Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:10]#[N:11])[CH:7]=[CH:8][CH:9]=1)(=O)[CH3:2].BrBr.[NH2:14][C:15](=[S:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17]>Cl.C(O)(=O)C.CCO>[C:10]([C:6]1[CH:5]=[C:4]([C:1]2[N:14]=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[S:21][CH:2]=2)[CH:9]=[CH:8][CH:7]=1)#[N:11]
Reactant: CCOC(=O)C(N)=S
Reactant: CC(=O)c1cccc(C#N)c1
Agent: BrBr
Agent: Cl
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)c1nc(-c2cccc(C#N)c2)cs1

Procedure:
At room temperature, 10 drops of a conc. aqueous hydrogen chloride solution are added to 5.00 g (34.4 mmol) of 3-acetylbenzenecarbonitrile in 40 ml of conc. acetic acid. 1.8 ml (34.4 mmol) of bromine in 10 ml of conc. acetic acid are subsequently added dropwise over a period of 1 h, and after the end of the addition, the reaction mixture is poured onto ice. After extraction of the aqueous phase with dichloromethane, the combined organic phases are dried over MgSO4, filtered and concentrated under reduced pressure. The solid obtained (8.00 g) is provided in 250 ml of EtOH and heated under reflux, a solution of 3.77 g (28.3 mmol) of ethyl amino(thioxo)acetate in 50 ml of ethanol is added dropwise and the mixture is stirred under reflux for 3 h. The reaction solution is cooled and the precipitate formed is collected by filtration. The mother liquor is concentrated under reduced pressure, the residue is taken up in a little ethanol and the solid formed is subsequently collected by filtration. 5.75 g (65% of theory) of the title compound are obtained after combining the solids.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:17])=[CH:9][C:10]2[CH:15]=[CH:14][C:13](O)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C(C1[O:22]C1)Cl.C(O)(C)C.[OH-].[Na+]>O>[OH:1][C:2]1([OH:22])[CH:7]=[CH:6][C:5]([C:8]([CH3:17])=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH2:3]1
Reactant: CC(=Cc1ccc(O)cc1)c1ccc(O)cc1
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CC(=Cc1ccccc1)C1=CCC(O)(O)C=C1
Temperature: 55 °C

Procedure:
4,4'-Dihydroxy-alpha-methylstilbene (152.73 grams, 1.35 hydroxyl equivalents) from A above, epichlorohydrin (624.58 grams, 6.75 moles), deionized water (54.31 grams, 8.0 percent by weight of the epichlorohyrin used) and isopropanol (336.31 grams, 35 percent by weight of the epichlorohydrin used) is added to a reactor and heated to 55° C. with stirring under a nitrogen atmosphere. Once the 55° C. reaction temperature is achieved, sodium hydroxide (48.6 grams, 1.22 moles) dissolves in deionized water (194.4 grams) is added dropwise to the reactor over a 45 minute period so as to maintain reaction temperature between 55° and 59° C. Ten minutes after completion of the aqueous sodium hydroxide addition, the stirring is stopped and the aqueous layer which separated from the reaction mixture is pipetted off and discarded. Stirring is resumed and after a total of twenty minutes following completion of the initial aqueous sodium hydroxide addition, a second solution of sodium hydroxide (21.6 grams, 0.54 mole) dissolved in deionized water (86.4 grams) is added to the reactor over a twenty minute period so as to maintain the 55° C. reaction temperature. Fifteen minutes after completion of the aqueous sodium hydroxide addition, the recovered reaction mixture is added to a separatory funnel and washed with 750 milliliters of deionized water. The separated organic layer is washed a second time (750 milliliters deionized water), recovered and then rotary evaporated under vacuum for 45 minutes at 110° C. then 30 minutes at 130° C. The product is recovered (218.6 grams) as a crystalline solid with an epoxide equivalent weight of 183.33.
Reaction SMILES: C(=O)(O)[O-].[Na+].[F:6][C:7]1[C:19]([F:20])=[C:18]([F:21])[C:17]([F:22])=[C:16]([F:23])[C:8]=1[O:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.[CH3:24][N:25]([CH2:27][CH2:28][CH2:29]Cl)[CH3:26]>CN(C)C=O>[CH3:24][N:25]([CH2:27][CH2:28][CH2:29][N:13]1[CH2:14][CH2:15][CH:10]([O:9][C:8]2[C:16]([F:23])=[C:17]([F:22])[C:18]([F:21])=[C:19]([F:20])[C:7]=2[F:6])[CH2:11][CH2:12]1)[CH3:26]
Reactant: Fc1c(F)c(F)c(OC2CCNCC2)c(F)c1F
Reactant: CN(C)CCCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCCN1CCC(Oc2c(F)c(F)c(F)c(F)c2F)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 51.9 %

Procedure:
A mixture of 10 g of sodium bicarbonate, 4.0 g of 4-(2,3,4,5,6-pentafluorophenoxy)piperidine, and 50 ml of dimethylformamide was treated, dropwise, with a solution of 2.00 g of dimethylaminopropyl chloride in 20 ml of dimethylformamide. After stirring at 80° C. for eight hours, the reaction mixture was filtered and the filtrate poured into water and extracted with ethyl acetate. The organic layer was washed with water followed by a saturated solution of sodium chloride and dried over anhydrous magnesium sulfate. After filtering, evaporation of the volatiles afforded a residue which was eluted with 20% methanol/dichloromethane on a silica gel column via flash chromatography. The desired fractions were evaporated to afford 2.74 g of 1-[3-(N,N-dimethylamino)propyl]-4-(2,3,4,5,6-pentaflurophenoxy)piperidine as an oil. The oil was dissolved in isopropanol and acidified to pH 1 with etheral hydrogen chloride to precipitate 1.8 g (28%) of 1-[3-dimethylaminopropyl]-4-(2,3,4,5,6-pentaflurophenoxy)piperidine hydrochloride, m.p. 260° C.(dec.).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[Cl:16][C:17]1(Cl)[CH2:22][O:21][CH2:20][CH2:19][O:18]1>>[C:6]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:19](=[O:18])[CH2:20][O:21][CH2:22][CH2:17][Cl:16])=[CH:15][CH:14]=1)(=[O:7])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: ClC1(Cl)COCCO1
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1
Product: O=C(COCCCl)Nc1ccc(C(=O)c2ccccc2)cc1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
A mixture of 1.60 g (8.12 mmol) of 4-aminobenzophenone and 1.11 g of 2-chlorodioxene (contains 6% of 2,2-dichlorodioxane) is heated at 80° C. with stirring for 24 hours, giving 2.6 g of N-(4-benzoylphenyl)-2-(2-chloroethoxy)acetamide as brown oil. ESI 318.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10](OCC)=[O:11])=[CH:4][C:3]=1[F:15].[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[CH2:10][OH:11])=[CH:4][C:3]=1[F:15]
Reactant: CCOC(=O)/C=C/c1ccc(Cl)c(F)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: OC/C=C/c1ccc(Cl)c(F)c1
Temperature: -78 °C
Yield: 93.8 %

Procedure:
(E)-Ethyl 3-(4-chloro-3-fluorophenyl)acrylate (18.3 g, 80.0 mmol) was combined with toluene (200 mL) and cooled to −78° C. Diisobutylaluminium hydride (“DIBAL-H”) (100 g, 176 mmol) (25% in toluene) was then added over one hour. The reaction was then allowed to agitate and warm up to ambient temperature over 2 hours. After agitating for an additional hour, the reaction was quenched with ice (200 g), and 6M HCl (100 mL) was added slowly. The aqueous layer was separated and extracted once with ethyl acetate. The combined organics were washed with brine, dried and evaporated to give a waxy solid, which was triturated with hexanes to give (E)-3-(4-chloro-3-fluorophenyl)prop-2-en-1-ol (14.0 g, 75.0 mmol, 93.7% yield) as a solid.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[C:14]2[N:13]=[CH:12][N:11]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=3)[C:10]=2[CH:9]=[C:8]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:7]=1)[CH:2]([CH3:4])[CH3:3].CN(C(ON1N=NC2[CH:41]=[CH:42][CH:43]=[N:44]C1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C1COCC1>[CH:43]1([NH:44][C:19](=[O:21])[C:18]2[CH:17]=[CH:16][C:15]([N:11]3[C:10]4[CH:9]=[C:8]([C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=5)[CH:7]=[C:6]([NH:5][CH2:1][CH:2]([CH3:3])[CH3:4])[C:14]=4[N:13]=[CH:12]3)=[CH:23][CH:22]=2)[CH2:41][CH2:42]1
Reactant: CC(C)CNc1cc(-c2ccccc2)cc2c1ncn2-c1ccc(C(=O)O)cc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CNc1cc(-c2ccccc2)cc2c1ncn2-c1ccc(C(=O)NC2CC2)cc1
Temperature: 23 °C
Reaction time: 20 h
Yield: 84.7 %

Procedure:
To a solution of 44 mg (114 μmol) 4-[4-(isobutylamino)-6-phenyl-1H-benzimidazol-1-yl]benzoic acid which was prepared according to intermediate example 4-2 in 2.8 mL THF were added 47.7 mg HATU, 22 μL N,N-diisopropylethylamine and the mixture was stirred at 23° C. for 20 hours. The solvent was removed and the residue purified by chromatography to give 41.0 mg (85%) of the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH2:5].[CH2:6]([N:24]=[C:25]=[O:26])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>>[CH2:6]([NH:24][C:25]([NH:1][CH2:2][CH2:3][CH2:4][NH2:5])=[O:26])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: NCCCN
Reactant: CCCCCCCCCCCCCCCCCCN=C=O
Product: CCCCCCCCCCCCCCCCCCNC(=O)NCCCN

Procedure:
19 grams (.25 mole) of 1,3 diaminopropane was reacted with 20 gms octadecyl isocyanate as in Example 2. Yield: 22.2 gms., melting point 116°-140°-150°C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[C:11]([NH:13][CH2:14][C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:18]=[CH:17][CH:16]=3)[C:10]([NH2:25])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[CH3:26][C:27](O)=O>>[CH3:26][C:27]1[N:13]([CH2:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)[C:11]2=[N:12][C:7]([N:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)=[CH:8][CH:9]=[C:10]2[N:25]=1
Reactant: CC(=O)O
Reactant: Nc1ccc(N2CCOCC2)nc1NCc1cccc2ccccc12
Product: Cc1nc2ccc(N3CCOCC3)nc2n1Cc1cccc2ccccc12
Temperature: 25 °C
Yield: 14 %

Procedure:
A mixture of 6-morpholino-N2-(naphthalen-1-ylmethyl)pyridine-2,3-diamine (3.2 g, 9.58 mmol) in CH3COOH (50 mL) was refluxed for 16 h. The mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by chromatography eluted with EtOAc/Pet Ether=1/1 and then recrystallized in EtOAc to afford the desired product as a pale solid (481 mg, 14%); LC/MS: MS (ES+) m/e 359 (MH+); 1H NMR (300 MHz, DMSO-d6) δ ppm 2.36 (s, 3H), 3.39 (t, J=4.8 Hz, 4H), 3.67 (t, J=4.8 Hz, 4H), 5.87 (s, 2H), 6.72-6.77 (m, 2H), 7.37-7.42 (m, 1H), 7.56-7.65 (m, 2H), 7.80 (d, J=8.7 Hz, 1H), 7.87 (d, J=8.4 Hz, 1H), 7.98-8.01 (m, 1H), 8.36-8.39 (m, 1H).
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9]CO)=[C:4]([C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:3]=1C.[OH-].[Na+]>C1(C)C=CC=CC=1>[C:8]([C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][C:4]=1[C:12]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:19])#[CH:9]
Reactant: Cc1ccc(C#CCO)c(C(=O)c2ccccc2)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: C#Cc1ccccc1C(=O)c1ccccc1
Temperature: 120 °C
Yield: 83.3 %

Procedure:
In a 100 ml two-necked flask having a reflux condenser were charged 2.6 g (9.9 mmol) of dimethylhydroxymethyl-2-benzoylphenylacetylene and 416 mg (10.4 mmol) of NaOH (Kishida Chemical Co., Ltd.; 0.7 mm particles, 98%) and air in the flask was replaced by Ar gas. 50 ml of toluene was added to the mixture and the mixture was heated at 120° C. under reflux for 0.25 hour. Toluene was added to the reaction mixture, and the mixture was washed with a saturated aqueous ammonium chloride solution and dried over magnesium sulfate. The solvent was removed by distillation under reduced pressure using an evaporator. The resultant crude reaction product was purified by column chromatography (Hexane/AcOEt=20/1) using silica gel to obtain 1.7 g of 2-ethynylbenzophenone as orange solid. (Yield: 82%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.[H-].[Na+].[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1/[CH:24]=[CH:25]/[CH2:26]Br.Cl>CN(C)C=O.C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH2:26]/[CH:25]=[CH:24]/[C:15]2[CH:16]=[CH:17][C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:14]=2)[C:9](=[O:11])[CH3:10])=[CH:6][CH:7]=1
Reactant: CC(=O)Cc1ccc(Cl)cc1
Reactant: BrC/C=C/c1ccc2ccccc2c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)C(C/C=C/c1ccc2ccccc2c1)c1ccc(Cl)cc1
Yield: 78 %

Procedure:
2.56 g of p-chlorophenylacetone was dissolved in a mixed solution of 5 ml of dimethylformamide and 5 ml of benzene, and a dimethylformamide 8 ml/benzene 8 ml solution containing 0.62 g of 60% oily sodium hydride and 3.50 g of (E)-3-(2-naphthyl)-2-propenyl bromide, was added under cooling with ice with stirring, followed by stirring at room temperature for 2 hours. The reaction solution was acidified by an addition of 1N hydrochloric acid and extracted by an addition of water and ethyl ether. Then, the organic layer was washed with a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The drying agent was filtered off, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1) to obtain 3.70 g of the above-identified compound.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:16]2[O:20][N:19]=[C:18]([C:21]([NH:23][CH:24]3[CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25]3)=[O:22])[N:17]=2)[CH2:11][C:12]([NH:14][OH:15])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[NH:26]1[CH2:25][CH:24]([NH:23][C:21]([C:18]2[N:17]=[C:16]([C@@H:10]([CH2:11][C:12]([NH:14][OH:15])=[O:13])[CH2:9][CH2:8][CH2:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[O:20][N:19]=2)=[O:22])[CH2:27]1
Reactant: CC(C)(C)OC(=O)N1CC(NC(=O)c2noc([C@H](CCCC3CCCCC3)CC(=O)NO)n2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(C[C@@H](CCCC1CCCCC1)c1nc(C(=O)NC2CNC2)no1)NO
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 98.2 %

Procedure:
A solution of tert-butyl 3-{[(5-{(1R)-4-cyclohexyl-1-[2-(hydroxyamino)-2-oxoethyl]butyl}-1,2,4-oxadiazol-3-yl)carbonyl]amino}-1-azetidinecarboxylate (Example 43) (160 mg, 0.33 mmol) in dichloromethane (10 ml) was cooled to 0° C. and treated with trifluoroacetic acid (7 ml) and the resulting mixture was stirred at 0° C. under a nitrogen atmosphere for 45 minutes. The solvent was removed under reduced pressure and the residue azeotroped from dichloromethane (×2). The residue was triturated with diethylether, filtered and dried to afford the title compound as a white solid (123 mg).
Reaction SMILES: [Cl:1][C:2]1[C:6]2[CH:7]=[C:8]([CH:20]=O)[C:9]([N:12]3[CH2:17][C@@H:16]([CH3:18])[O:15][C@H:14]([CH3:19])[CH2:13]3)=[C:10]([F:11])[C:5]=2[O:4][N:3]=1.[NH:22]1[C:27](=[O:28])[CH2:26][C:25](=[O:29])[NH:24][C:23]1=[O:30]>CC(O)C>[Cl:1][C:2]1[C:6]2[CH:7]=[C:8]3[C:9](=[C:10]([F:11])[C:5]=2[O:4][N:3]=1)[N:12]1[CH2:17][C@@H:16]([CH3:18])[O:15][C@@H:14]([CH3:19])[C@@H:13]1[C:26]1([C:25](=[O:29])[NH:24][C:23](=[O:30])[NH:22][C:27]1=[O:28])[CH2:20]3
Reactant: O=C1CC(=O)NC(=O)N1
Reactant: C[C@@H]1CN(c2c(C=O)cc3c(Cl)noc3c2F)C[C@@H](C)O1
Solvent: CC(C)O
Product: C[C@@H]1CN2c3c(cc4c(Cl)noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1
Yield: 26.5 %

Procedure:
A mixture of 3-chloro-6-((2R,6R)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-5-carbaldehyde (Intermediate 535, 764 mg, 2.44 mmol) and pyrimidine-2,4,6(1H,3H,5H)-trione (313 mg, 2.44 mmol) in iPrOH (3 ml) was heated at reflux for 3 days. Solvent was removed and the residue was recrystallized from methanol. The solids obtained were recrystallized from 1:1 EtOH-Water to afford 273 mg of product consistent with desired product.
Reaction SMILES: [C@@H:1]1([O:12][C:13]2[C:17]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[C:16]([CH3:27])[N:15]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:14]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].CC1C=CC=C(C)N=1.Cl[C:43]([O:45][CH2:46][CH3:47])=[O:44].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(#N)C>[CH2:46]([O:45][C:43]([O:11][CH2:10][C@H:8]1[O:9][C@@H:1]([O:12][C:13]2[C:17]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[C:16]([CH3:27])[N:15]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:14]=2)[C@H:2]([OH:3])[C@@H:4]([OH:5])[C@@H:6]1[OH:7])=[O:44])[CH3:47]
Reactant: COc1ccc(Cc2c(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)nn(-c3ccccc3)c2C)cc1
Reactant: CCOC(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CC#N
Solvent: Cc1cccc(C)n1
Product: CCOC(=O)OC[C@H]1O[C@@H](Oc2nn(-c3ccccc3)c(C)c2Cc2ccc(OC)cc2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(β-D-glucopyranosyloxy)-4-[(4-methoxyphenyl)methyl]-5-methyl-1-phenyl-1H-pyrazole (0.18 g) and 2,6-dimethylpyridine (0.069 mL) in acetonitrile (5 mL) was added ethyl chloroformate (0.045 mL), and the mixture was stirred at room temperature overnight. To the reaction mixture was added 10% aqueous citric acid solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=15/1) to give the title compound (0.13 g).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].C(=O)([O-])[O-].[K+].[K+].[NH:19]1[CH2:26][CH2:25][CH2:24][C@@H:20]1[C:21]([OH:23])=[O:22]>CN(C)C(=O)C.O.[Cu]I>[CH2:8]([O:7][C:5]([C:4]1[CH:3]=[C:2]([N:19]2[CH2:26][CH2:25][CH2:24][C@@H:20]2[C:21]([OH:23])=[O:22])[CH:12]=[CH:11][CH:10]=1)=[O:6])[CH3:9]
Reactant: O=C(O)[C@H]1CCCN1
Reactant: CCOC(=O)c1cccc(I)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1cccc(N2CCC[C@@H]2C(=O)O)c1
Temperature: 25 °C
Yield: 19.2 %

Procedure:
Add ethyl 3-iodobenzoate (1.5 mL, 8.9 mmol), potassium carbonate (1.3 g, 9.4 mmol) and copper (I) iodide (0.17 g, 0.89 mmol) to a solution of D-proline (1.00 g, 8.69 mmol) in N,N-dimethylacetamide (20 mL). Bubble Argon through the mixture for 30 min then heat the reaction to 90° C. for 15 hours. Cool the mixture to room temperature, dilute with water, and filter to remove insoluble material. Wash the filtrate with diethyl ether and adjust the pH of the aqueous phase to slightly acidic by the addition of a 2 N solution of hydrochloric acid. Extract the mixture with methylene chloride and wash the combined organic phase with brine. Dry over anhydrous sodium sulfate and concentrate under reduced pressure to provide an oil. Re-dissolve the material in methylene chloride and concentrate under a stream of nitrogen to provide 0.44 g (19.2%) of (R)-1-(3-ethoxycarbonyl-phenyl)-pyrrolidine-2-carboxylic acid as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](O)=[O:19])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[C:21]([C:24]1[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=1[NH2:26])(=[O:23])[CH3:22]>C(O)(=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](=[O:19])[NH:26][C:25]3[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=3[C:21](=[O:23])[CH3:22])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: O=C(O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Reactant: CC(=O)c1ccccc1N
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(=O)c1ccccc1NC(=O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Yield: 16.4 %

Procedure:
A procedure similar to that described in Example 51 was carried out with 9-bromo-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (170 mg, 1 mmol) and o-acetylaniline (90 mg, 0.67 mmol) to give 50 mg of the title compound (21%) after chromatography of the crude product on a silica gel column with 1% acetic acid/ethyl acetate as an eluent: mp>270° C.; 1H NMR (270 MHz, DMSO-d6) δ12.06 (bs, 1H), 11.12 (s, 1H), 8.20 (bd, 1H, J=8.1 Hz), 7.96 (d, 2H, J=8.1 Hz), 7.60 (t, 1H, J=8.1 Hz), 7.23 (t, 1H, J=8.1 Hz), 7.23 (d, 1H, J =2 Hz), 7.17 (d, 1H, J=2 Hz), 5.14~5.26 (m, 1H), 3.04 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.83 (dm, 1H, J=17.1 Hz), 2.64~2.76 (m, 2H), 2.60 (s, 3H), 2.16 (dm, 1H, J=13.5 Hz), 1.82~1.97 (m, 1H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][CH:18]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl[C:27]1[N:32]=[CH:31][C:30]([CH2:33][CH3:34])=[CH:29][N:28]=1>>[CH2:33]([C:30]1[CH:29]=[N:28][C:27]([N:23]2[CH2:24][CH2:25][CH:20]([CH:18]3[O:17][C:14]4=[CH:15][N:16]=[C:11]([C:8]5[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=5)[CH:12]=[C:13]4[CH2:19]3)[CH2:21][CH2:22]2)=[N:32][CH:31]=1)[CH3:34]
Reactant: CCc1cnc(Cl)nc1
Reactant: CS(=O)(=O)c1ccc(-c2cc3c(cn2)OC(C2CCNCC2)C3)cc1
Product: CCc1cnc(N2CCC(C3Cc4cc(-c5ccc(S(C)(=O)=O)cc5)ncc4O3)CC2)nc1

Procedure:
The title compound is prepared from 5-(4-methanesulfonyl-phenyl)-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine and 2-chloro-5-ethylpyrimidine following a procedure analogous to that described in Example 1. LC (method 5): tR=1.14 min; Mass spectrum (ESI+): m/z=465 [M+H]+.
Reaction SMILES: Cl.CC1(C)[O:7][CH:6]([CH2:8][N:9]2[C:21]3[C:20]4[CH:19]=[CH:18][C:17]([C:22]5[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=5)=[CH:16][C:15]=4[N:14]=[C:13]([NH2:28])[C:12]=3[N:11]=[C:10]2[CH2:29][O:30][CH2:31][CH3:32])[CH2:5][O:4]1>C1COCC1>[NH2:28][C:13]1[C:12]2[N:11]=[C:10]([CH2:29][O:30][CH2:31][CH3:32])[N:9]([CH2:8][CH:6]([OH:7])[CH2:5][OH:4])[C:21]=2[C:20]2[CH:19]=[CH:18][C:17]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)=[CH:16][C:15]=2[N:14]=1
Reactant: CCOCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1CC1COC(C)(C)O1
Agent: Cl
Solvent: C1CCOC1
Product: CCOCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1CC(O)CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.6 %

Procedure:
Hydrochloric acid (12 mL of 1 N) was added to a solution of 1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine (0.75 g, 1.73 mmol) in THF, and the reaction was stirred overnight at ambient temperature. The THF was removed under reduced pressure, and 1% aqueous sodium hydroxide was added to the remaining solution to adjust to pH 9. A precipitate formed, was isolated by filtration, washed with water, and dried in an oven at 60° C. to provide 0.61 g of 3-[4-amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]propane-1,2-diol as a white solid, mp 218–220° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2F)=[N:10][NH2:11])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+]>CN1CCCC1=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:11][N:10]=2)=[CH:4][CH:3]=1
Reactant: NN=C(Nc1ccc(Br)cc1)c1ccccc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Brc1ccc(Nc2n[nH]c3ccccc23)cc1
Temperature: 100 °C
Yield: 25.6 %

Procedure:
To a solution of N1-(4-bromophenyl)-2-fluoro-1-benzenecarbohydrazonamide (1.2 g, 0.00391 mol) in N-methylpyrrolidinone (25 mL), potassium tert-butoxide (0.50 g, 0.0041 mol) was added and the resulting solution was heated at 100° C. under an atmosphere of nitrogen for 3 hours. The reaction mixture was cooled to ambient temperature, the solvent was removed under reduced pressure and the residue partitioned between saturated solution of sodium bicarbonate in water (50 mL) and ethyl acetate (50 mL). The organic phase was washed with brine, dried with magnesium sulfate and concentrated. The residue was purified by flash chromatography on silica using ethyl acetate/n-heptane (1:5) as mobile phase to yield N-(4-bromophenyl)-N-(1H-3-indazolyl)amine (0.29 g, 0.0010 mol) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].[C:10](N1C=CN=C1)(N1C=CN=C1)=[O:11]>C(Cl)Cl.C(#N)C>[F:8][C:6]1[CH:5]=[CH:4][C:3]2[O:9][C:10](=[O:11])[NH:1][C:2]=2[CH:7]=1
Reactant: Nc1cc(F)ccc1O
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CC#N
Product: O=c1[nH]c2cc(F)ccc2o1

Procedure:
A solution of 2-amino-4-fluorophenol (4.0 g), carbonyldiimidazole (1.7 g) in DCM (100 ml) and acetonitrile (30 ml) was stirred at RT for 5 h. The solvent was removed under reduced pressure and the residue purified by chromatography on silica eluting with 30% ethylacetate/isohexane, yield 4.0 g.