Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][NH:7][C:8]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]=[C:10]([NH:20][C:21](=[O:24])[CH2:22]Cl)[CH:9]=1)(=[O:3])[CH3:2].[F:25][C:26]1[CH:38]=[CH:37][C:29]([CH2:30][CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:28][CH:27]=1.CCOC(C)=O>CC(O)C>[C:1]([NH:4][CH2:5][CH2:6][NH:7][C:8]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]=[C:10]([NH:20][C:21](=[O:24])[CH2:22][N:34]2[CH2:35][CH2:36][CH:31]([CH2:30][C:29]3[CH:28]=[CH:27][C:26]([F:25])=[CH:38][CH:37]=3)[CH2:32][CH2:33]2)[CH:9]=1)(=[O:3])[CH3:2]
Reactant: Fc1ccc(CC2CCNCC2)cc1
Reactant: CC(=O)NCCNc1cc(NC(=O)CCl)nc(-c2ccccc2)n1
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CC(=O)NCCNc1cc(NC(=O)CN2CCC(Cc3ccc(F)cc3)CC2)nc(-c2ccccc2)n1

Procedure:
This compound was prepared from chloroacetamide 6 (77 mg; 0.221 mmol) and 4-(4-fluorobenzyl)-piperidine (7.9) (47 mg; 0.24 mmol) in a manner analogous to 8.8 yielding a white crystalline solid (80.5 mg; 72%) after silica gel chromatography (12-8:1 EtOAc:i-PrOH). LC (method B) tR=13.1 min; 1H NMR (200 MHz, CDCl3) δ 9.51 (brs, 1H), 8.37 (m, 2H), 7.48 (m, 3H), 7.22 (s, 1H), 7.11 (m, 2H), 6.98 (m, 2H), 6.58 (brs, 1H), 5.45 (brt, J=5.4 Hz, 1H), 3.68 (m, 2H), 3.53 (m, 2H), 3.11 (s, 2H), 2.89 (m, 2H), 2.57 (m, 2H), 2.20 (m, 2H), 1.86 (s, 3H), 1.80-1.30 (m, 5H); ESIMS 505.0 (42) [MH+], 253.1 (100).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:6]([C:16]2[NH:20][C:19]3[C:21]4[C:26]([CH:27]=[CH:28][C:18]=3[N:17]=2)=[CH:25][C:24]2[C:29]3[C:34]([CH2:35][O:36][C:23]=2[CH:22]=4)=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][CH:30]=3)[CH2:5]1.Br[C:47]1[NH:51][C:50]([C@@H:52]2[CH2:56][CH2:55][CH2:54][N:53]2[C:57](=[O:68])[C@@H:58]([NH:63][C:64](=[O:67])[O:65][CH3:66])[C@H:59]([O:61][CH3:62])[CH3:60])=[N:49][CH:48]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:66][O:65][C:64]([NH:63][C@H:58]([C:57]([N:53]1[CH2:54][CH2:55][CH2:56][C@H:52]1[C:50]1[NH:51][C:47]([C:32]2[CH:33]=[C:34]3[CH2:35][O:36][C:23]4[CH:22]=[C:21]5[C:26]([CH:27]=[CH:28][C:18]6[N:17]=[C:16]([C@@H:6]7[CH2:5][C@H:4]([CH2:3][O:2][CH3:1])[CH2:8][N:7]7[C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[NH:20][C:19]=65)=[CH:25][C:24]=4[C:29]3=[CH:30][CH:31]=2)=[CH:48][N:49]=1)=[O:68])[C@@H:59]([CH3:60])[O:61][CH3:62])=[O:67]
Reactant: COCC1CC(c2nc3ccc4cc5c(cc4c3[nH]2)OCc2cc(B3OC(C)(C)C(C)(C)O3)ccc2-5)N(C(=O)OC(C)(C)C)C1
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(Br)[nH]1)[C@@H](C)OC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CS(C)=O
Product: COC[C@H]1C[C@@H](c2nc3ccc4cc5c(cc4c3[nH]2)OCc2cc(-c3cnc([C@@H]4CCCN4C(=O)[C@@H](NC(=O)OC)[C@@H](C)OC)[nH]3)ccc2-5)N(C(=O)OC(C)(C)C)C1
Temperature: 85 °C
Reaction time: 6 h
Yield: 40.6 %

Procedure:
To a solution of tert-butyl 4-(methoxymethyl)-2-[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,11-dihydroisochromeno[4′,3′:6,7]-naphtho[1,2-d]imidazol-2-yl]pyrrolidine-1-carboxylate (1.0 g, 3.2 mmol) in a mixture of DMSO (2.0 mL) and dioxanes (2.0 mL) was added methyl (2S,3R)-1-((S)-2-(5-bromo-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methoxy-1-oxobutan-2-ylcarbamate (0.24 g, 0.62 mmol), tetrakis(triphenylphosphine)palladium (0.050 g, 0.043 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.030 g, 0.041 mmol), and aqueous potassium carbonate (2M, 0.65 mL, 1.3 mmol). The solution was degassed with argon for 5 min and heated, with stirring, to 85° C. for 6 h. The solution was cooled to room temperature and diluted with EtOAc. The organic layer was washed with water and brine. The aqueous layers were backextracted with EtOAc (3×). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (20% to 100% EtOAc(w/5% MeOH)/Hexanes to 60% MeOH/EtOAc) to afford tert-butyl (2S,4S)-2-[9-(2-{(2S)-1-[N-(methoxycarbonyl)-O-methyl-L-threonyl]pyrrolidin-2-yl}-1H-imidazol-5-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate (0.20 g, 63%).
Reaction SMILES: S(Cl)(Cl)=O.[OH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:8][CH:7]=1.[CH3:17]O>>[OH:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:11]=1
Reactant: O=C(O)CCc1ccc(O)cc1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)CCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution obtained beforehand by adding thionyl chloride (18.3 ml, WAKO) dropwise to methanol (250 ml) under ice cooling was added dropwise with a solution of 3-(4-hydroxyphenyl)propionic acid (16.6 g, TCI) in methanol (50 ml) under ice cooling, stirred for 30 minutes, then warmed to room temperature and further stirred for 1.5 hours. The reaction mixture was concentrated under reduced pressure and then extracted with diethyl ether (200 ml). The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate, saturated aqueous ammonium chloride and saturated brine. The organic layer was dried, and then the solvent was evaporated under reduced pressure to obtain the title compound (Intermediate 1, 17.95 g).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[S:3]([O:6][C:7]1[CH:17]=[CH:16][C:10]2[C:11](=[O:15])[CH:12]=[CH:13][O:14][C:9]=2[CH:8]=1)(=[O:5])=[O:4].[CH:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.N1CCCC1>CO>[F:19][C:2]([F:1])([F:18])[S:3]([O:6][C:7]1[CH:17]=[CH:16][C:10]2[C:11](=[O:15])[C:12](=[CH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:13][O:14][C:9]=2[CH:8]=1)(=[O:5])=[O:4]
Reactant: O=c1ccoc2cc(OS(=O)(=O)C(F)(F)F)ccc12
Reactant: O=Cc1ccccc1
Solvent: C1CCNC1
Solvent: CO
Product: O=C1C(=Cc2ccccc2)COc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
To a stirred solution of the product of Step C (27 g, 91.2 mmole) in 183 mL of methanol was added benzaldehyde (11.1 mL, 109 mmole) followed by pyrrolidine (9.1 mL, 109 mmole). The mixture was stirred at room temperature overnight, cooled to 0° C. and filtered. The solid was washed once with 50 mL of ice-cold methanol and then dried in vacuo; 35.2 g, (75% yield) of the title product was recovered.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[C:31]([NH:35][C:36](=[O:39])[CH2:37][CH3:38])[CH:32]=[CH:33][CH:34]=2)[CH2:25][CH2:24]1>>[F:18][C:15]1[CH:16]=[CH:17][C:12]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:9]([NH:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:30]=[C:31]([NH:35][C:36](=[O:39])[CH2:37][CH3:38])[CH:32]=[CH:33][CH:34]=3)[CH2:25][CH2:24]2)=[O:11])=[CH:13][CH:14]=1
Reactant: CCC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: O=C(O)C(c1ccc(F)cc1)c1ccc(F)cc1
Product: CCC(=O)Nc1cccc(C2CCN(CCCNC(=O)C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)c1

Procedure:
Example 21 was prepared from bis(4-fluorophenyl)acetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}propanamide according to the procedures described in Scheme 10: ESMS m/e: 520.3 (M+H)+.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:28]=[CH:27][C:17]([CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])=[C:16]([F:29])[CH:15]=1.[I:30]I>C1COCC1>[Cl:13][C:14]1[CH:28]=[CH:27][C:17]([CH2:18][O:19][Si:20]([C:23]([CH3:24])([CH3:25])[CH3:26])([CH3:22])[CH3:21])=[C:16]([F:29])[C:15]=1[I:30]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(Cl)cc1F
Reactant: II
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)[Si](C)(C)OCc1ccc(Cl)c(I)c1F
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of diisopropylamine (3.09 mL, 21.8 mmol) in THF (60 mL) under at 0° C. was added n-butyllithium (6.83 mL, 20.0 mmol) dropwise over 5 min. After 10 min, the reaction mixture was cooled to −78° C., and a solution of (4-chloro-2-fluorobenzyloxy)(tert-butyl)dimethylsilane (5.00 g, 18.2 mmol) in THF (15 mL) was added slowly over 5 min. After 2 h at −78° C., a solution of iodine (5.54 g, 21.8 mmol) in THF (25 mL) was added over 10 min. After a further 20 min at −78° C., the reaction mixture was warmed to RT and was quenched with sodium thiosulfate, followed by water (100 mL). The separated aqueous solution was extracted with diethyl ether (2×60 mL). The combined organic phases were washed with saturated aqueous solution of sodium bicarbonate, and brine. The resulting organic solution was then dried over magnesium sulfate and concentrated under reduced pressure. Flash chromatography on silica gel (dichloromethane: hexane=10:90) gave (4-chloro-2-fluoro-3-iodobenzyloxy)(tert-butyl)dimethylsilane as colorless oil. 1H NMR (300 MHz, CDCl3) δ ppm 7.30 (1H, t, J=7.5 Hz), 7.17 (1H, d, J=7.1 Hz), 4.65 (2H, s), 0.75-0.85 (9H, m), 0.01 (6 H, s)
Reaction SMILES: COCC(O)C.[OH-].[Na+].[C:9](OC)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:19]1(=[O:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.S(=O)(=O)(O)O>>[C:9]([CH:20]1[CH2:21][CH2:22][CH2:23][CH2:24][C:19]1=[O:25])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)c1ccccc1
Reactant: O=C1CCCCC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: COCC(C)O
Product: O=C1CCCCC1C(=O)c1ccccc1
Yield: 65 %

Procedure:
1-Methoxy-2-propanol (61.3 g; 0.68 mol), sodium hydroxide (16.0 g; 0.40 mol), and xylenes (300 mL) were placed into a four-necked, round bottom, half-liter flask equipped with a stirrer, a thermometer, and an Oldershaw column with a Dean-Stark trap and a condenser. The mixture was heated to boiling with stirring under a blanket of nitrogen and the water was azeotroped out (temperature of reflux 106-116° C.). When no more water was collected (23 mL of lower phase) some solvent was distilled off (215 mL), while xylenes (432.2 g, dry) were replaced, until no more alcohol was detected in the distillate (temperature of reflux 137° C.). The mixture in the flask was cooled down to and kept at 80° C. and the fractionation column and trap were replaced with a reflux condenser while maintaining the nitrogen stream. Methyl benzoate (68.1 g; 0.50 mol) was added, and slow addition over a period of 10 minutes of cyclohexanone (24.5 g, 0.250 mol) by means of a syringe pump was begun. After 19 minutes from the beginning of the addition of the ketone, the mixture was cooled down (an ice bath was used), and acidified by slow addition of 98% sulfuric acid (slightly over 24.5 g) with stirring. The mixture was transferred to a 1 L separatory funnel, washed with aqueous sodium bicarbonate, and then with water. Evaporation of the organic layer under vacuum and recrystallization from heptane afforded 32.86 g of BCH (65% yield based on cyclohexanone), with a purity of 99% (GC).
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH2:9]C)=[CH:6][CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:17][O:18][CH2:19][C:20]#[CH:21]>C(#N)C.C(OCC)C>[CH3:9][O:8][C:7]1[C:2]([C:21]#[C:20][CH2:19][O:18][CH3:17])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: C#CCOC
Reactant: CCOc1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CC#N
Product: COCC#Cc1ncccc1OC
Temperature: 25 °C

Procedure:
To a solution of commercially available 2-chloro-3 ethoxy pyridine (1 eq.) in acetonitrile (1.9M) was added PdCl2(CH3CN)2 (0.015 eq.), Cs2CO3 (2.4 eq.) and 2-(dicyclohexylphosphino)-2′-6′-dimethoxy-1-1′-biphyl (S—PHOS; 0.044 eq.). The suspension was sonicated for 5 min then 3-methoxyprop-1-yne (1.7 eq.) was added. The final mixture was stirred 12 h at 100° C., cooled down to room temperature, diluted with diethylether. The organic fraction was washed with water, brine, dried over Na2SO4, filtered and concentrated. Purification by column chromatography on silica gel, eluting with CH2Cl2/Acetone 5% afforded the desired compound.
Reaction SMILES: Cl.[Br:2][C:3]1[C:21]([CH3:22])=[CH:20][C:6]([O:7][C@H:8]2[CH2:12][CH2:11][N:10]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:9]2=[O:19])=[C:5]([F:23])[CH:4]=1.C(N(C(C)C)C(C)C)C.Cl[C:34]1[N:39]=[CH:38][C:37]([CH2:40][CH3:41])=[CH:36][N:35]=1.O>CS(C)=O>[Br:2][C:3]1[C:21]([CH3:22])=[CH:20][C:6]([O:7][C@H:8]2[CH2:12][CH2:11][N:10]([CH:13]3[CH2:18][CH2:17][N:16]([C:34]4[N:39]=[CH:38][C:37]([CH2:40][CH3:41])=[CH:36][N:35]=4)[CH2:15][CH2:14]3)[C:9]2=[O:19])=[C:5]([F:23])[CH:4]=1
Reactant: CCc1cnc(Cl)nc1
Reactant: Cc1cc(O[C@H]2CCN(C3CCNCC3)C2=O)c(F)cc1Br
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: CCc1cnc(N2CCC(N3CC[C@H](Oc4cc(C)c(Br)cc4F)C3=O)CC2)nc1
Temperature: 110 °C
Yield: 59.9 %

Procedure:
(S)-3-(4-bromo-2-fluoro-5-methylphenoxy)-1-(piperidin-4-yl)pyrrolidin-2-one hydrochloride (600 mg, 1.47 mmol) was dissolved in DMSO (10 mL) and N-ethyl-N-isopropylpropan-2-amine (641 μl, 3.68 mmol) and 2-chloro-5-ethylpyrimidine (252 mg, 1.77 mmol) were added and the reaction heated to 110° C. overnight. The reaction was cooled to ambient temperature, poured into water and extracted with EtOAc, dried over Na2SO4, filtered and concentrated. The residue was purified over silica gel (60% EtOAc in hexanes) to afford (S)-3-(4-bromo-2-fluoro-5-methylphenoxy)-1-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)pyrrolidin-2-one (420 mg, 0.880 mmol, 59.8% yield) as a tan solid.
Reaction SMILES: [C:1]1([CH2:7][C@H:8]([NH:13][C:14]([C:16]2[CH:21]=[N:20][CH:19]=[CH:18][N:17]=2)=[O:15])[C:9]([O:11]C)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.C(N(CC)CC)C.[Li+].[Br-]>C(#N)C>[C:1]1([CH2:7][C@H:8]([NH:13][C:14]([C:16]2[CH:21]=[N:20][CH:19]=[CH:18][N:17]=2)=[O:15])[C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)c1cnccn1
Agent: [Br-]
Agent: [Li+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)O)c1cnccn1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Dissolve (S)-Methyl 3-phenyl-2-(pyrazine-2-carboxamido)propanoate (57.65 g) in 572 ml of acetonitrile and add 11.7 ml water and 84 ml of triethylamine. Cool the reaction mixture to 0° C. on ice bath and add 175.0 g of LiBr in several portions at vigorous stirring. After 10 minutes of stirring, increase the temperature to ambient temperature. (NB. A HPLC sample showed 99.97% conversion with 98.78% content of the desired product).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[O:8])=[C:5]([NH:12][C:13](=O)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH2:21][CH2:22][CH3:23])[CH:4]=1.[OH-].[Na+].Cl>N1C=CC=CC=1>[CH3:1][S:2][C:3]1[CH:4]=[C:5]2[C:6]([C:7](=[O:8])[NH:9][C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])=[N:12]2)=[CH:10][CH:11]=1
Reactant: CCCOc1ccccc1C(=O)Nc1cc(SC)ccc1C(N)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: CCCOc1ccccc1-c1nc2cc(SC)ccc2c(=O)[nH]1

Procedure:
A stirred solution of 4-methylthio-2-(2-propoxybenzamido)benzamide (0.85 g) and pyridine (1 ml) in 2 Normal aqueous sodium hydroxide was heated under reflux for 2 hours. The cooled reaction mixture was acidified with concentrated hydrochloric acid and the resultant mixture was extracted with chloroform (3×25 ml). The combined extracts were washed with water and then brine, dried (magnesium sulphate) and evaporated under reduced pressure to yield a solid which was recrystallised from ethanol to yield the title compound, 0.61 g, m.p. 156.5°-158.5° C.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([OH:14])=O)[CH:7]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.ClC(OC)=O.[NH2:30][C:31]1[CH:47]=[CH:46][C:34]([CH2:35][S:36]([CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])(=[O:38])=[O:37])=[CH:33][CH:32]=1>C(Cl)Cl.O>[CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:30][C:31]3[CH:32]=[CH:33][C:34]([CH2:35][S:36]([CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])(=[O:38])=[O:37])=[CH:46][CH:47]=3)=[O:14])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: CCCN(CC1CC1)c1cc(C(=O)O)ncn1
Reactant: CCOC(=O)CCS(=O)(=O)Cc1ccc(N)cc1
Agent: COC(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc(CS(=O)(=O)CCC(=O)OCC)cc2)ncn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A cooled (0° C.) solution of 6-((cyclopropylmethyl)(propyl)amino)pyrimidine-4-carboxylic acid (Intermediate 21, 0.2 g; 0.85 mmol) in DCM (5 ml) was treated with triethylamine (0.13 ml; 0.93 mmol) and methyl chloroformate (0.085 ml; 1.1 mmol). After stirring at 0° C. for 30 minutes, ethyl 3-(4-aminobenzylsulfonyl)propanoate (Intermediate 42, 230 mg; 0.85 mmol) was added. After stirring at 0° C. for 5 minutes and RT for 1 hour water was added and the mixture passed through a hydrophobic frit. The solvent was removed in vacuo and the residue purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc to give the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]([Cl:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)[N:3]=1.Cl[CH2:21][CH:22]=O.O>C(O)C>[Cl:12][C:11]1[C:2]2[N:3]([CH:21]=[CH:22][N:1]=2)[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:10]=1
Reactant: COC(=O)c1cc(Cl)c(N)nc1-c1cccc(F)c1
Reactant: O=CCCl
Solvent: CCO
Solvent: O
Product: COC(=O)c1cc(Cl)c2nccn2c1-c1cccc(F)c1
Yield: 87 %

Procedure:
A solution of methyl 6-amino-5-chloro-2-(3-fluorophenyl)nicotinate (0.19 g, 0.66 mmol) in ethanol (4 mL) at 60° C. was treated with 50 wt % chloroactaldehyde in water (0.34 mL, 2.6 mmol) dropwise. The reaction mixture was stirred at reflux for 2 hours. The reaction mixture was concentrated and purified by flash column chromatography with ethyl acetate in hexanes (0-60%) to give the desired product (180 mg, 87%). LCMS calculated for C15H11ClFN2O2 (M+H)+: m/z=305.0. found: 304.8.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]([CH2:19][CH2:20][O:21][CH3:22])[C:11](=[O:18])[C:12]([C:15]([OH:17])=O)=[CH:13][N:14]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.C(Cl)(=O)C(Cl)=O.[CH:29]12[CH2:36][CH:33]([CH2:34][CH2:35]1)[C:32](=[O:37])[CH2:31][C:30]2=[O:38].C(N(CC)CC)C.OC(C)(C)C#N>ClCCl.CN(C)C=O>[F:8][C:6]1[CH:5]=[C:4]([C:9]2[N:10]([CH2:19][CH2:20][O:21][CH3:22])[C:11](=[O:18])[C:12]([C:15]([C:31]3[C:32](=[O:37])[CH:33]4[CH2:36][CH:29]([CH2:35][CH2:34]4)[C:30]=3[OH:38])=[O:17])=[CH:13][N:14]=2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: O=C1CC(=O)C2CCC1C2
Reactant: COCCn1c(-c2cc(F)cc(F)c2)ncc(C(=O)O)c1=O
Agent: CC(C)(O)C#N
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCCn1c(-c2cc(F)cc(F)c2)ncc(C(=O)C2=C(O)C3CCC(C3)C2=O)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 2-(3,5-difluorophenyl)-1,6-dihydro-1-(2-methoxyethyl)-6-oxo-5-pyrimidinecarboxylic acid (i.e. the product from Example 9, Step D) (0.25 g, 0.81 mmol) in 10 mL of dichloromethane was added oxalyl chloride (0.21 g, 1.6 mmol) and one drop of N,N-dimethylformamide. The reaction mixture was stirred at room temperature for 2 h and then concentrated under reduced pressure. The remaining crude oil was re-dissolved in dichloromethane (10 mL) and then treated with bicyclo[3.2.1]octane-2,4-dione (0.12 g, 0.88 mmol) (prepared according to U.S. Pat. No. 6,815,563) and triethylamine (0.16 g, 1.6 mmol). After 30 min at room temperature, a catalytic amount of 2-hydroxy-2-methyl-propanenitrile (0.0075 g, 0.088 mmol) and triethylamine (0.16 g, 1.6 mmol) were added and the reaction mixture was stirred at ambient temperature over night. The reaction mixture was then concentrated under reduced pressure and purified by medium pressure liquid chromatography on silica gel eluting with 0 to 10% methanol in chloroform to provide 0.180 g of the title compound (also known as 3-[[2-(3,5-difluorophenyl)-1,6-dihydro-1-(2-methoxyethyl)-6-oxo-5-pyrimidinyl]carbonyl]biciclo[3.2.1]octane-2,4-dione), a compound of the present invention, as a solid.
Reaction SMILES: [CH2:1]([C:8]1[N:16]([CH2:17][CH2:18][NH:19][CH2:20][CH3:21])[C:15]2[C:14](=[O:22])[N:13]([CH2:23][CH2:24][CH3:25])[C:12](=[O:26])[N:11]([CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][C:32]([N+:35]([O-])=O)=[CH:31][CH:30]=3)[C:10]=2[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN.[H][H]>[Pd]>[NH2:35][C:32]1[CH:31]=[CH:30][C:29]([CH2:28][CH2:27][N:11]2[C:10]3[N:9]=[C:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[N:16]([CH2:17][CH2:18][NH:19][CH2:20][CH3:21])[C:15]=3[C:14](=[O:22])[N:13]([CH2:23][CH2:24][CH3:25])[C:12]2=[O:26])=[CH:34][CH:33]=1
Reactant: CCCn1c(=O)c2c(nc(Cc3ccccc3)n2CCNCC)n(CCc2ccc([N+](=O)[O-])cc2)c1=O
Reactant: [H][H]
Agent: [Pd]
Agent: NN
Solvent: O
Product: CCCn1c(=O)c2c(nc(Cc3ccccc3)n2CCNCC)n(CCc2ccc(N)cc2)c1=O

Procedure:
By the method of Example 3, 8-benzyl-3-[2-(4-nitrophenyl)ethyl]-1-propylxanthine, is reacted with sodium carbonate, 1,2-dichloroethane and ethylamine to yield 8-benzyl-7-(2-ethylamino)ethyl-3-[2-(4-nitrophenyl)ethyl]-1-propylxanthine. By the method of Example 4, 8-benzyl-7-(2-ethylamino)ethyl-3-[2-(4-nitrophenyl)ethyl]-1-propylxanthine is reduced with hydrazine hydrate or hydrogen gas in the presence of a palladium catalyst to yield 3-[2-(4-aminophenyl)ethyl]-8-benzyl-7-(2-ethylamino)ethyl-1-propylxanthine free base. The corresponding dihydrochloride salt is then made on exposure to an excess of hydrogen chloride in solution.
Reaction SMILES: [CH2:1]([C@H:8]([NH:18][C:19]([C:21]1[NH:22][C:23]2[C:28]([CH:29]=1)=[CH:27][C:26]([Cl:30])=[CH:25][CH:24]=2)=[O:20])[C:9]([N:11]1[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.ClC(Cl)C(O)=O>C1(C)C=CC=CC=1.CS(C)=O.C(OCC)(=O)C>[CH2:1]([C@H:8]([NH:18][C:19]([C:21]1[NH:22][C:23]2[C:28]([CH:29]=1)=[CH:27][C:26]([Cl:30])=[CH:25][CH:24]=2)=[O:20])[C:9](=[O:10])[N:11]1[CH2:12][CH2:13][C:14](=[O:17])[CH2:15][CH2:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)N1CCC(O)CC1)c1cc2cc(Cl)ccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C(O)C(Cl)Cl
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C1CCN(C(=O)[C@H](Cc2ccccc2)NC(=O)c2cc3cc(Cl)ccc3[nH]2)CC1
Temperature: 10 °C
Reaction time: 2 h

Procedure:
5-Chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-2-(4-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-amide (Example 46, 669 mg) was added in one portion at 0° C. to a mixture of 1-(3-dimethylaminopropyl)3-ethylcarbodiimide hydrochloride (DEC, 1.80 g, 9.4 mmol) and dichloroacetic acid (307 mg, 1.5 mmol) in anhydrous toluene (e mL) and anhydrous dimethylsulfoxide (e mL). The mixture was stirred at 0-20° C. for 2 h, diluted with ethyl acetate, the resulting solution washed twice with 1 N HCl, twice with saturated aqueous NaHCO3, dried, concentrated and the residue purified by chromatography on silica gel eluted with 25%, 50%, and 75% ethyl acetate-hexanes giving a foam (424 mg, 64%).
Reaction SMILES: Cl.[CH2:2]([NH:5][C:6]1[CH:16]=[CH:15][C:9]([CH2:10][CH2:11][C:12](Cl)=[O:13])=[CH:8][CH:7]=1)[CH:3]=[CH2:4].C(Cl)Cl.[OH:20][CH:21]([CH2:26][CH3:27])[C:22]([O:24][CH3:25])=[O:23].C(N(CC)CC)C>CCOCC>[CH2:2]([NH:5][C:6]1[CH:16]=[CH:15][C:9]([CH2:10][CH2:11][C:12]([O:20][CH:21]([C:22]([O:24][CH3:25])=[O:23])[CH2:26][CH3:27])=[O:13])=[CH:8][CH:7]=1)[CH:3]=[CH2:4]
Reactant: C=CCNc1ccc(CCC(=O)Cl)cc1
Reactant: CCC(O)C(=O)OC
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C=CCNc1ccc(CCC(=O)OC(CC)C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 10.0 g. 4-(allylamino)hydrocinnamoyl chloride hydrochloride in 200 ml. methylene chloride is added dropwise a solution of 3 g. methyl 2-hydroxybutyrate and 5 g. triethylamine in 100 ml. ether. After 17 hours stirring at room temperature, the precipitate is collected and washed with several portions of ether. The ether solution is washed with water, dried and evaporated to yield 1-(methoxycarbonyl)propyl 4-(allylamino)hydrocinnamate as a white solid.