Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:6][C:7]([OH:9])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:22][C:23]1[C:28]2[C:29](=[O:43])[N:30]3[CH2:42][CH2:41][C@H:31]3[C:32]3[N:33]([CH:34]=[N:35][C:36]=3[C:37](=[N:39]O)[NH2:38])[C:27]=2[CH:26]=[CH:25][CH:24]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C=O>[Cl:22][C:23]1[C:28]2[C:29](=[O:43])[N:30]3[CH2:42][CH2:41][C@H:31]3[C:32]3[N:33]([CH:34]=[N:35][C:36]=3[C:37]3[N:39]=[C:7]([CH2:6][N:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)[O:9][N:38]=3)[C:27]=2[CH:26]=[CH:25][CH:24]=1
Reactant: NC(=NO)c1ncn2c1[C@@H]1CCN1C(=O)c1c(Cl)cccc1-2
Reactant: O=C(O)CN1CCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: O=C1c2c(Cl)cccc2-n2cnc(-c3noc(CN4CCCC4)n3)c2[C@@H]2CCN12
Reaction time: 8 h
Yield: 31.7 %

Procedure:
2.55 g (13.5 mmol) of 1-pyrrolidine-acetic acid were dissolved in 20 ml of N,N-dimethylformamide and treated portionwise with 2.6 g (15.9 mmol) of 1,1'-carbonyldiimidazole. After stirring for 45 minutes 3.9 g (12.3 mmol) of (S)-8-chloro-12,12a-dihydro-9-oxo-9H,11H- azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxamidoxime were added and the mixture was stirred at 90° overnight. 0.2 g of p-toluenesulphonic acid was added and the mixture was stirred at 90° for a further 4 hours. The reaction mixture was concentrated. By chromatography of the residue on silica gel while eluting with methylene chloride/methanol 19/1 and recrystallization from ethyl acetate and hexane there were obtained 1.6 g (32%) of (S)-8-chloro-12,12a-dihydro-1-[5-(pyrrolidin-1-ylmethyl)-1,2,4-oxadiazol-3-yl]-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one of m.p. 117°-120°, which was converted into the hydrochloride.
Reaction SMILES: [C:1]([O:6]CC)(=O)[CH:2]([CH3:4])[OH:3].[CH2:9]([NH2:12])[CH2:10][CH3:11]>>[CH2:9]([NH:12][C:1](=[O:6])[CH:2]([CH3:4])[OH:3])[CH2:10][CH3:11]
Reactant: CCOC(=O)C(C)O
Reactant: CCCN
Product: CCCNC(=O)C(C)O
Temperature: 60 °C
Reaction time: 16 h
Yield: 76.2 %

Procedure:
A mixture of 35.4 gm (0.3 mole) of ethyl lactate and 19.4 gm (0.33 mole) of propylamine were stirred together at 60° C. for 16 hours and subsequently distilled under reduced pressure. 30 gm (76% of theory) of N-propyl-lactic acid amide of boiling point 152° C./9 torr and of refractive index (nD20) 1.4563 were obtained.
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6][C:7](=[NH:9])S.[OH-].[Na+].[NH2:12][CH2:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]([OH:22])=[O:21])[CH2:16][CH2:15]1>O>[NH:12]([CH2:13][C@H:14]1[CH2:15][CH2:16][C@H:17]([C:20]([OH:22])=[O:21])[CH2:18][CH2:19]1)[C:7]([NH2:9])=[NH:6]
Reactant: N=C(N)S
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: N=C(N)NC[C@H]1CC[C@H](C(=O)O)CC1

Procedure:
Isothiourea sulfate (21.2 g) was dissolved in water (40 ml) and a 2N solution of sodium hydroxide (46 ml) was dropwise added under ice-cooling. The mixture was stirred at said temperature for 30 minutes and trans-4-aminomethylcyclohexanecarboxylic acid dissolved in boiling water (100 ml) was dropwise added and the mixture was stirred at room temperature for 24 hours. After completion of the reaction, the reaction mixture was cooled and the resultant crystals were collected by filtration. The crystals were thoroughly washed with cold water and dried to give 18.5 g of trans-4-guanidinomethylcyclohexanecarboxylic acid, melting point 325° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[C:5]([Cl:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[CH:22]=[C:23]([CH2:27][CH2:28][CH2:29][OH:30])[CH:24]=[CH:25][CH:26]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>O1CCOCC1>[Cl:19][C:5]1[C:6]([NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)=[N:7][C:2]([NH:20][C:21]2[CH:22]=[C:23]([CH2:27][CH2:28][CH2:29][OH:30])[CH:24]=[CH:25][CH:26]=2)=[N:3][CH:4]=1
Reactant: Nc1cccc(CCCO)c1
Reactant: COc1cccc(CCNc2nc(Cl)ncc2Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cccc(CCNc2nc(Nc3cccc(CCCO)c3)ncc2Cl)c1
Temperature: 100 °C
Yield: 90.3 %

Procedure:
To a solution of 2,5-dichloro-N-[2-(3-methoxyphenyl)ethyl]pyrimidin-4-amine (0.50 g, 1.7 mmol) (prepared according to Example 8, Step A) and 3-(3-aminophenyl)propan-1-ol (0.34 g, 2.3 mmol) in 1,4-dioxane (14.3 mL) was added p-toluenesulfonic acid monohydrate (0.12 g, 0.61 mmol). The mixture was heated at 100° C. for 16 hours and the reaction was complete. To the mixture was added NaHCO3 aqueous solution (saturated). The organic solvent was removed under vacuum. Water and EtOAc were added to the residue. The aqueous layer was extracted with EtOAc twice. The combined organic layers were dried over Na2SO4, filtered, and concentrated (then triturated with cold EtOAc) to give the desired product as a light brown gel (0.634 g, 92%). LCMS for C22H26ClN4O2 (M+H)+: m/z=413.0.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:44])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH2:41][CH3:42])([C:22]3[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]([OH:39])([C:35]([F:38])([F:37])[F:36])[C:31]([F:34])([F:33])[F:32])=[C:24]([CH3:40])[CH:23]=3)[CH2:20][CH3:21])=[CH:15][C:14]=2[CH3:43])=[CH:9][CH:8]=1>CO.O1CCCC1>[CH2:20]([C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:10]2[CH:11]=[CH:12][C:7]([CH2:6][C:5]([OH:44])=[O:4])=[CH:8][CH:9]=2)=[C:14]([CH3:43])[CH:15]=1)([C:22]1[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]([OH:39])([C:31]([F:33])([F:34])[F:32])[C:35]([F:37])([F:38])[F:36])=[C:24]([CH3:40])[CH:23]=1)[CH2:41][CH3:42])[CH3:21]
Reactant: CCC(CC)(c1ccc(/C=C/C(O)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)cc2)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(/C=C/C(O)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(-c2ccc(CC(=O)O)cc2)c(C)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 60.5 %

Procedure:
A 1 N sodium hydroxide aqueous solution (0.071 mL, 0.071 mmol) was added to a solution of (4′-{1-ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-1-butenyl)-phenyl]-propyl}-2′-methyl-biphenyl-4-yl)acetic acid methyl ester (Example 46-(1); 14.1 mg, 0.024 mmol) in methanol-tetrahydrofuran (1:1, 1 mL), and the mixture was stirred at 60° C. for one hour. Then, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform:methanol=10:3, saturated with water) to give the target compound as a colorless oil (8.4 mg, 61%).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[ClH:9].[F:10][C:11]1[CH:12]=[C:13]([CH:35]=[CH:36][CH:37]=1)[CH2:14][N:15]1[C:19]2=[C:20]([N:24]3[CH2:33][CH2:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH2:25]3)[N:21]=[CH:22][CH:23]=[C:18]2[CH:17]=[C:16]1[CH3:34]>ClCCl>[ClH:9].[Br:1][C:17]1[C:18]2[C:19](=[C:20]([N:24]3[CH2:33][CH2:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH2:25]3)[N:21]=[CH:22][CH:23]=2)[N:15]([CH2:14][C:13]2[CH:35]=[CH:36][CH:37]=[C:11]([F:10])[CH:12]=2)[C:16]=1[CH3:34]
Reactant: Cc1cc2ccnc(N3CCc4ccccc4C3)c2n1Cc1cccc(F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: Cl
Solvent: ClCCl
Product: Cc1c(Br)c2ccnc(N3CCc4ccccc4C3)c2n1Cc1cccc(F)c1
Reaction time: 1 h
Yield: 8.9 %

Procedure:
N-Bromosuccinimide (41 mg, 0.23 mmol) and silica gel (100 mg) were added to a solution of 2-[1-(3-fluorobenzyl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-7-yl]-1,2,3,4-tetrahydroisoquinoline hydrochloride (88 mg, 0.23 mmol) prepared in Example 613 in dichloromethane (2 ml). The reaction mixture was stirred for 1 hour and then filtered. The resulting filtrate was concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/5, v/v). The resulting product was dissolved in ethyl acetate, saturated with hydrochloric acid gas, and then filtered to give 10 mg of the titled compound as a white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10](=[O:12])[NH:9][C:8]3[CH:13]=[CH:14][CH:15]=[CH:16][C:7]2=3)[CH2:3][CH2:2]1.[CH2:17]1[O:27][C:20]2([CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]2)[O:19][CH2:18]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[O:19]1[C:20]2([CH2:25][CH2:24][CH:23]([N:1]3[CH2:2][CH2:3][C:4]4([O:11][C:10](=[O:12])[NH:9][C:8]5[CH:13]=[CH:14][CH:15]=[CH:16][C:7]4=5)[CH2:5][CH2:6]3)[CH2:22][CH2:21]2)[O:27][CH2:17][CH2:18]1
Reactant: O=C1Nc2ccccc2C2(CCNCC2)O1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: O=C1Nc2ccccc2C2(CCN(C3CCC4(CC3)OCCO4)CC2)O1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
Spiro[4H-3,1-benzoxazine-4,4′-piperidin]-2(1H)-one (A4) (400 mg, 1.83 mmol) was suspended in anhydrous 1,2-dichloroethane (8.0 mL) and treated with 1,4-cyclohexanedione mono-ethylene ketal (viia) (429 mg, 2.75 mmol), glacial acetic acid (220 mg, 3.66 mmol), and sodium triacetoxyborohydride (776 mg, 3.66 mmol). The reaction flask was flushed with nitrogen and stirred for 60 hours at room temperature. The reaction was diluted with dichloromethane (25 mL), quenched with 1.0 N NaOH (10 mL), and stirred at room temperature vigorously for 30 minutes. The layers were separated and the aqueous layer was extracted once with dichloromethane (10 mL). The pooled organic layers were washed with water (1×25 mL) and saturated brine (1×25 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to afford crude 1′-(1,4-dioxaspiro[4.5]decan-8-yl)spiro[benzo[d][1,3]oxazine-4,4′-piperidin]-2(1H)-one (viiib) as a white solid. LC/MS m/z 359.2 [M+H]+, retention time 1.61 min (RP-C18, 10-99% CH3CN/0.05% TFA).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([NH2:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[Br:12]Br>CC(O)=O>[CH3:1][C:2]1[NH:3][C:4]2[C:10]([Br:12])=[C:9]([NH2:11])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: BrBr
Reactant: Cc1nc2ccc(N)cc2[nH]1
Solvent: CC(=O)O
Product: Cc1nc2ccc(N)c(Br)c2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.6 %

Procedure:
To a solution of 0.9 g (6.1 mmol) of 2-methyl-5-aminobenzimidazole in 50 ml of AcOH was added 0.16 ml of Br2 (3.1 mmol) dropwise and resulting reaction mixture was stirred for 1 h at 25° C. Reaction mixture was concentrated in vacuo and purified on silica gel column chromatography (20% Isopropanol/EtOAC) to yield 0.56 g (2.5 mmol, 41%) of the desired product.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-])=O.Br[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-Nitrophenol (25.0 g, 180 mmol) and ethyl bromoacetate (20.0 ml, 180 mmol) were dissolved in N,N-dimethylformamide (40 ml), and potassium carbonate (27.4 g, 198 mmol) was added. The mixture was stirred at room temperature for 16 hours under a nitrogen atmosphere. The reaction mixture was poured into water (100 ml) and extracted with an equivalent mixture of n-hexane and ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, low boiling matters were distilled away from the filtrate under reduced pressure to quantitatively give 40.5 g of ethyl 4-aminophenoxyacetate as a colorless solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:10])[NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1B(O)O)([CH3:13])[CH3:12].C(N(CC)CC)C>ClCCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]([CH3:10])[NH:9][C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([CH:11]([CH3:13])[CH3:12])[CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)c1ccccc1B(O)O
Reactant: CN(N)C(=O)OC(C)(C)C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC(C)c1cccc(NN(C)C(=O)OC(C)(C)C)c1
Temperature: 50 °C
Yield: 26.7 %

Procedure:
A mixture of N-methyl-hydrazinecarboxylic acid tert-butyl ester (Intermediate 1; 300 mg, 2.05 mmol), 2-isopropylphenylboronic acid (Lancaster; 330 mg, 2.01 mmol), copper(II) acetate (373 mg, 2.05 mmol) and triethylamine (287 μL, 2.05 mmol) in 1,2-dichloroethane (4 mL) was heated in an oil bath at 50° C. for 3 h. The mixture was allowed to cool, and it was then adsorbed onto silica gel and purified by chromatography using an ISCO 40 g column, eluting with 5% ethyl acetate/hexanes, to give N′-(3-isopropyl-phenyl)-N-methyl-hydrazinecarboxylic acid tert-butyl ester (142 mg, 26%) as an oil.
Reaction SMILES: [F:1][C:2]1[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)[CH:11]=2)=[C:6]([F:25])[CH:5]=[CH:4][C:3]=1[OH:26].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:34][C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36].O>CN(C=O)C>[F:1][C:2]1[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)[CH:11]=2)=[C:6]([F:25])[CH:5]=[CH:4][C:3]=1[O:26][CH2:34][C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36]
Reactant: COc1cc(CNc2c(F)ccc(O)c2F)cc(-c2cccc(F)c2)c1
Reactant: CC(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(CNc2c(F)ccc(OCC(=O)OC(C)C)c2F)cc(-c2cccc(F)c2)c1
Reaction time: 1 h
Yield: 62.6 %

Procedure:
To a solution of 2,4-difluoro-3-[[3-(3-fluorophenyl)-5-methoxy-phenyl]methylamino]phenol (see example 16) (1.0 g, 2.78 mmol, 1.0 eq) in DMF (10 mL) was added Cs2CO3 (1.36 g, 3.34 mmol, 1.5 eq) at room temperature. The reaction mixture was stirred for 1 h, then isopropyl 2-bromoacetate (624 mg, 3.34 mmol, 1.2 eq) was added and the reaction mixture was stirred for h. The resulting mixture was poured into water and extracted with EtOAc. The organic extract was washed with water and brine, dried (Na2SO4) and evaporated in vacuo. The residue obtained was purified by column chromatography, (EtOAc:petroleum ether 0:1 to 1:20) to give the title compound as a colourless oil (0.8 g, 62%).
Reaction SMILES: [CH3:1][CH:2]([CH3:9])[CH2:3][C:4]([O:6][CH2:7]Br)=[O:5].[C:10]([O:13][CH2:14][C:15]1[CH2:16][S:17][C@@H:18]2[C@H:25]([NH:26][C:27](=[O:37])/[C:28](/[C:32]3[O:33][CH:34]=[CH:35][CH:36]=3)=[N:29]\[O:30][CH3:31])[C:24](=[O:38])[N:19]2[C:20]=1[C:21]([OH:23])=[O:22])(=[O:12])[NH2:11].[K]>CN(C)C=O>[C:10]([O:13][CH2:14][C:15]1[CH2:16][S:17][C@@H:18]2[C@H:25]([NH:26][C:27](=[O:37])/[C:28](/[C:32]3[O:33][CH:34]=[CH:35][CH:36]=3)=[N:29]\[O:30][CH3:31])[C:24](=[O:38])[N:19]2[C:20]=1[C:21]([O:23][CH2:7][O:6][C:4](=[O:5])[CH2:3][CH:2]([CH3:9])[CH3:1])=[O:22])(=[O:12])[NH2:11]
Reactant: CC(C)CC(=O)OCBr
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(N)=O)CS[C@H]12)c1ccco1
Agent: [K]
Solvent: CN(C)C=O
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OCOC(=O)CC(C)C)=C(COC(N)=O)CS[C@H]12)c1ccco1

Procedure:
Bromomethyl 3-methylbutanoate (1.328 g, 6.7 mmole) was added to a solution of (6R,7R)-3-carbamoyloxymethyl-7-[(Z)-2-(fur-2-yl)-2-methoxyiminoacetamido]ceph-3-em-4-carboxylic acid, potassium salt (2.772 g, 6 mmole) in purified N,N dimethylformamide (18 ml). The mixture was allowed to react for 15 minutes and was then worked up as described in Example 4 to give the slightly impure title compound (2.809 g).
Reaction SMILES: NC1C=CC=CC=1.F[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16]>C(N(C(C)C)CC)(C)C>[N+:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:9]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1ccccc1F
Solvent: Nc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccccc1
Temperature: 120 °C
Reaction time: 16 h
Yield: 402.9 %

Procedure:
0.46 mL (5.0 mmole) of aniline was added to a 10 mL diisopropylethylamine solution of 437 mg (1.0 mmole) of fluoronitrobenzene compound (1B-8) and the mixture was stirred for 16 hours at 120° C. The solvent was removed under reduced pressure, 1N hydrochloride was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with anhydrous magnesium sulfate. The solvent was removed under reduced pressure, yielding 496 mg (97 percent) of nitrobenzene compound (1B-9).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]([OH:10])=O)[C:4]([CH3:11])=[N:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClN1C(=O)CCC1=O.[CH:39]1([CH2:42][N:43]2[C:51]3[N:50]=[C:49]([CH2:52][C:53]4[CH:58]=[CH:57][C:56]([NH:59][CH3:60])=[CH:55][CH:54]=4)[NH:48][C:47]=3[C:46](=[O:61])[N:45]([CH2:62][C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][C:64]=3[F:69])[C:44]2=[O:70])[CH2:41][CH2:40]1>ClCCl>[CH:39]1([CH2:42][N:43]2[C:51]3[N:50]=[C:49]([CH2:52][C:53]4[CH:54]=[CH:55][C:56]([N:59]([CH3:60])[C:8]([C:5]5[C:4]([CH3:11])=[N:3][N:2]([CH3:1])[C:6]=5[CH3:7])=[O:10])=[CH:57][CH:58]=4)[NH:48][C:47]=3[C:46](=[O:61])[N:45]([CH2:62][C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][C:64]=3[F:69])[C:44]2=[O:70])[CH2:41][CH2:40]1
Reactant: CNc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Reactant: Cc1nn(C)c(C)c1C(=O)O
Agent: O=C1CCC(=O)N1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1nn(C)c(C)c1C(=O)N(C)c1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64.5 %

Procedure:
A mixture of 1,3,5-trimethyl-1H-pyrazole-4-carboxylic acid (71 mg, 0.46 mmol) in dichloromethane (2.5 mL) at 0° C. was treated with triphenylphosphine (145 mg, 0.55 mmol) and N-chlorosuccinimide (74 mg, 0.55 mmol). This mixture was stirred at 0° C. for 30 min and then was warmed to 25° C. for 10 min. At this time, the reaction was treated with a solution of 3-cyclopropylmethyl-1-(2-fluoro-benzyl)-8-(4-methylamino-benzyl)-3,7-dihydro-purine-2,6-dione (400 mg, 0.92 mmol) in dichloromethane (2.5 mL). The reaction was stirred at 25° C. for 24 h. At this time, the reaction was diluted with dichloromethane (50 mL) and then was washed with a saturated aqueous sodium bicarbonate solution (1×50 mL). The aqueous layer was re-extracted with dichloromethane (2×50 mL). The combined organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 3:97 methanol/dichloromethane) afforded impure product. The resulting residue was purified by HPLC (15–60% acetonitrile/water (0.075% trifluoroacetic acid in both solvents) over 40 min). Fractions with the desired product were combined and concentrated in vacuo. The resulting residue was diluted with dichloromethane (50 mL) and was washed with a saturated aqueous sodium bicarbonate solution (50 mL). The water layer was re-extracted with dichloromethane (2×50 mL). The organic layers were combined and dried with magnesium sulfate, filtered and concentrated under reduced pressure. The resulting solid was dried in vacuo for 24 h to afford 1,3,5-trimethyl-1H-pyrazole-4-carboxylic acid {4-[3-cyclopropylmethyl-1-(2-fluoro-benzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-phenyl}-methyl-amide (169 mg, 65%) as a white solid: (ES)+-HRMS m/e calcd for C31H32N7O3F (M+H)+ 570.2623, found 570.2619.
Reaction SMILES: Br[C:2]1[C:11]([O:12][C:13]2[C:22]3[C:17](=[CH:18][C:19]([O:25][CH3:26])=[C:20]([O:23][CH3:24])[CH:21]=3)[N:16]=[CH:15][CH:14]=2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29](B(O)O)[CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:24][O:23][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][C:19]=1[O:25][CH3:26])[N:16]=[CH:15][CH:14]=[C:13]2[O:12][C:11]1[C:2]([C:29]2[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=2)=[N:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: OB(O)c1cccnc1
Reactant: COc1cc2nccc(Oc3cc4ccccc4nc3Br)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3cc4ccccc4nc3-c3cccnc3)c2cc1OC
Temperature: 25 °C
Yield: 32.1 %

Procedure:
4-(2-Bromo-quinolin-3-yloxy)-6,7-dimethoxy-quinoline (compound 281) (50 mg), tetrakistriphenylphosphine palladium(0) (14 mg), and 3-pyridineboronic acid (42 mg) were suspended in a mixed solvent composed of N,N-dimethylformamide (1 ml) and a 2 N aqueous potassium carbonate solution (1 ml), and the mixture was stirred at 80° C. for 3 hr. The reaction solution was cooled to room temperature, the reaction solution was then filtered, and the solvent was removed from the filtrate by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-chloroform to give the title compound (16 mg, yield 33%).
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][C:5]1[C:9]2[C:10]([Cl:28])=[CH:11][C:12]([O:15][CH2:16][C:17]3[C:18]([CH3:27])=[N:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=3)=[C:13]([F:14])[C:8]=2[S:7][CH:6]=1.C1COCC1.[OH-].[Na+].Cl>CO>[Cl:28][C:10]1[C:9]2[C:5]([CH2:4][C:3]([OH:29])=[O:2])=[CH:6][S:7][C:8]=2[C:13]([F:14])=[C:12]([O:15][CH2:16][C:17]2[C:18]([CH3:27])=[N:19][C:20]([C:23]([F:24])([F:26])[F:25])=[CH:21][CH:22]=2)[CH:11]=1
Reactant: COC(=O)Cc1csc2c(F)c(OCc3ccc(C(F)(F)F)nc3C)cc(Cl)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc(C(F)(F)F)ccc1COc1cc(Cl)c2c(CC(=O)O)csc2c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
To a mixture of methyl(4-chloro-7-fluoro-6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methoxy)-1-benzothiophen-3-yl)acetate (150.2 mg), THF (dry) (1.5 mL) and MeOH (1.5 mL) was added 1N NaOH (1.01 mL). The mixture was stirred at room temperature for 2 h. The mixture was neutralized with 1N HCl. The resulting precipitate was collected by filtration to give a solid. The solid was crystallized from EtOAc-hexane to give the title compound (126.6 mg).
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].[F:15][CH:16]([F:39])[C:17]1[N:37]=[CH:36][C:35]([CH3:38])=[CH:34][C:18]=1[C:19]([NH:21][C:22]1[C:31]2[CH2:30][CH2:29][C:28]([CH3:33])([CH3:32])[CH2:27][C:26]=2[CH:25]=[CH:24][CH:23]=1)=O>O1CCOCC1>[F:15][CH:16]([F:39])[C:17]1[C:18]([C:19](=[S:2])[NH:21][C:22]2[C:31]3[CH2:30][CH2:29][C:28]([CH3:33])([CH3:32])[CH2:27][C:26]=3[CH:25]=[CH:24][CH:23]=2)=[CH:34][C:35]([CH3:38])=[CH:36][N:37]=1
Reactant: Cc1cnc(C(F)F)c(C(=O)Nc2cccc3c2CCC(C)(C)C3)c1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: C1COCCO1
Product: Cc1cnc(C(F)F)c(C(=S)Nc2cccc3c2CCC(C)(C)C3)c1
Yield: 91 %

Procedure:
In a microwave sealable tube, P2S5 (36 mg, 0.164 mmol, 0.5 eq) is added to a solution of 2-(difluoromethyl)-N-(6,6-dimethyl-5,6,7,8-tetrahydronaphthalen-1-yl)-5-methylnicotinamide (113 mg, 0.32 mmol, 1 eq) in 3 ml of dioxane. The tube is sealed and the reaction is microwaved 20 min at 130° C. The resulting solution is filtered through alumina and washed with dioxane. The solvent is evaporated and the residue purified by chromatography on silica gel to give pure material (91%)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:7]=[C:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[CH:20]=O)[CH:9]=[C:10]([Cl:12])[CH:11]=1)[CH3:2].[CH2:23]([NH2:25])[CH3:24]>>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:7]=[C:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[CH2:20][NH:25][CH2:23][CH3:24])[CH:9]=[C:10]([Cl:12])[CH:11]=1)[CH3:2]
Reactant: CCN
Reactant: CCOC(=O)Cc1cc(Cl)cc(-c2ccc(F)cc2C=O)c1
Product: CCNCc1cc(F)ccc1-c1cc(Cl)cc(CC(=O)OCC)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 5, using the following starting materials: (5-chloro-4′-fluoro-2′-formyl-biphenyl-3-yl)-acetic acid ethyl ester and ethylamine (2M in THF).