Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:8][CH:9]=2)[NH:4][N:3]=1.[CH3:15]C(C)([O-])C.[K+].IC>C1COCC1>[I:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([S:11]([CH3:14])(=[O:12])=[O:13])=[CH:8][CH:9]=2)[N:4]([CH3:15])[N:3]=1
Reactant: CC(C)(C)[O-]
Reactant: CS(=O)(=O)c1ccc2c(I)n[nH]c2c1
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: Cn1nc(I)c2ccc(S(C)(=O)=O)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60.7 %

Procedure:
In a round-bottomed flask, 3-iodo-6-methylsulfonyl-1H-indazole (396 mg, 1.23 mmol) was dissolved in THF (4.4 ml). The orange solution was cooled to 0° C. and potassium tert-butoxide (200 mg, 1.78 mmol) was added. The reaction mixture was stirred at 0° C. for 30 min then iodomethane (0.11 ml, 1.76 mmol) was added dropwise. After the addition was complete, the ice bath was removed and the reaction mixture was stirred at room temperature for 4 h then quenched with water and extracted with EtOAc (2×). The combined organic layers were washed with water and brine then dried over sodium sulfate, filtered and concentrated. The residue was absorbed on silica gel and chromatographed with EtOAc/hexanes (gradient: 0-30% EtOAc) to give 251 mg (61%) of 3-iodo-6-methanesulfonyl-1-methyl-1H-indazole as an off-white solid. The minor regioisomer 3-iodo-6-methanesulfonyl-2-methyl-2H-indazole was also observed, but not isolated.
Reaction SMILES: C(Br)C.[Mg].II.[CH2:7]([O:9][C:10](=[O:17])[CH:11]([CH2:15][CH3:16])[C:12]([OH:14])=O)[CH3:8].[CH2:18]([O:25][CH2:26][CH2:27]C(Cl)=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>O1CCCC1.C1(C)C=CC=CC=1>[CH2:7]([O:9][C:10](=[O:17])[CH:11]([CH2:15][CH3:16])[C:12](=[O:14])[CH2:27][CH2:26][O:25][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:8]
Reactant: O=C(Cl)CCOCc1ccccc1
Reactant: CCOC(=O)C(CC)C(=O)O
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: CCBr
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C(CC)C(=O)CCOCc1ccccc1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 96.3 %

Procedure:
Ethyl bromide (5 ml) is added dropwise into a 2 l five-necked flask equipped with a mechanical stirrer, a condenser, a dropping funnel, a thermometer and an Argon inlet tube charged with magnesium turnings (26.6 g), anhydrous tetrahydrofuran (100 ml) and iodine (a few crystals). After 1 or 2 minutes, once the reaction begins, the mixture is stirred and diluted with anhydrous tetrahydrofuran (510 ml). Ethyl bromide (86.6 ml) is gradually added, over a period of 45 minutes keeping the temperature at about 30°-35° C. When the ethyl bromide has been added stirring is continued for an additional 30 minutes and the mixture is cooled to about -10° C. Then a solution of ethyl malonic acid monoethyl ester (87.7 g) in anhydrous tetrahydrofuran (80 ml) is slowly added dropwise (60 minutes) into the above mixture. When the addition is complete, the mixture is stirred for one hour at room temperature and for an additional hour at about 75° C. The mixture is then cooled to 15° C. and a solution of 3-benzyloxypropionyl chloride (108.8 g) in anydrous tetrahydrofuran (50 ml) is added drop by drop over a period of 15 minutes. After stirring at room temperature for two hours, the reaction mixture is allowed to stand at room temperature overnight and gradually poured into a 3-l beaker, equipped with a mechanical stirrer and a thermometer, containing 8% HCl (295 ml) and toluene (295 ml), keeping the temperature at about 10°-15° C. After stirring for a few minutes, the aqueous phase is separated and extracted with toluene (three 150-ml portions). The toluene extracts are combined, washed with a 15% phosphate buffer pH 6.5 (two 250-ml portions), dried over Na2SO4 and concentrated to dryness yielding 5-benzyloxy-3-oxo-2-ethyl-pentanoic acid ethyl ester (146.8 g). The ethylmalonic acid monoethyl ester used in this step has been prepared as follows:
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][Si](C(C)(C)C)(C)C)[CH2:12][C@@H:11]([NH:23][C:24]2[CH:29]=[C:28]([NH:30][C@@H:31]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH2:33][C@@H:32]3[O:40][CH3:41])[N:27]=[CH:26][N:25]=2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CC(O)=O>C1COCC1.O>[Si:1]([O:8][C@@H:9]1[CH2:10][C@@H:11]([NH:23][C:24]2[CH:29]=[C:28]([NH:30][C@H:31]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH2:33][C@H:32]3[O:40][CH3:41])[N:27]=[CH:26][N:25]=2)[CH2:12][C@@H:13]1[CH2:14][OH:15])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CO[C@H]1Cc2ccccc2[C@H]1Nc1cc(N[C@@H]2C[C@@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)C2)ncn1
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CO[C@@H]1Cc2ccccc2[C@@H]1Nc1cc(N[C@H]2C[C@H](CO)[C@H](O[Si](C)(C)C(C)(C)C)C2)ncn1
Reaction time: 8 h
Yield: 73.6 %

Procedure:
To a solution of N-[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentyl]-N′-[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]pyrimidine-4,6-diamine (0.188 g, 0.314 mmol) in THF (1.70 mL) and H2O (1.70 mL) was added AcOH (5.08 mL). The solution was stirred overnight then concentrated in vacuo and purified by flash chromatography (0 to 5% MeOH/EtOAc) to obtain the title compound (0.112 g, 74%). LC/MS: Rt=1.46 min, ES+ 485 (Formic Acid).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH:7][C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10](O)=O)[N:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[N:3]=1.P(Cl)(Cl)([Cl:25])=O>>[Cl:25][C:10]1[C:9]2[C:8](=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:7]=[C:5]2[N:4]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:3]=[C:2]([CH3:1])[C:6]=12
Reactant: Cc1cc(Nc2ccccc2C(=O)O)n(-c2ccccn2)n1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1nn(-c2ccccn2)c2nc3ccccc3c(Cl)c12
Temperature: 25 °C
Yield: 42.9 %

Procedure:
A solution of 2-[[3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-yl]amino]benzoic acid (50.2 g, 0.17 mol) in phosphorous oxychloride (120 mL, 1.27 mol) was heated under reflux for 1 hour. The solution was cooled to room temperature and concentrated under reduced pressure, and the residue was poured into iced water. The solution was made basic by the addition of a sodium hydroxide solution, and the organic matter was extracted with chloroform. The extract was washed with saturated brine and water, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (chloroform:methanol=98:2) to give the title compound (21.5 g, 43% yield).
Reaction SMILES: C([Si]([O:8][CH2:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[N:19]=[C:20]=S)(C)C)(C)(C)C.[NH2:22][C@H:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24]1>>[C@H:23]1([NH:22][C:20]2[O:8][CH2:9][C:10]3[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=3[N:19]=2)[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24]1
Reactant: N[C@@H]1CCc2ccccc21
Reactant: CC(C)(C)[Si](C)(C)OCc1cc([N+](=O)[O-])ccc1N=C=S
Product: O=[N+]([O-])c1ccc2c(c1)COC(N[C@@H]1CCc3ccccc31)=N2
Yield: 92.9 %

Procedure:
Prepared from tert-butyl-(2-isothiocyanato-5-nitro-benzyloxy)-dimethyl-silane (Example C1) (3.89 g, 12.0 mmol; HPLC: 4.446 min) and commercially available (R)-(−)-1-aminoindane (1.54 mL, 12.0 mmol; HPLC 0.4 min) according to the procedure described for Example 1. Obtained the title compound as a yellow foam (3.45 g, 93%; HPLC 1.954 min), MS (ISN) m/e=308.5 [(M−H)−].
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C:15]1=[O:20].C([O:24][C:25]1[CH2:30][CH2:29][CH2:28][C:27](=O)[CH:26]=1)(C)C.Cl>CCOCC.O>[CH3:13][N:14]1[CH2:19][CH2:18][CH2:17][CH:16]([C:27]2[CH2:28][CH2:29][CH2:30][C:25](=[O:24])[CH:26]=2)[C:15]1=[O:20]
Reactant: CC(C)OC1=CC(=O)CCC1
Reactant: CN1CCCCC1=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCOCC
Solvent: O
Product: CN1CCCC(C2=CC(=O)CCC2)C1=O
Temperature: 20 °C
Reaction time: 0.17 h

Procedure:
n-Butyllithium (1.4 M in hexane, 120 ml) was treated at 20° C. under dry nitrogen with diisopropylamine (27 ml, 19.2 g) in dry ether (25 ml). The mixture was stirred for 10 minutes at 20° C. after completion of the addition and then 1-methyl-2-piperidone (20 g) in ether (25 ml) was added dropwise over 10 minutes. The mixture was stirred for a further 10 minutes, and then 3-isopropoxy-2-cyclohexenone (19.4 g) in ether (25 ml) was added dropwise over 10 minutes. The mixture was stirred at 20° C. for a further 2 hours and was then hydrolysed by the addition, dropwise at first, of a mixture of conc. hydrochloric acid (50 ml) and water (50 ml). The mixture was cooled in a water bath during the acidification to moderate the reaction. The mixture was cooled to room temperature (from 35° C.) and the organic phase was separated and dried (MgSO4). Removal of the solvent left a mobile yellow oil (0.63 g). The aqueous phase was extracted exhaustively with chloroform (10×40 ml) and the combined extracts were washed with water (100 ml), and saturated aqueous sodium chloride solution (100 ml), and dried (MgSO4). Evaporation left a pale green oil (25.79 g). The two fractions were combined and distilled, giving two fractions A, bp<120° C./1 mm (4.6 g), colourless, mobile liquid; and B, bp 150° C.-164° C./0.07 mm (14.46 g), yellow oil solidifying to a light yellow mass, mp 41°-62° C. Fraction A was identified by IR as slightly impure 1-methyl-2-piperidone (23% recovery), while fraction B was identified by IR and NMR as the title compound.
Reaction SMILES: CC([O-])(C)C.[K+].C1COCC1.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([CH2:21][C:22]([NH2:24])=[O:23])=[CH:13]1.C([O:27][C:28](=O)[C:29]([C:31]1[CH:32]=[CH:33][CH:34]=[C:35]2[C:39]=1[N:38]([CH3:40])[CH:37]=[CH:36]2)=O)C.Cl>CN(C=O)C.CCOC(C)=O>[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([C:21]2[C:22](=[O:23])[NH:24][C:28](=[O:27])[C:29]=2[C:31]2[CH:32]=[CH:33][CH:34]=[C:35]3[C:39]=2[N:38]([CH3:40])[CH:37]=[CH:36]3)=[CH:13]1
Reactant: NC(=O)Cc1c[nH]c2ccccc12
Reactant: CCOC(=O)C(=O)c1cccc2ccn(C)c12
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1ccc2cccc(C3=C(c4c[nH]c5ccccc45)C(=O)NC3=O)c21
Temperature: 60 °C
Reaction time: 7 h

Procedure:
A 1.0 M solution of KOtBu in THF (6 mL, 6 mmol) was added to a solution of 2-(1H-indol-3-yl)-acetamide (296 mg, 1.70 mmol) and (1-methyl-1H-indol-7-yl)-oxo-acetic acid ethyl ester (381 mg, 1.65 mmol) in DMF (20 mL). The deep red-orange solution was stirred 7 h at 60° C., allowed to cool overnight and 1N HCl added. The orange mixture was poured into EtOAc, and the EtOAc layer was separated and washed with 1N HCl, water (3×), saturated aq NaHCO3 (2×) and brine, dried (MgSO4), filtered and concentrated onto SiO2. Flash chromatography (1:1 EtOAc:hexanes) afforded the title compound as a 1:1 solvate with EtOAc (514 mg, 72%) as a bright orange-red solid. Heating under vacuum at 70° C. afforded material which was used without further purification. 1H NMR (400 MHz, DMSO-d6) 11.85 (br s, 1H), 11.13 (s, 1H), 7.93 (d, J=3 Hz, 1H), 7.61 (dd, J=8, 1.5 Hz, 1H), 7.33 (d, J=8 Hz, 1H), 7.26 (d, J=3 Hz, 1H), 6.93–7.0 (m, 2H), 6.88 (d, J=7 Hz, 1H), 6.46–6.52 (d, J=7 Hz, 1H), 6.35 (d, J=7 Hz, 1H), 3.68 (s, 3H). MS (electrospray, m/z) 342.1 (M++1), 340.2 (M−−1). HRMS 342.1249 (M++1, calcd for C21H16N3O2 342.1242).
Reaction SMILES: [I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+].[NH2:9][C:10]1[C:11]2[N:12]([C:16]([CH3:20])=[C:17]([CH3:19])[N:18]=2)[CH:13]=[CH:14][CH:15]=1.[CH3:21][C:22]1[C:27]([CH2:28]Cl)=[C:26]([N+:30]([O-:32])=[O:31])[CH:25]=[CH:24][CH:23]=1>CC(C)=O>[CH3:21][C:22]1[C:27]([CH2:28][NH:9][C:10]2[C:11]3[N:12]([C:16]([CH3:20])=[C:17]([CH3:19])[N:18]=3)[CH:13]=[CH:14][CH:15]=2)=[C:26]([N+:30]([O-:32])=[O:31])[CH:25]=[CH:24][CH:23]=1
Reactant: Cc1cccc([N+](=O)[O-])c1CCl
Reactant: Cc1nc2c(N)cccn2c1C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Cc1cccc([N+](=O)[O-])c1CNc1cccn2c(C)c(C)nc12
Temperature: 25 °C
Yield: 49.5 %

Procedure:
15.0 g of sodium iodide and 31.0 g of sodium carbonate are added at RT to a solution of 8-amino-2,3-dimethylimidazo[1,2-a]pyridine (14.7 g) and 6-methyl-2-nitrobenzyl chloride (18.6 g) in 100 ml of acetone and the mixture is then heated at boiling under reflux for 6 h. After cooling the solution to RT and concentrating, the residue is dissolved in a mixture of 200 ml of ethyl acetate and 200 ml of water and the organic phase is separated off. After three further extractions with 100 ml of ethyl acetate each, the combined organic phases are dried over magnesium sulfate and then concentrated to 80 ml. 12.1 g of the title compound crystallize as a slightly yellow solid. The mother liquor is concentrated. Chromatographic purification of the residue on silica gel (eluent: toluene/dioxane=6:1) gives a further 14 g of the crystalline product. Recrystallization of both fractions from ethyl acetate gives 21.5 g (76%) of the title compound of m.p. 160-162° C.
Reaction SMILES: [CH2:1]=[CH2:2].[OH:3][C:4]1[C:13]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:12][C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=1.[OH-:22].[Na+]>C(O)(C)(C)C>[OH:22][CH2:1][CH2:2][N:5]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[N:12]=[C:13]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:4]1=[O:3]
Reactant: Oc1nc2c(nc1CCc1ccccc1)CCCC2
Reactant: C=C
Reactant: [OH-]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: O=c1c(CCc2ccccc2)nc2c(n1CCO)CCCC2
Temperature: 60 °C
Reaction time: 3 h
Yield: 90.9 %

Procedure:
Ethylene chlorodrohydrin (9.0 g) was added to a solution of 2-hydroxy-3-(2-phenylethyl)-5,6,7,8-tetrahydroquinoxaline (5.59 g, 22 mM) in aqueous 5N NaOH and t-butanol (60 ml), and stirred at 60° C. for 3 hours. The t-butanol was distilled off in vacuo, water was added to the residue, and the mixture was extracted three times with chloroform. The extract was dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 170 g) packed with chloroform, and eluted with chloroform-methanol (200:1) to obtain compound 645 (6.73 g, yield: 90.9%).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[Cl:6][C@@H:7]([CH3:11])[C:8](Cl)=[O:9].O.ClCCl>C(Cl)(Cl)Cl>[CH2:1]([N:3]([CH2:4][CH3:5])[C:8](=[O:9])[C@@H:7]([Cl:6])[CH3:11])[CH3:2]
Reactant: CCNCC
Reactant: C[C@H](Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCN(CC)C(=O)[C@H](C)Cl
Temperature: 0 °C

Procedure:
Diethylamine (480 cc) is added to a solution of (S)-2-chloropropionyl chloride (175.2 g) in chloroform (900 cc), which is maintained at 0° C., in the course of 1 hour. Distilled water (400 cc) and dichloromethane (300 cc) are added to the reaction mixture. The organic phase is decanted and then washed with an aqueous 2N hydrochloric acid solution (300 cc) and then with distilled water (400 cc). The organic phase is dried over sodium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the vicinity of 30° C. The residue obtained is distilled under reduced pressure (17 Pa). (S)-N,N-Diethyl-2-chloropropionamide (161.9 g) in the form of a colourless oil [b.p.17Pa =83°-85° C.; [α]D20 =+39.7°(c=10.4 ; CHCl3)] is thereby obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([Cl:8])=[N:6][CH:7]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([NH:9][S:28]([C:25]2[CH:24]=[CH:23][C:22]([O:21][CH3:20])=[CH:27][CH:26]=2)(=[O:30])=[O:29])[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1cc(Br)cnc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)Nc2cc(Br)cnc2Cl)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 68.4 %

Procedure:
A round bottom flask was charged with 5-bromo-2-chloropyridin-3-amine (2.50 g, 12.1 mmol) and 24 mL THF and the solution was cooled to −78° C. under nitrogen. 1.0 M LiHMDS (24.1 ml, 24.1 mmol) was added slowly and the solution was stirred for 10 min at −78° C. 4-methoxybenzene-1-sulfonyl chloride (3.49 g, 16.9 mmol) dissolved in a minimum amount of THF (˜5 mL) was added slowly, and the cooling bath was removed after 10 min. The reaction was stirred at room temperature overnight and was quenched with saturated NH4Cl. The layers were separated, and the organic portion was diluted with CH2Cl2, washed with 1 N HCl and brine. The organic portion was dried with MgSO4, filtered and concentrated. The crude material was dissolved in CH2Cl2 (˜20 mL) and ether was added (˜40 mL) in portions over 15 min. After allowing to stand in the freezer for 1 h, the solids were filtered and washed with ether. N-(5-bromo-2-chloropyridin-3-yl)-4-methoxybenzenesulfonamide (3.127 g, 68.7% yield) was isolated as a white crystalline solid. MS (ESI pos. ion) m/z calc'd for C12H10BrClN2O3S: 377.6. found 378.8.
Reaction SMILES: Br[CH:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[Cl:16])[C:9](=[O:17])[C:8]2[C:7]([Cl:18])=[CH:6][CH:5]=[CH:4][C:3]1=2.[NH2:19][C:20]1[C:21]([CH3:26])=[CH:22][CH:23]=[CH:24][CH:25]=1.O>C1COCC1>[C:21]1([CH3:26])[C:20]([NH:19][CH:2]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[Cl:16])[C:9](=[O:17])[C:8]3[C:7]([Cl:18])=[CH:6][CH:5]=[CH:4][C:3]2=3)=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C1c2cccc(Cl)c2C(Br)c2cccc(Cl)c21
Reactant: Cc1ccccc1N
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccccc1NC1c2cccc(Cl)c2C(=O)c2cccc(Cl)c21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of compound (6) (2.0 mmol) in dry THF (20 ml) was added dropwise a solution of o-toluidine (10 ml) in dry THF (10 ml) under N2. The reaction mixture was stirred at room temperature for 24 hours. Water (250 ml) was added and then extracted with dichloromethane. The combined organic extracts were washed with water, dried (MgSO4), and concentrated. The resulting precipitate was collected by filtration, washed with water and further purified by crystallization (CH3CN).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)/[CH:9]=[CH:10]/[N:11](C)C)=[C:4]([N+:15]([O-:17])=[O:16])[CH:3]=1.Cl.[CH:19]1([NH:24]N)[CH2:23][CH2:22][CH2:21][CH2:20]1.O.C(OCC)(=O)C.[OH-].[Na+]>C(O)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:24]([CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[N:11]=[CH:10][CH:9]=2)=[C:4]([N+:15]([O-:17])=[O:16])[CH:3]=1
Reactant: NNC1CCCC1
Reactant: CN(C)/C=C/C(=O)c1ccc(Br)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(Br)ccc1-c1ccnn1C1CCCC1
Temperature: 25 °C
Reaction time: 60 h
Yield: 72.7 %

Procedure:
Under a nitrogen atmosphere, to a solution of 1.15 g of (2E)-1-(4-bromo-2-nitrophenyl)-3-(dimethylamino)prop-2-en-1-one in 9.2 mL of acetic acid was added 1.05 g of cyclopentylhydrazine hydrochloride, followed by stirring at room temperature for 60 hours. The reaction mixture was poured into a mixture of water/ethyl acetate, followed by adjusting to pH 10 with a 6 M aqueous sodium hydroxide solution. The aqueous layer was separated, and then the organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and then the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain 940 mg of 5-(4-bromo-2-nitrophenyl)-1-cyclopentyl-1H-pyrazole.
Reaction SMILES: C[O-].[Na+].[OH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11]([C:15]([OH:17])=[O:16])=[N:10][CH:9]=[CH:8]2.[Cl:18][C:19]1[CH:24]=[C:23](Cl)[N:22]=[CH:21][N:20]=1>CO.CN(C=O)C>[Cl:18][C:19]1[N:20]=[CH:21][N:22]=[C:23]([O:4][C:5]2[CH:6]=[C:7]3[C:12](=[CH:13][CH:14]=2)[C:11]([C:15]([OH:17])=[O:16])=[N:10][CH:9]=[CH:8]3)[CH:24]=1
Reactant: O=C(O)c1nccc2cc(O)ccc12
Reactant: Clc1cc(Cl)ncn1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(O)c1nccc2cc(Oc3cc(Cl)ncn3)ccc12
Temperature: 10 °C
Reaction time: 14 h

Procedure:
40 ml (20 mMol) of a 0.5 M solution of sodium methylate in MeOH are added to a suspension of 1.9 g (10 mMol) 6-hydroxy-isoquinoline-1-carboxylic acid (CAS 174299-07-1) in 50 ml MeOH and sonicated until a solution is obtained. The solvent is then evaporated off. The residue is dried in high vacuum for 4 h and 100 ml DMF are added. The suspension is cooled to 10° C. and a solution of 1.55 g (10 mMol) 4,6-dichloropyrimidine in 25 ml DMF is added. The reaction mixture is stirred at room temperature for 14 h. The solvent is evaporated off and the mixture is partitioned between H2O/EtOAc. After extraction, the aqueous phase is neutralized with a 1 N solution of HCl. The suspension is extracted with EtOAc, washed with H20 and brine, dried (MgSO4) and concentrated to give a beige powder: 1H-NMR (DMSO-d6): δ ppm 7.60 (s, 1H), 7.68 (dd, J=9.4, 2.3 Hz, 1H), 7.98 (d, J=2.3 Hz, 1H), 8.04 (d, J=5.5 Hz, 1H), 8.59 (d, J=5.9 Hz, 1H), 8.66 (s, 1H), 8.68 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][CH:24]=1)[CH2:6][NH:7][C:8]1[CH:13]=[C:12]([C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=2[NH2:21])[N:11]=[CH:10][N:9]=1.CCN=C=NCCCN(C)C.Cl.[CH3:39][O:40][C:41]([C:43]1[CH:44]=[C:45]([CH:49]=[CH:50][CH:51]=1)[C:46](O)=[O:47])=[O:42]>ClCCl.CN(C)C1C=CN=CC=1>[F:26][C:2]([F:25])([F:1])[C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][CH:24]=1)[CH2:6][NH:7][C:8]1[N:9]=[CH:10][N:11]=[C:12]([C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=2[NH:21][C:46]([C:45]2[CH:44]=[C:43]([CH:51]=[CH:50][CH:49]=2)[C:41]([O:40][CH3:39])=[O:42])=[O:47])[CH:13]=1
Reactant: COC(=O)c1cccc(C(=O)O)c1
Reactant: Nc1ccc(Cl)cc1-c1cc(NCc2cccc(C(F)(F)F)c2)ncn1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)c1cccc(C(=O)Nc2ccc(Cl)cc2-c2cc(NCc3cccc(C(F)(F)F)c3)ncn2)c1
Temperature: 30 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
Into a 100-mL round bottom flask, was placed a solution of N-(3-(trifluoromethyl)benzyl)-6-(2-amino-5-chlorophenyl)pyrimidin-4-amine (500 mg, 1.32 mmol, 1.00 equiv) in dichloromethane (30 mL), EDC.HCl (380 mg, 1.98 mmol, 1.50 equiv), N,N-dimethylpyridin-4-amine (242 mg, 1.98 mmol, 1.50 equiv), and 3-(methoxycarbonyl)benzoic acid (357 mg, 1.98 mmol, 1.50 equiv). The resulting solution was stirred for 2 h at 30° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with petroleum ether/ethyl acetate (2:1). The product was obtained as 400 mg (56%) of a yellow solid.
Reaction SMILES: C([O:8][C@H:9]([C@@H:11]1[N:16]2[C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=[C:19]([NH2:27])[C:18]=3[N:28]=[C:15]2[CH2:14][O:13][CH2:12]1)[CH3:10])C1C=CC=CC=1.Cl>CO.[Pd].C(O)C>[NH2:27][C:19]1[C:18]2[N:28]=[C:15]3[CH2:14][O:13][CH2:12][C@H:11]([C@@H:9]([OH:8])[CH3:10])[N:16]3[C:17]=2[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1
Reactant: C[C@H](OCc1ccccc1)[C@H]1COCc2nc3c(N)nc4ccccc4c3n21
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCO
Product: C[C@H](O)[C@H]1COCc2nc3c(N)nc4ccccc4c3n21
Reaction time: 24 h
Yield: 32.1 %

Procedure:
(11R)-11-[(1S)-1-(Benzyloxy)ethyl]-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-6-amine (512 mg, 1.37 mmol) was dissolved in 30 mL of methanol and the solution was placed in a pressure bottle. Palladium on carbon (10%, 200 mg) and 2.5 mL of 3 M HCl in ethanol were then added and the reaction mixture was shaken under H2 at 50 PSI (3.4×105 Pa). After 24 hours, the reaction mixture was filtered through a pad of CELITE filter agent. The pad was rinsed with methanol and the combined filtrates were concentrated under reduced pressure. The residue was dissolved in H2O and the solution was made basic by the addition of concentrated aqueous NH4OH solution. The aqueous solution was extracted with 10% MeOH/CHCl3 several times and the combined organic layers were concentrated under reduced pressure. Chromatography (SiO2, 25-75% CMA/CHCl3) gave an off-white powder. Crystallization from ethyl acetate and methanol gave 125 mg of the desired compound as a white, fluffy solid, mp 207.6-208.7° C.