C(=O)(O)[O-].[Na+].[F:14][C:15]1[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[C:16]=1[CH2:17][NH:18][C:19]1[C:24]([N+:25]([O-])=O)=[CH:23][N:22]=[C:21]([NH:28][C:29]2[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=2[N+:36]([O-])=O)[N:20]=1>O.C1COCC1>[F:43][C:39]1[CH:40]=[CH:41][CH:42]=[C:15]([F:14])[C:16]=1[CH2:17][NH:18][C:19]1[C:24]([NH2:25])=[CH:23][N:22]=[C:21]([NH:28][C:29]2[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=2[NH2:36])[N:20]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1Nc1ncc([N+](=O)[O-])c(NCc2c(F)cccc2F)n1
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc(F)cc1Nc1ncc(N)c(NCc2c(F)cccc2F)n1
Reaction time: 0.5 h

Procedure:
A freshly prepared solution of sodium hydrosulfite (tech, 100 mg) and sodium bicarbonate (50 mg) in H2O (5 mL) was added to a solution of N4-(2,6-difluorobenzyl)-N2-(5-fluoro-2-nitrophenyl)-5-nitropyrimidine-2,4-diamine (75) (24 mg) in THF (5 mL). The mixture was stirred vigorously for 30 min and extracted with DCM (3×). The combined organics were washed with brine, dried, filtered and concentrated to yield the intermediate N4-(2,6-difluorobenzyl)-N2-(2-amino-5-fluorophenyl)pyrimidine-2,4,5-triamine (76) for use in the next step. A catalytic amount of para-toluene sulfonic acid monohydrate was added to a solution of the intermediate and trimethyl orthoformate (1 mL) in MeOH (2 mL), after 2 hr conc. HCl (1 mL) was added and the mixture was heated at 50° C. for 4 hr. The reaction solvents were removed and the crude material was purified via preparative HPLC to give 9-(2,6-Difluorobenzyl)-2-(6-fluoro-1H-benzo[d]imidazol-1-yl)-9H-purine (78) as the TFA salt in low yield (0.8 mg) MH+=404, 1H NMR (5% CD3OD/CDCl3) δ 9.1 (s, 1H), 9.0 (s, 1H), 8.3 (d, 1H), 8.2 (s, 1H), 7.6 (m, 1H), 7.0 (t, 1H), 6.9 (m, 2H), 5.5 (s, 2H) ppm, 19F NMR δ−76.6 (s, TFA), −114.5 (m), −117.1 (m).
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4]2[O:9][CH2:8][CH:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23.[C:21]([O:25][C:26]([NH:28][C@H:29]1[C@@H:33]([CH3:34])[CH2:32][NH:31][CH2:30]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]>CS(C)=O>[C:21]([O:25][C:26]([NH:28][C@H:29]1[C@@H:33]([CH3:34])[CH2:32][N:31]([C:3]2[C:2]([F:1])=[CH:15][C:14]3[C:13](=[O:16])[C:12]([C:17]([OH:19])=[O:18])=[CH:11][N:6]4[CH:7]([CH3:10])[CH2:8][O:9][C:4]=2[C:5]=34)[CH2:30]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC1COc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Reactant: C[C@H]1CNC[C@H]1NC(=O)OC(C)(C)C
Solvent: CS(C)=O
Product: CC1COc2c(N3C[C@H](C)[C@H](NC(=O)OC(C)(C)C)C3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Reaction time: 2 h
Yield: 70.7 %

Procedure:
A mixture of 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid (0.5 g), anhydrous dimethyl sulfoxide (10 ml) and cis-3-t-butoxycarbonylamino-4-methylpyrrolidine (0.54 g) was stirred for 2 hours at 90°-100° C. and then concentrated. To the residue was added methanol and the resulting precipitate was collected by filtration and then washed with cold methanol to give the title compound (0.58 g) as yellowish powder, mp 219°-220° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][OH:7].N[C:9](N)=[O:10].N>>[CH2:2]1[NH:1][C:9](=[O:10])[N:4]([CH2:5][CH2:6][OH:7])[CH2:3]1
Reactant: NC(N)=O
Reactant: NCCNCCO
Agent: N
Product: O=C1NCCN1CCO
Temperature: 230 °C
Yield: 97.6 %

Procedure:
A mixture of 93.3 g of 2-(2-aminoethylamino)ethanol (0.9 moles) and 52.1 g of urea (0.87 moles) was heated slowly to 230° C. with stirring. The evolution of ammonia began when the temperature reached 130° C. The reaction mixture was heated at 230° C. for 2 hours. The mixture solidified to a light-yellow solid after it had cooled to room temperature to afford 110.5 g of hydroxyethylethyleneurea. Recrystallized from acetone, M.P.: 55-57.5° C.; 1H NMR (DMSO-d6): δ6.3 (s, 1H), 4.6 (s, 1H), 3.5-3.0 (m, 8H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([NH2:20])=[N:18][CH:17]=[C:16]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=3)[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[Cl:29][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][CH:26]=1)[CH2:22][O:21][C:16]1[N:15]=[C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[C:19]([NH2:20])=[N:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(OCc3cccc(Cl)c3)cnc2N)CC1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1ncc(OCc2cccc(Cl)c2)nc1N1CCNCC1
Temperature: 40 °C
Yield: 16.6 %

Procedure:
3′-Amino-6′-(3-chloro-benzyloxy)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester I-3s (150 mg, 357 μmol) was dissolved in 1,4-dioxane (6 mL) and an HCl solution (0.90 mL, 4 M in 1,4-dioxane, 3.6 mmol) was added with stirring at 40° C. The solution was stirred at 40° C. for 18 h and concentrated in vacuo to approximately 2 mL. The mixture was diluted with Et2O. The resulting brown solid was collected by filtration and washed twice with Et2O. The solid was purified by preparative HPLC to give the title compound 3-P as a tan solid (19 mg, 17% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH2:5][C@H:6]([NH:14][C:15]([C:17]1[CH:21]=[C:20]([OH:22])[N:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[F:29])[N:18]=1)=[O:16])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:13])[CH3:2].FC1C=CC=CC=1N1C(O)=CC(C(O)=O)=N1.N[C@H](C1C=CC=CC=1C)CC(OCC)=O.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:69][C:70]1([CH3:74])[CH2:73][O:72][CH2:71]1>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:30])[CH2:5][C@H:6]([NH:14][C:15]([C:17]1[CH:21]=[C:20]([O:22][CH2:69][C:70]2([CH3:74])[CH2:73][O:72][CH2:71]2)[N:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[F:29])[N:18]=1)=[O:16])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:13])[CH3:2]
Reactant: CCOC(=O)C[C@H](NC(=O)c1cc(O)n(-c2ccccc2F)n1)c1ccccc1C
Reactant: CC1(CBr)COC1
Agent: CCOC(=O)C[C@H](N)c1ccccc1C
Agent: O=C(O)c1cc(O)n(-c2ccccc2F)n1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCOC(=O)C[C@H](NC(=O)c1cc(OCC2(C)COC2)n(-c2ccccc2F)n1)c1ccccc1C
Temperature: 65 °C
Reaction time: 4 h

Procedure:
101 mg (0.245 mmol) of (S)-3-{[1-(2-fluoro-phenyl)-5-hydroxy-1H-pyrazole-3-carbonyl]-amino}-3-(2-methyl-phenyl)-propionic acid ethyl ester (prepared from 1-(2-fluoro-phenyl)-5-hydroxy-1H-pyrazole-3-carboxylic acid and ethyl (S)-3-amino-3-(2-methyl-phenyl)-propionate analogously as described in synthesis example 2) were dissolved in 3 ml of DMF, and 160 mg (0.5 mmol) of cesium carbonate and 41.3 mg (0.245 mmol) of 3-bromomethyl-3-methyl-oxetane were added. The mixture was stirred for 4 h at 65° C. After evaporation of the solvent the residue was subjected to an aqueous work-up with EA and 10% aqueous solution of citric acid. After removal of the solvent from the organic phase 100 mg (82%) of the product are obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:24]=2[N:23]=[C:22]([CH:25]=O)[CH:21]=[CH:20]3)[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[I:28][C:29]1[CH:34]=[CH:33][N:32]=[C:31]([NH:35][NH2:36])[CH:30]=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:27])[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:24]=2[N:23]=[C:22](/[CH:25]=[N:36]/[NH:35][C:31]2[CH:30]=[C:29]([I:28])[CH:34]=[CH:33][N:32]=2)[CH:21]=[CH:20]3)[CH2:11][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC1CCN(c2cccc3ccc(C=O)nc23)CC1
Reactant: NNc1cc(I)ccn1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC1CCN(c2cccc3ccc(/C=N/Nc4cc(I)ccn4)nc23)CC1
Reaction time: 1 h

Procedure:
To tert-butyl(1-(2-formylquinolin-8-yl)piperidin-4-yl)methylcarbamate (112 mg, 0.303 mmol) in DCM (20 mL) was added 1-(4-iodopyridin-2-yl)hydrazine (78.4 mg, 0.333 mmol). The reaction mixture was stirred for 1 hour and then taken on to directly to the next step.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24])[N:6]2[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1.C(N(CC)CC)C.[CH2:32]([NH:34][C:35]1([C:41]([NH2:43])=[O:42])[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)[CH3:33]>CC(C)=O.O>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([N:6]2[C:5]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])=[N:4][C:3]3[C:7]2=[N:8][CH:9]=[N:10][C:2]=3[N:38]2[CH2:37][CH2:36][C:35]([NH:34][CH2:32][CH3:33])([C:41]([NH2:43])=[O:42])[CH2:40][CH2:39]2)=[CH:12][CH:13]=1
Reactant: Clc1ccc(-n2c(-c3ccccc3Cl)nc3c(Cl)ncnc32)cc1
Reactant: CCNC1(C(N)=O)CCNCC1
Solvent: O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CCNC1(C(N)=O)CCN(c2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a pale orange solution of 6-chloro-9-(4-chlorophenyl)-8-(2-chlorophenyl)-9H-purine I-(4A-7)c (1.00 g, 2.66 mmol) in acetone (13 ml) at room temperature was added triethylamine (410 μl, 2.94 mmol). A solution of 4-ethylamino-piperidine-4-carboxylic acid amide I-(7A-80)f in water (1.5 ml) was then added to give a clear yellow reaction solution. After stirring at room temperature for 3 days the cloudy white reaction mixture was diluted with water (11 ml). After stirring 1 hour at room temperature followed by 1 hour at 0° C., the precipitate was collected on a sintered glass funnel and rinsed with cold 1:1, acetone: H2O. The solid was dried, in vacuo, to give title compound 20A-1 as a colorless solid (1.22 g, 90%): +ESI MS (M+1) 510.2; 1H NMR (400 MHz, CD3OD) δ 8.19 (s, 1H), 7.57 (d, J=7.0 Hz,1H), 7.45–7.35 (m, 5H), 7.26 (d, J=8.7 Hz, 2H), 4.54 (br s, 2H), 4.24 (br s, 2H), 2.51 (q, J=7.0 Hz, 2H), 2.12–2.06 (m, 2H), 1.76–1.72 (m, 2H) 1.10 (t, J=7.0 Hz, 3H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].Cl.[C:12]([C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH2:19])=[CH:16][CH:15]=1)#[N:13].N1C=CC=CC=1>O1CCCC1.C(OCC)(=O)C.Cl>[C:12]([C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH:19][C:5](=[O:6])[C:4]2[CH:8]=[CH:9][CH:10]=[C:2]([I:1])[CH:3]=2)=[CH:16][CH:15]=1)#[N:13]
Reactant: O=C(Cl)c1cccc(I)c1
Reactant: N#Cc1ccc(CN)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: N#Cc1ccc(CNC(=O)c2cccc(I)c2)cc1
Temperature: 0 °C
Reaction time: 72 h
Yield: 50 %

Procedure:
An aliquot of 3-iodobenzoyl chloride (1.1 g, 4.2 mmol) was taken up in tetrahydrofuran (“THF”, 25 mL), and cooled to approximately 0° C. in an ice-water bath. To the cold solution were added 4-cyanobenzylamine hydrochloride (0.71 g, 4.2 mmol) and pyridine (0.66 g, 8.3 mmol). The solution gradually warmed to room temperature, and was stirred for 72 hours. The reaction mixture was diluted with ethyl acetate (25 mL) and aqueous HCl (25 mL). The organic phase was separated, dried (MgSO4), filtered, and rotary evaporated. The resulting crude product was purified using silica gel chromatography (elution with dichloromethane/THF [9:1]) to give N-(4-cyano-benzyl)-3-iodo-benzamide (0.76 g, 51%) as a white solid. 1H-NMR (DMSO-d6) δ 9.2 (t, 1H), 8.2 (s, 1H), 7.9 (m, 2H), 7.8 (d, 2H), 7.5 (d, 2H), 7.3 (m, 1H), 4.5 (d, 2H) ppm.
Reaction SMILES: [C:1]([C:4]([NH:9][CH2:10][C:11]1[N:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][C:12]=1[C:13]([OH:15])=[O:14])([CH3:8])[CH:5]([CH3:7])[CH3:6])(=[O:3])[NH2:2].C([O-])(=O)C.[Na+].BrBr>C(O)(=O)C>[CH2:20]([C:17]1[CH:18]=[N:19][C:11]([C:10]2[NH:2][C:1](=[O:3])[C:4]([CH:5]([CH3:7])[CH3:6])([CH3:8])[N:9]=2)=[C:12]([CH:16]=1)[C:13]([OH:15])=[O:14])[CH3:21]
Reactant: CCc1cnc(CNC(C)(C(N)=O)C(C)C)c(C(=O)O)c1
Agent: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCc1cnc(C2=NC(C)(C(C)C)C(=O)N2)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 51.2 %

Procedure:
A mixture of 0.8 g of 2-{[(1-carbamoyl-1,2-dimethylpropyl)amino]methyl}-5-ethylnicotinic acid (2.7 mmol) and 0.56 g sodium acetate (6.8 mmol) in 10 mL acetic acid is warmed until homogeneous and cooled to room temperature. The solution is treated with 0.88 g bromine (5.45 mmol), and the reaction is stirred at 25° C. for 16 hours, then at 75° C. for three days. The reaction mixture is partitioned between CH2Cl2 and water, and the organic phase is dried and concentrated in vacuo. The residue is recrystallized from ethyl acetate-hexanes to afford 0.4 g of the title product having mp 172°-175° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([CH2:14][CH:15]2[CH2:19][CH2:18][N:17]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:16]2=[O:26])=[C:9]([Cl:27])[CH:8]=1)(=O)=O.[F:30][C:31]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[C:33]([F:39])[C:32]=1B(O)O>>[CH:20]1([N:17]2[CH2:18][CH2:19][CH:15]([CH2:14][C:10]3[C:11]([Cl:13])=[CH:12][C:7]([C:32]4[C:31]([F:30])=[CH:36][C:35]([O:37][CH3:38])=[CH:34][C:33]=4[F:39])=[CH:8][C:9]=3[Cl:27])[C:16]2=[O:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: O=C1C(Cc2c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc2Cl)CCN1C1CCCCC1
Reactant: COc1cc(F)c(B(O)O)c(F)c1
Product: COc1cc(F)c(-c2cc(Cl)c(CC3CCN(C4CCCCC4)C3=O)c(Cl)c2)c(F)c1
Yield: 105.5 %

Procedure:
Using the procedure to synthesize Example 81 and using reagents 3,5-dichloro-4-((1-cyclohexyl-2-oxopyrrolidin-3-yl)methyl)phenyl trifluoromethanesulfonate (Example 240) (500 mg, 1.0 mmol) and 2,6-difluoro-4-methoxyphenylboronic acid (590 mg, 3.2 mmol) affords 494 mg (100%) of 1-Cyclohexyl-3-(3,5-dichloro-2′,6′-difluoro-4′-methoxy-biphenyl-4-ylmethyl)-pyrrolidin-2-one. Charge a flask with 1-cyclohexyl-3-(3,5-dichloro-2′,6′-difluoro-4′-methoxy-biphenyl-4-ylmethyl)-pyrrolidin-2-one (500 mg, 1.1 mmol), dissolve in dry methylene chloride (10 mL) and cool to 0° C. under nitrogen. Add BBr3 (0.25 mL, 2.7 mmol) and stir at 0° C. for 1.5 hours. Pour into saturated aqueous sodium bicarbonate and extract with methylene chloride. Dry over sodium sulfate, filter and concentrate in vacuo to yield 470 mg (97%) of the title compound.
Reaction SMILES: COCCN(S(F)(F)[F:11])CCOC.[F:14][C:15]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=1[CH:22]1[CH2:32][CH2:31][CH:30]([O:33][Si:34]([CH:41]([CH3:43])[CH3:42])([CH:38]([CH3:40])[CH3:39])[CH:35]([CH3:37])[CH3:36])[C:25]2=[N:26][CH:27]=[CH:28][CH:29]=[C:24]2[CH:23]1O.C(N(CC)CC)C>ClCCCl>[F:14][C:15]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=1[CH:22]1[CH2:32][CH2:31][CH:30]([O:33][Si:34]([CH:41]([CH3:43])[CH3:42])([CH:38]([CH3:40])[CH3:39])[CH:35]([CH3:37])[CH3:36])[C:25]2=[N:26][CH:27]=[CH:28][CH:29]=[C:24]2[CH:23]1[F:11]
Reactant: CC(C)[Si](OC1CCC(c2cccc(F)c2F)C(O)c2cccnc21)(C(C)C)C(C)C
Reactant: COCCN(CCOC)S(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC(C)[Si](OC1CCC(c2cccc(F)c2F)C(F)c2cccnc21)(C(C)C)C(C)C
Temperature: 23 °C
Reaction time: 2 h

Procedure:
Deoxo-Fluor® (0.148 g, 0.670 mmol) was added dropwise to a solution of (5S,6S,9R and 5R,6R,9S)-6-(2,3-difluorophenyl)-9-((triisopropylsilyl)oxy)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-5-ol (prepared according to the procedures described by Leahy, D. K et al Org. Lett. 2012, 14, 4938-4941, 0.30 g, 0.67 mmol) and triethylamine (0.093 mL, 0.67 mmol) in 1,2-dichloroethane (2 mL) at 0° C. The resulting mixture was gradually warmed to 23° C. and stirred for 2 h, then partitioned between saturated aqueous sodium bicarbonate solution and dichloromethane (3×). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash chromatography on silica gel, eluting with 35% dichloromethane in petroleum ether to give the title compound as a racemic mixture. MS: m/z=450.2 (M+1).