Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(S([NH2:10])(=O)=O)C=CC=CC=1.[OH-].[Na+].[CH:13]1([N:19]=[C:20]=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.O>CC(C)=O>[CH:13]1([NH:19][C:20](=[O:21])[NH2:10])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: NS(=O)(=O)c1ccccc1
Reactant: O=C=NC1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: NC(=O)NC1CCCCC1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
6.0 g of 4-(β-<1-ethyl-1,2-dihydro-2-oxo-nicotinamido>-ethyl)-benzenesulfonamide (melting point 215 - 216° C, prepared from 4-(β-aminoethyl)-benzenesulfonamide and 1-ethyl-1,2-dihydro-2-oxo-nicotinic acid chloride) were suspended in 60 ml acetone. After the addition of 8.55 ml 2N sodium hydroxide solution, the reaction mixture was cooled to 0° C, 2.35 g of cyclohexyl isocyanate in 5 ml acetone were added dropwise while stirring and stirring was continued for 1 hour at 0° C and for 4 hours at room temperature. The volume of the reaction mixture was then doubled by adding water, the mixture was filtered and the filtrate acidified with 2N hydrochloric acid. The precipitate was dissolved in dilute ammonia solution and precipitated again with dilute hydrochloric acid, stirred with sodium bicarbonate solution and recrystallized from methanol. The N-[4-(β-<1-ethyl-1,2-dihydro-2-oxo-nicotinamido>-ethyl)-benzenesulfonyl]-N'-cyclohexyl urea obtained in this manner melted at 189 - 190° C.
Reaction SMILES: [CH3:1]/[C:2](=[CH:9]\[C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[CH:13]2)/[C:3]([NH:5][CH2:6][CH2:7][CH3:8])=[O:4].Br[CH2:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][C:22]=1[O:31][CH3:32].C(OCC)(=O)C>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[CH3:32][O:31][C:22]1[CH:23]=[C:24]([CH:29]=[CH:30][C:21]=1[CH2:20][C:13]1[C:12]2[C:16](=[CH:17][CH:18]=[C:10](/[CH:9]=[C:2](/[C:3](=[O:4])[NH:5][CH2:6][CH2:7][CH3:8])\[CH3:1])[CH:11]=2)[NH:15][CH:14]=1)[C:25]([O:27][CH3:28])=[O:26]
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Reactant: CCCNC(=O)/C(C)=C/c1ccc2[nH]ccc2c1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCCNC(=O)/C(C)=C/c1ccc2[nH]cc(Cc3ccc(C(=O)OC)cc3OC)c2c1
Yield: 53.3 %

Procedure:
A mixture of E-α-methyl-N-propylindol-5-acrylamide (1.75 g) and silver carbonate (1.99 g) in dry toluene (30 ml) was stirred and heated under reflux for 18 hr, under an atmosphere of nitrogen. The mixture was cooled to 80°, methyl 4-bromomethyl-3-methoxybenzoate (2.06 g) added, and the mixture stirred at 85° for 15 hours. The mixture was cooled, ethyl acetate (50 ml) added, the salts were removed by filtration through diatomaceous earth, the filter pad was washed with ethyl acetate, and the filtrate evaporated. The product was purified by flash chromatography, eluting with 5:2:3 hexane:methylene chloride:ethyl acetate, to give methyl E-3-methoxy-4-[5-[2-(propylcarbamoyl)-1-propenyl]indol-3-ylmethyl]benzoate (1.62 g, 53%) as a solid foam; mp 55°-60°; partial NMR (250 MHz, DMSO-d6): 0.87(t, 3H, CH2CH2CH3), 1.47(m, 2H, CH2CH2CH3), 1.99 (d, J=0.98 Hz, 3H, CCH3), 3.10(m, 2H, CH2CH2CH3), 3.82(s, 3H, OCH3), 3.91(s, 3H, OCH3), 4.05(s, 2H, ArCH2Ar'), 7.93(br t, NHCO), 11.0(br s, 1H, H1 -indole).
Reaction SMILES: C(O[C:4]([C:6]1[N:11]=[CH:10][C:9]2[N:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[C:17]([Cl:22])[CH:16]=3)[S:14][C:8]=2[C:7]=1[OH:23])=[O:5])C.[NH2:24][CH2:25][C:26]([OH:28])=[O:27].C[O-].[Na+].CO>>[Cl:22][C:17]1[CH:16]=[C:15]([C:13]2[S:14][C:8]3[C:7]([OH:23])=[C:6]([C:4]([NH:24][CH2:25][C:26]([OH:28])=[O:27])=[O:5])[N:11]=[CH:10][C:9]=3[N:12]=2)[CH:20]=[CH:19][C:18]=1[F:21]
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1ncc2nc(-c3ccc(F)c(Cl)c3)sc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)CNC(=O)c1ncc2nc(-c3ccc(F)c(Cl)c3)sc2c1O
Temperature: 25 °C
Yield: 52.4 %

Procedure:
A mixture of 2-(3-chloro-4-fluoro-phenyl)-7-hydroxy-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (101 mg, 0.29 mmole) and glycine (429 mg, 5.72 mmole) in 0.5 M sodium methoxide/methanol (10.9 ml, 5.43 mmole) was refluxed for 4 days before it was cooled to room temperature and concentrated in vacuo. The residue was dissolved in water (100 ml) and extracted with dichloromethane (3×50 ml). The remaining aqueous layer was acidified to pH=3 with 1N HCl (6.5 ml). The resulting precipitate was filtered, washed with water and dried in vacuo to give the title compound as a brown solid (58 mg). 1H NMR (DMSO-d6, 200 MHz): δ=9.50 (br s, 1H), 8.89 (s, 1H), 8.36 (m, 1H), 8.16 (m, 1H), 7.65 (t, 1H), 4.03 (d, 2H, J=5.8 Hz); MS: (+) m/z 382.19 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=O.C(N(CC)CC)C.C(Cl)(=O)OCC(C)C.[NH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.Cl>ClCCl>[Cl:1][C:2]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([NH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:10]
Reactant: O=C(O)CCCOc1ccc(Cl)cc1Cl
Reactant: Nc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCCOc1ccc(Cl)cc1Cl)Nc1ccccc1
Temperature: -30 °C
Reaction time: 3 h
Yield: 77.1 %

Procedure:
To a solution of the 4-(2,4-dichloro-phenoxy)-butyric acid (9.8 g, 40 mmol) and triethylamine (6.0 ml, 40 mmol) in dichloromethane (150 mL) was added dropwise isobutyl chlorocarbonate (6 mL, 40 mol) at −30° C. After stirring at −30° C. for 3 h, aniline (4 mL 40 mol) was added dropwise. The reaction mixture was stirred for 3 h at −30° C. and then allowed to warm up to RT. Aqueous HCl (5%, 100 mL) was added and stirring was continued for 0.5 h. The phases were separated, the aqueous layer was extracted with dichloromethane (2×200 mL). The combined organic extracts were washed with water and brine, dried over Na2SO4 and concentrated in vacuo to give the product (10 g, 77.5%). 1H-NMR (CDCl2): δ 7.49 (d, 2H, J=8.0 Hz), 7.38 (d, 1H, J=2.4 Hz), 7.31 (t, 2H, J=8.0 Hz), 7.18 (dd, 1H, J1=8.8 Hz, J2=2.4 Hz) 7.12 (t, 1H, J=8.0), 6.87 (d, 1H, J=8.8 Hz), 4.12 (t, 2H, J=6.4 Hz), 2.64 (t, 2H, J=6.4 Hz), 2.25 (p, 2H, J=6.4 Hz).
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:49][O:50][C:51]1[CH:52]=[C:53]([C:59]2[CH:64]=[CH:63][CH:62]=[C:61]([NH2:65])[CH:60]=2)[CH:54]=[CH:55][C:56]=1[O:57][CH3:58]>CN(C=O)C>[CH3:49][O:50][C:51]1[CH:52]=[C:53]([C:59]2[CH:64]=[CH:63][CH:62]=[C:61]([NH:65][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:60]=2)[CH:54]=[CH:55][C:56]=1[O:57][CH3:58]
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Reactant: COc1ccc(-c2cccc(N)c2)cc1OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2cccc(NC(=O)c3cc4cccc(O)c4oc3=O)c2)cc1OC
Temperature: 25 °C
Yield: 18.4 %

Procedure:
DIEA (0.013 mL, 0.072 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.014 g, 0.065 mmol) and HATU (0.027 g, 0.072 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3′,4′-Dimethoxy-biphenyl-3-ylamine (0.015 g, 0.065 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and the solvent removed under vacuum to give 0.005 g of product in 19% yield: LCMS (ESI) m/z 418 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:23]=[C:22]([CH2:24][CH3:25])[CH:21]=[CH:20][C:10]=1[O:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][C:13]=1[F:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:33][CH2:34][CH2:35][OH:36]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:23]=[C:22]([CH2:24][CH3:25])[CH:21]=[CH:20][C:10]=1[O:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][CH2:33][CH2:34][CH2:35][OH:36])=[CH:14][C:13]=1[F:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCCCBr
Reactant: CCc1ccc(Oc2ccc(N)cc2F)c(OCc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1ccc(Oc2ccc(NCCCO)cc2F)c(OCc2ccccc2)c1
Reaction time: 2 h
Yield: 68.3 %

Procedure:
4-[2-(benzyloxy)-4-ethylphenoxy]-3-fluoroaniline (500 mg, 1.48 mmol), K2CO3 (1.23 g, 8.9 mmol) and 3-bromo-1-propanol (410 mg, 2.9 mmol) were taken in dry DMF (2 ml) in a microwave vial and was subjected to microwave at 180° C. for 2 h. The reaction mixture was filtered over celite and the residue washed thoroughly with ethyl acetate. The combined organic fractions including the filtrate were washed with water, brine, dried over Na2SO4 and concentrated. The crude obtained was combined with earlier crude products obtained from a 100 mg and 200 mg batches and purified together by column chromatography over silica gel using 40% ethylacetate in pet ether as eluant to get 400 mg (42.6%) of pure title compound.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[CH:11]=[C:12]([O:15][CH2:16][CH3:17])[CH:13]=[CH:14][C:9]=3[NH:8][C:7]2=[O:18])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:19][O:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[C:25]([O:33][CH3:34])[CH:24]=1)=[O:22]>>[CH:1]1([N:6]2[C:10]3[CH:11]=[C:12]([O:15][CH2:16][CH3:17])[CH:13]=[CH:14][C:9]=3[N:8]([S:29]([C:26]3[CH:27]=[CH:28][C:23]([C:21]([O:20][CH3:19])=[O:22])=[CH:24][C:25]=3[O:33][CH3:34])(=[O:31])=[O:30])[C:7]2=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)c(OC)c1
Reactant: CCOc1ccc2[nH]c(=O)n(C3CCCC3)c2c1
Product: CCOc1ccc2c(c1)n(C1CCCC1)c(=O)n2S(=O)(=O)c1ccc(C(=O)OC)cc1OC
Yield: 72.7 %

Procedure:
This compound is prepared by the procedure described in EXAMPLE 107 step A) starting from 1 g of 3- cyclopentyl-5-ethoxy-1,3-dihydro-2H-benzimidazol-2-one and 1.2 g of 4-methoxycarbonyl-2-methoxybenzenesulfonyl chloride. It is chromatographed on silica using a DCM/AcOEt mixture (95/5; v/v) as the eluent to give 1.4 g of the expected product. M.p.=151° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C@H:6]([NH2:11])[CH2:5]2.Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>ClCCl>[CH2:16]([O:15][C:13](=[O:14])[NH:11][C@@H:6]1[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=2)[CH2:7]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: N[C@H]1Cc2ccc(Br)cc2C1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Product: O=C(N[C@H]1Cc2ccc(Br)cc2C1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
(S)-5-Bromo-indan-2-ylamine (1.0 g) suspended in dichloromethane (10 ml) is cooled to 0° C. and benzyl chloroformate (0.74 ml) is added dropwise and the reaction mixture is stirred for 0.5 hour. The solution is filtered to give (S)-(5-Bromo-indan-2-yl)-carbamic acid benzyl ester. PdCl2(dppf)2 (59 mg) is placed in a dry flask under argon and isobutyl zinc bromide (50 ml, 0.5 M solution in THF) is added. (5-Bromo-indan-2-yl)-carbamic acid benzyl ester (2.50 g) is dissolved in dry THF (2 ml) and the solution is added to the reaction mixture. The reaction mixture is stirred at 50° C. for 18 hours then quenched with HCl(aq) (2M) and partitioned between ethyl acetate and water. The organic layer is dried over MgSO4, filtered and the solvent removed in vacuo. The title compound is obtained by flash column chromatography (silica, eluent ethyl acetate/iso-hexane 1:4). 1H nmr (CDCl3, 400 MHz); 7.35 (m, 5H), 7.10 (d, 1H), 7.00 (s, 1H), 6.90 (d, 1H), 5.1 (s, 2H), 4.55 (m, 1H), 3.30 (m, 2H), 2.75 (dt, 2H), 2.45 (d, 2H), 1.80 (m, 1H), 0.90 (d, 6H).
Reaction SMILES: [C-]1C2C(=CC=CC=2)C=CC=1.[Li+].C1(S[C:19]2([O:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:25][CH:24]=3)[CH2:21][CH2:20]2)C=CC=CC=1.[N:35]1[CH:40]=[CH:39][CH:38]=[C:37]([CH2:41][CH2:42][CH:43]=[O:44])[CH:36]=1>O1CCCC1>[C:26]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:25]=[CH:24][C:23]([O:22][C:19]2([CH:43]([OH:44])[CH2:42][CH2:41][C:37]3[CH:36]=[N:35][CH:40]=[CH:39][CH:38]=3)[CH2:20][CH2:21]2)=[CH:28][CH:27]=1
Reactant: c1ccc(SC2(Oc3ccc(-c4ccccc4)cc3)CC2)cc1
Reactant: O=CCCc1cccnc1
Agent: [Li+]
Agent: [c-]1cccc2ccccc12
Solvent: C1CCOC1
Product: OC(CCc1cccnc1)C1(Oc2ccc(-c3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Lithium naphthalenide (0.625M, 7.4 ml; prepared by adding equimolar quantities of naphthalene and lithium metal to tetrahydrofuran, under nitrogen, and stirring at room temperature overnight) was added slowly to a stirred solution of 4-(1-phenylsulfanyl-cyclopropoxy)biphenyl (0.7 g) in dry tetrahydrofuran at −78° C., under nitrogen, and then stirred at this temperature for 15 minutes. To this was added a solution of 3-pyridinepropanal (0.3 g, prepared according to the method of Example 3 of International Patent Application No. WO-A-92/19593) in dry tetrahydrofuran (15 ml), and the stirring was continued at −78° C. for 5 minutes, then allowed to warm up to room temperature. The reaction was quenched with saturated aqueous ammonium chloride solution, and extracted into diethyl ether (3×30 ml). The combined extracts were washed with brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a pale yellow gum, which was further purified by reverse phase HPLC to give the title compound as a pale yellow gum (0.11 g).
Reaction SMILES: S([O-])(O[CH3:5])(=O)=O.[F:7][C:8]([C:11]1[C:12](=[O:25])[C:13]([OH:24])=[N:14][N:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:16]=1[CH3:17])([F:10])[F:9]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.CCOCC>[F:9][C:8]([C:11]1[C:12](=[O:25])[C:13]([O:24][CH3:5])=[N:14][N:15]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:16]=1[CH3:17])([F:7])[F:10]
Reactant: Cc1c(C(F)(F)F)c(=O)c(O)nn1-c1ccccc1
Reactant: COS(=O)(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1nn(-c2ccccc2)c(C)c(C(F)(F)F)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
Tetrabutylammonium bromide (635 mg), 6N soda (13 ml), and methyl sulfate (5.59 ml) are added to a solution of Compound 1 (5.31 grams) in THF. After 1 hour 30 minutes of stirring at 25° C., the solution is evaporated under vacuum, dissolved in water, and extracted with ethyl acetate. After washing with water, drying, filtration and evaporation under vacuum, a residue is obtained which is dissolved in ether and recrystallized from a 60/40 mixture of dioxane and hexane, to provide Compound 2 (3.97 grams; yield 71%).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][S:7][C:8]2[C:9](=[O:16])[O:10][C:11]([CH3:15])=[CH:12][C:13]=2[OH:14])=[CH:4][CH:3]=1.[OH:19]O>C(O)(=O)C>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][S:7]([C:8]2[C:9](=[O:16])[O:10][C:11]([CH3:15])=[CH:12][C:13]=2[OH:14])=[O:19])=[CH:4][CH:3]=1
Reactant: Cc1cc(O)c(SCc2ccc(Cl)cc2)c(=O)o1
Reactant: OO
Solvent: CC(=O)O
Product: Cc1cc(O)c(S(=O)Cc2ccc(Cl)cc2)c(=O)o1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3-p-Chlorobenzylthio-4-hydroxy-6-methyl-2-pyrone (11.3 g., 0.0400 mol), 30% hydrogen peroxide (5.14 g., 0.0440 mol) and 50 ml. glacial acetic acid were combined and stirred at room temperature for 4 hours. Then stored at room temperature over night. The reaction mixture, containing a crystalline solid, was added to 200 ml. of icewater. The precipitate was collected and dried. The solids were recrystallized from a mixture of cyclohexane-toluene to recover 8.6 g. (72 percent) of the desired compound, m.p. 150°-151°C. One additional recrystallization from cyclo-hexane-toluene gave the pure compound as white platelets, m.p. 151°-152°C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9]2)([O-:3])=[O:2].[H-].[Na+].Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>CN(C)C=O>[CH2:25]([O:24][C:22]([CH2:21][N:11]1[C:12]2[C:8](=[CH:7][CH:6]=[CH:5][C:4]=2[N+:1]([O-:3])=[O:2])[CH:9]=[C:10]1[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:23])[CH3:26]
Reactant: CCOC(=O)c1cc2cccc([N+](=O)[O-])c2[nH]1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(C(=O)OCC)cc2cccc([N+](=O)[O-])c21
Temperature: 25 °C
Yield: 78 %

Procedure:
To a solution of ethyl 7-nitro-1H-indole-2-carboxylate (2.00 g, 8.45 mmol) in N,N-dimethylformamide (50 ml) was added 60% sodium hydride (0.34 g, 8.54 mmol), and the reaction mixture was stirred at room temperature until it became transparent. Then, ethyl bromoacetate (1.43 g, 8.54 mmol) was added and the resulting mixture was stirred at 50-60° C. for 4 hours. The reaction mixture was cooled to room temperature and poured into ice water, followed by extraction with ethyl acetate (three times). The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: ethyl acetate/n-hexane=5/95) to obtain ethyl 1-ethoxycarbonylmethyl-7-nitro-1H-indole-2-carboxylate (2.11 g).
Reaction SMILES: Cl.[CH:2]([NH2:4])=[NH:3].CC[O-].[Na+].[CH3:9][O:10][CH:11]([C:16](OC)=[O:17])[C:12](OC)=[O:13].C(O)(=O)C>C(O)C>[CH3:9][O:10][C:11]1[C:12]([OH:13])=[N:3][CH:2]=[N:4][C:16]=1[OH:17]
Reactant: N=CN
Reactant: COC(=O)C(OC)C(=O)OC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: COc1c(O)ncnc1O
Temperature: 25 °C

Procedure:
5 g (6.2 mmoles) of formamidine hydrochloride is added at 0° C. and in small quantities into a single-necked flask containing 30 ml of absolute ethanol and 90 ml of a solution of sodium ethylate at a concentration of 1.7 mol/l in ethanol. Stirring is maintained at ambient temperature for about twenty minutes, then 8.5 ml of dimethyl methoxymalonate is added dropwise. Stirring is maintained for 16 hours. The reaction mixture is then acidified with pure acetic acid to a pH between 4 and 5, then concentrated to dryness in the presence of cyclohexane. After impasting the crude product obtained is chromatographed on silicagel eluting with a mixture of methylene chloride-methanol (85-15) and 2% water-acetic acid (1-1). 9.5 g of the expected product is obtained containing a small quantity of sodium acetate salts.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[CH2:11][C:10](=[O:15])[CH2:9]2)=[CH:4][CH:3]=1.[Br:16]Br>CC(O)=O>[Br:16][CH:11]1[C:12](=[O:14])[CH2:13][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:9][C:10]1=[O:15]
Reactant: O=C1CC(=O)CC(c2ccc(Cl)cc2)C1
Reactant: BrBr
Solvent: CC(=O)O
Product: O=C1CC(c2ccc(Cl)cc2)CC(=O)C1Br
Yield: 29.3 %

Procedure:
To a stirred solution of 5-(4-chlorophenyl)cyclohexane-1,3-dione (5 g, 22.6 mmol) in AcOH (40 mL) at r.t. was added bromine (3.61 g, 1.15 mL, 22.6 mmol) dropwise. The reaction was then carried out according to Method A to give the title compound (2.0 g, 66%) as a white solid. δH (DMSO-d6) 7.38 (4H, m), 3.41-3.38 (1H, m), 2.97-2.85 (2H, m), 2.67 (2H, dd, J 16.4 and 4.2 Hz), 2.50 (1H, bs).
Reaction SMILES: [NH2:1][C@H:2]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:3]([N:5]1[CH2:10][CH2:9][CH:8]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][C:12]2=[O:18])[CH2:7][CH2:6]1)=[O:4].[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1>C(#N)C>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:1][C@@H:2]([C:3]([N:5]2[CH2:10][CH2:9][CH:8]([N:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][C:12]3=[O:18])[CH2:7][CH2:6]2)=[O:4])[C:19]([CH3:22])([CH3:21])[CH3:20])=[O:32])=[CH:26][CH:25]=1
Reactant: CN1CCN(C2CCN(C(=O)[C@H](N)C(C)(C)C)CC2)C(=O)C1
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: CC#N
Product: CN1CCN(C2CCN(C(=O)[C@H](NC(=O)Nc3ccc(Cl)cc3)C(C)(C)C)CC2)C(=O)C1
Yield: 26.7 %

Procedure:
To a solution of 1-(1-((2R)-2-amino-3,3-dimethylbutyroyl)-4-piperidinyl)-4-methylpiperazin-2-one (0.12 g) obtained in Example 103d) in acetonitrile (5 ml) was added 4-chlorophenyl isocyanate (57 mg), and mixed at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified with silica gel column (ethyl acetate) to obtain the title compound as colorless powder (46 mg, 27%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][NH2:8].[CH2:9]([O:11][C:12](=[O:19])[CH:13]([CH:17]=O)[C:14](=O)[CH3:15])[CH3:10].N1C=CC=CC=1>C(O)C>[CH2:9]([O:11][C:12]([C:13]1[C:14]([CH3:15])=[N:8][N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH:17]=1)=[O:19])[CH3:10]
Reactant: CCOC(=O)C(C=O)C(C)=O
Reactant: NNc1ccccn1
Solvent: CCO
Solvent: c1ccncc1
Product: CCOC(=O)c1cn(-c2ccccn2)nc1C

Procedure:
Similar to Example 1, equimolar amounts of 2-pyridylhydrazine and 2-formyl-3-oxo-butyric acid ethyl ester were combined in a solution of 50% pyridine in ethanol. Analysis showed that the resulting solid was determined to be the named product (m.p. 49° C.-50° C.).
Reaction SMILES: O.[C:2]1([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=[C:4]([OH:5])[CH:3]=1.[F:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:22])=[C:16]([S:18](Cl)(=[O:20])=[O:19])[CH:17]=1.C([O-])(O)=O.[Na+]>C(OCC)C>[F:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:22])=[C:16]([S:18]([O:5][C:4]2[CH:3]=[C:2]([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=2)(=[O:20])=[O:19])[CH:17]=1
Reactant: Cc1cc(O)cc(O)c1
Reactant: Cc1ccc(F)cc1S(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: Cc1cc(O)cc(OS(=O)(=O)c2cc(F)ccc2C)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 100.6 %

Procedure:
To a solution of 1.00 g (8.05 mmol) of orcinol monohydrate and 1.63 g (7.38 mmol) of 5-fluoro-2-methylbenzenesulfonyl chloride in 20 mL of diethyl ether was added 20 mL of saturated aqueous NaHCO3 and the biphasic mixture stirred vigorously at ambient temperature for 3 days. The layers were separated and the aqueous layer extracted with 2×30 mL of ethyl acetate. The combined organic layers were washed with 50 mL of brine, dried (Na2SO4) and concentrated to give 2.2 g of an orange syrup. Crystallization from dichloromethane-hexane (two crops) afforded 1.24 g (54%) of the title compound as a light orange powder: 1H-NMR (300 MHz; CDCl3) δ 7.57 (dd, 1H, J=8.2, 2.8 Hz), 7.36 (dd, 1H, J=8.6, 5.2 Hz), 7.22 (td, 1H, J=8.4, 2.8 Hz), 6.52 (m, 1H), 6.39 (m, 1H), 6.30 (t, 1H, J=2.2 Hz), 2.69 (s, 3H) and 2.21 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.C(O[CH2:16][O:17][CH2:18][CH2:19][O:20][C:21](=[O:23])[CH3:22])(=O)C>>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:16][O:17][CH2:18][CH2:19][O:20][C:21](=[O:23])[CH3:22])=[C:4]([Cl:11])[N:3]=1
Reactant: CC(=O)OCCOCOC(C)=O
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Product: CC(=O)OCCOCn1cnc2c(Cl)nc(Cl)nc21
Temperature: 138 °C
Reaction time: 0.33 h
Yield: 64 %

Procedure:
2,6-Dichloropurine 5.5 g and 2-oxa-1,4-butanediol diacetate 513 g were placed in a flask and partially evacuated and then heated to 138° C., initially the mixture was too thick to stir but gradually gave rise to a melt which was stirred, and after 20 minutes was completely melted and the reaction mixture heated for 10 minutes more (total heat time = 30 minutes). The mixture was then cooled to room temperature and para-toluenesulphonic acid 150 mg was added, the vacuum reapplied and heating resumed with stirring. After 20 minutes heating vigorous bubbling was noted; the mixture was cooled to room temperature; chloroform was added, and the solution was extracted once with saturated aqueous sodium bicarbonate and once with water. The chloroform phase was dried over anhydrous sodium sulphate and evaporated. The residual oil was dissolved in benzene and applied to a column of 200 g. of silica gel in benzene. Benzene elution removed the acetate by-products. Ether elution gave 2,6-dichloro-9-(2-acetyloxyethoxymethyl)purine (64% yield). Recrystallization from benzene gave lustrous white flakes, m.p. 96°-99° C.