Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:6]2[S:7][CH:8]=[CH:9][C:5]=2[C:4](=O)[NH:3][CH:2]=1.[Cl:11]C1C2SC=CC=2N=CN=1>>[Cl:11][C:4]1[C:5]2[CH:9]=[CH:8][S:7][C:6]=2[N:1]=[CH:2][N:3]=1
Reactant: O=c1[nH]cnc2sccc12
Reactant: Clc1ncnc2ccsc12
Product: Clc1ncnc2sccc12
Yield: 93 %

Procedure:
Starting from thieno[2,3-d]pyrimidin-4(3H)-one (204) [J. Med. Chem., 1999, 42, 26, 5437-5447, Bull. Soc. Chim. Fr., 1975, 587-591] and following the procedure described above for the synthesis of compound 20 (scheme 4, example 22), title compound 205 was obtained in 93% yield. LRMS (M+1) 169.1 (100%), 171.1 (32%).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[O:7][C:6]2[CH:8]=[C:9]([N+:13]([O-])=O)[C:10]([NH2:12])=[CH:11][C:5]=2[CH:4]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:3]1[OH:21].[H][H]>C(O)C.[C].[Pd]>[CH3:1][C:2]1([CH3:22])[O:7][C:6]2[CH:8]=[C:9]([NH2:13])[C:10]([NH2:12])=[CH:11][C:5]=2[CH:4]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:3]1[OH:21]
Reactant: CC1(C)Oc2cc([N+](=O)[O-])c(N)cc2C(N2CCCC2)C1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC1(C)Oc2cc(N)c(N)cc2C(N2CCCC2)C1O
Yield: 94.3 %

Procedure:
0.20 g (0.65 mmol) of 3,4-dihydro-2,2-dimethyl-3-hydroxy-4-(1-pyrrolidinyl)-6-amino-7-nitro-2H-benzo[b]pyran were dissolved in 34.9 g of ethanol and hydrogen gas was blown in the presence of 0.15 g of 5% palladium-carbon, as a catalyst, at room temperature for 3 hours under one atmospheric pressure while stirring. The reaction liquid was filtered under suction to remove the catalyst therefrom, and the solvent was distilled off to obtain 170 mg (yield: 94%) of 3,4-dihydro-2,2-dimethyl-3-hydroxy-4-(1-pyrrolidinyl)-6,7-diamino-2H-benzo[b]pyran as a dark red oil.
Reaction SMILES: [CH3:1][C:2]([CH3:6])=[CH:3][CH2:4][OH:5].[H-].[Na+].[CH2:9]([CH:11]1[O:13][CH2:12]1)Br>C1COCC1>[CH3:1][C:2]([CH3:6])=[CH:3][CH2:4][O:5][CH2:9][CH:11]1[O:13][CH2:12]1
Reactant: BrCC1CO1
Reactant: CC(C)=CCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)=CCOCC1CO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of dimethylallyl alcohol (17.3 g, 20.5 mL, 0.2 mol) in dry THF (200 mL), sodium hydride (4.8 g, 0.2 mol) was added in portions and the mixture was stirred at room temperature for 1 hour. Epibromohydrin (27.4 g, 17.12 mL, 0.2 mol) was added to this reaction mixture dropwise and the mixture was stirred at room temperature for 24 hours. THF was removed on a rotary evaporator and the residue was taken up in ether and filtered. The ether solution was concentrated on a rotary evaporator and the brown oil obtained was distilled under vacuum to yield the title product. bp. 93-94° C./10 mm. Yield: 17.2 g (60.5%). 1H NMR (CDCl3) δ1.68 and 1.75 (s, 6H, CH3), 2.61 and 2.88 (dd,2H, oxirane CH2), 3.17 (m, 1H, oxirane CH), 3.38 and 3.7 (m, 2H, CH2OCH2CH), 4.05 (m, 2H, CH2OCH2CH), 5.35 .(m, 1H, >C═CH).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH3:32])=[C:5]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[C:6]=1[C:7]([NH:9][C@H:10]([C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=1)[CH3:11])=[O:8].[C:33]1([S:39]([NH2:42])(=[O:41])=[O:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1>[CH3:1][C:2]1[S:3][C:4]([CH3:32])=[C:5]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:24][CH:23]=2)[C:6]=1[C:7]([NH:9][C@H:10]([C:12]1[CH:13]=[CH:14][C:15]([C:16]([NH:42][S:39]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)(=[O:41])=[O:40])=[O:18])=[CH:19][CH:20]=1)[CH3:11])=[O:8]
Reactant: NS(=O)(=O)c1ccccc1
Reactant: Cc1sc(C)c(C(=O)N[C@@H](C)c2ccc(C(=O)O)cc2)c1Cc1ccc(C(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Product: Cc1sc(C)c(C(=O)N[C@@H](C)c2ccc(C(=O)NS(=O)(=O)c3ccccc3)cc2)c1Cc1ccc(C(F)(F)F)cc1

Procedure:
4-{(1S)-1-[({2,5-Dimethyl-4-[4-(trifluoromethyl)benzyl]-3-thienyl}carbonyl)amino]ethyl}benzoic acid from Example 12 (200 mg, 0.433 mmol) was treated with benzenesulfonamide (85.0 mg, 0.542 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (166 mg, 0.866 mmol) and 4-dimethylaminopyridine (66.0 mg, 0.542 mmol) under conditions similar to Example 18. The crude was purified by Combi Flash chromatography system (25% THF/CHCl3 for 5 min., then 50% for 5 min.) to afford the desired product as a white solid. MS (−APCI): m/z 599 (M−1)−.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]([NH:19][C:20](=O)C)=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:7]=1C1OCCCO1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CC(C)=O.O>[CH3:1][O:2][C:3]([C:4]1[N:19]=[CH:20][C:7]2[C:6]([CH:5]=1)=[CH:11][CH:10]=[CH:9][C:8]=2[F:12])=[O:23]
Reactant: COC(=O)C(=Cc1cccc(F)c1C1OCCCO1)NC(C)=O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)c1cc2cccc(F)c2cn1
Yield: 75.8 %

Procedure:
2-Acetylamino-3-(2-[1,3]dioxan-2-yl-3-fluoro-phenyl)-acrylic acid methyl ester (10.6 g, 32.8 mmol) and pyridinium para-toluene sulfonate (2.06 g, 8.2 mmol) are heated to reflux for 20 hours in an acetone/water (120 ml/15 ml) mixture. The solvents are removed by evaporation and the aqueous residue is extracted with ethylacetate. The organic layer is washed with brine and dried over MgSO4 and evaporated. The crude product is recrystallised from ethylacetate/ether to afford 5.1 g of the desired compound. MS (ES+): m/e=206.2 (MH+)
Reaction SMILES: [OH-].[Na+].CN([CH2:6][C:7]1[C:11]2[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:10]=2[NH:9][CH:8]=1)C.C([O:19][C:20](=[O:26])[CH2:21][NH:22]C(=O)C)C.CNC>C1(C)C(C)=CC=CC=1>[Cl:16][C:14]1[CH:15]=[C:10]2[C:11](=[CH:12][CH:13]=1)[C:7]([CH2:6][C@@H:21]([C:20]([OH:26])=[O:19])[NH2:22])=[CH:8][NH:9]2
Reactant: CCOC(=O)CNC(C)=O
Reactant: CN(C)Cc1c[nH]c2cc(Cl)ccc12
Agent: CNC
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Product: N[C@@H](Cc1c[nH]c2cc(Cl)ccc12)C(=O)O
Temperature: 90 °C
Reaction time: 12 h
Yield: 84 %

Procedure:
Under inert atmosphere and rapid stirring 52 mg of NaOH are pulverized into anhydrous xylene (20 ml), heating the suspension at approximately 90° C. 550 mg of 6-chlorogramine (prepared as described in example 1) and 460 mg of ethyl-acetamido-acetate are then added. The mixture is refluxed for approximately 7 hours and the development of dimethylamine, extremely vigorous at the start of the heating, practically ceases after about 6 hours of heating. The reaction mixture is cooled for 12 hours at 5° C. and then filtered to recover the abundant precipitate. This crude solid is treated with a hot solution of benzene/absolute ethanol, and the insoluble material is hot-filtered. The solution is left to rest at 5° C. for 12 hours. Crystals slowly separate, which are filtered and dried. 750 mg of ethyl-α-acetamido-α-cyano-β-(6-chloro-indole-3-yl)-propioanate are recovered, with a yield of 84%. 600 mg of this compound are added to 15 ml of water, containing 40 mg of NaOH and the mixture is boiled for 24 hours. During this time the solid material dissolves and ammonia is developed. After the reflux time, the reaction mixture is cooled at room temperature and neutralized with acetic acid at 50%. It is filtered, recovering and washing with cold water the solid which has formed. After drying 410 mg of 6-chloro-DL-tryptophan are recovered, with a yield of 95%.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:13][C:14]2[CH:18]=[C:17]([CH3:19])[NH:16][N:15]=2)[N:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1.C([O-])([O-])=O.[Na+].[Na+].CN(C)C=O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:20][O:21][C:22]1[CH:27]=[C:26]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:13][C:14]3[CH:18]=[C:17]([CH3:19])[NH:16][N:15]=3)[N:3]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: Cc1cc(Nc2cc3cc(O)ccc3c(Br)n2)n[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc(-c2nc(Nc3cc(C)[nH]n3)cc3cc(O)ccc23)c1
Temperature: 180 °C
Yield: 55.3 %

Procedure:
The mixture of 1-Bromo-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-6-ol (300 mg), 3-methoxy-phenylboronic acid (318 mg), Na2CO3 (400 mg), Tetrakis(triphenylphosphine)palladium(0) (100 mg), N,N-dimethylformamide (DMF) (2 ml) and water (2 ml) was heated at 180° C. for 30 minutes under microwave irradiation. After reaction finished, the mixture was sent to preparative LC-MS and 1-(3-methoxy-phenyl)-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-6-ol (180 mg) was produced as a solid. LC-MS m/e 347(MH+).
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:11]2[N:12]([CH3:16])[C:13](=[O:15])[NH:14][C:10]=2[CH:9]=[CH:8][CH:7]=1)[CH2:4][CH3:5])[CH3:2].[Cl:17]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Cl:17][C:9]1[C:10]2[NH:14][C:13](=[O:15])[N:12]([CH3:16])[C:11]=2[C:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[CH:7][CH:8]=1
Reactant: CCC(CC)c1cccc2[nH]c(=O)n(C)c12
Reactant: O=C1CCC(=O)N1Cl
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCC(CC)c1ccc(Cl)c2[nH]c(=O)n(C)c12
Temperature: 70 °C
Reaction time: 48 h
Yield: 67.8 %

Procedure:
2,2′-Azobisisobutyronitrile (AIBN) (94 mg, 0.57 mmol) was added to a mixture of 7-(1-ethylpropyl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (2.90 g, 13.3 mmol) and N-chlorosuccinimide (1.95 g, 14.6 mmol) in carbon tetrachloride (250 mL). The mixture was stirred at 70° C. for 2 days. The reaction was concentrated in vacuo, extracted with ethyl acetate and washed with brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to give residue. The residue was crystallized from ethanol/iso-propanol to afford the title compound as colorless crystals (2.28 g, 68%). mp 165-166° C.
Reaction SMILES: Br.[N:2]1[C:3](=[O:11])[CH2:4][N:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=12.[CH3:12][C:13]1[C:21]2[C:20]([CH:22]=O)=[CH:19][S:18][C:17]=2[CH:16]=[CH:15][CH:14]=1>C(O)C>[CH3:12][C:13]1[C:21]2[C:20]([CH:22]=[C:4]3[N:5]4[CH:10]=[CH:9][CH:8]=[CH:7][C:6]4=[N:2][C:3]3=[O:11])=[CH:19][S:18][C:17]=2[CH:16]=[CH:15][CH:14]=1
Reactant: Cc1cccc2scc(C=O)c12
Reactant: O=C1CN2C=CC=CC2=N1
Agent: Br
Solvent: CCO
Product: Cc1cccc2scc(C=C3C(=O)N=C4C=CC=CN34)c12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 1.6 g (7.4 mmol) of imidazo[1,2-a]pyridin-2-one hydrobromide salt and 1.2 g (6.7 mmol) of 4-methyl-benzo[b]thiophene-3-carbaldehyde in 40 mL of ethanol is heated at reflux for 1 h and then cooled to room temperature. The precipitate is collected. The isolated solid is suspended in 40 mL of 2M potassium carbonate solution and the resulting mixture is stirred for 48 h at room temperature. The solid is collected and washed with water to give the desired compound.
Reaction SMILES: [N+:1]([CH2:4][C:5]1[CH:6]=[N:7][NH:8][CH:9]=1)([O-:3])=[O:2].[O:10]1[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11]1.O.CC1C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[N+:1]([CH2:4][C:5]1[CH:6]=[N:7][N:8]([CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15][O:10]2)[CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])Cc1cn[nH]c1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=[N+]([O-])Cc1cnn(C2CCCCO2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 430 mg of 4-(nitromethyl)-1H-pyrazole in 4.3 ml of ethyl acetate were added 0.62 ml of 3,4-dihydro-2H-pyran and 129 mg of 4-methylbenzenesulfonic acid monohydrate, followed by stirring at room temperature for 3 hours. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the solvent was then evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 213 mg of 4-(nitromethyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:13]2[C@H:22]3[C:23]([O:25][CH2:26][C@@H:21]3[C@@H:20]([OH:27])[C:19]3[CH:18]=[C:17]4[O:28][CH2:29][O:30][C:16]4=[CH:15][C:14]2=3)=[O:24])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9]C.CS(O)(=O)=O.CSC>FC(F)(F)C(O)=O>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([C@H:13]2[C@H:22]3[C:23]([O:25][CH2:26][C@@H:21]3[C@H:20]([OH:27])[C:19]3[CH:18]=[C:17]4[O:28][CH2:29][O:30][C:16]4=[CH:15][C:14]2=3)=[O:24])[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[OH:9]
Reactant: COc1cc([C@@H]2c3cc4c(cc3[C@H](O)[C@H]3COC(=O)[C@H]23)OCO4)cc(OC)c1OC
Agent: CS(=O)(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: CSC
Product: COc1cc([C@@H]2c3cc4c(cc3[C@@H](O)[C@H]3COC(=O)[C@H]23)OCO4)cc(OC)c1O
Reaction time: 9 h
Yield: 65562924 %

Procedure:
10 g (24 nmol) of podophyllotoxin are dissolved in 60 ml of trifluoroacetic acid. There are successively added 5.4 ml (72 mmol) of methanesulfonic acid. Stirring is carried out for 9 hours, 5.4 ml (72 mmol) of dimethyl sulfide are again added and stirring is carried out for 9 hours. The mixture is discharged onto ice (600 ml) and extracted with ethyl acetate (3×300 ml). The organic phases are washed with water and then with NaHCO3 solution until neutral. After drying over sodium sulfate, filtration and evaporation, there are obtained 6.3 g of 4′-demethylepipodophyllotoxin, which is used directly in the next step.
Reaction SMILES: Cl.[NH2:2][OH:3].[N:4]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:18](=[O:25])[C:17](=O)[CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7][CH2:6][CH2:5]1>C(O)C.O>[N:4]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:18](=[O:25])[C:17](=[N:2][OH:3])[CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: NO
Reactant: O=C1C=C(c2ccc(N3CCCC3)cc2)c2ccccc2C1=O
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=C1C(=NO)C=C(c2ccc(N3CCCC3)cc2)c2ccccc21
Yield: 84 %

Procedure:
A solution of hydroxylamine hydrochloride (0.08 mol) in anhydrous ethanol (50 cm3) was added dropwise to a stirred solution of 4-(4-pyrrolidinophenyl)-1,2-naphthoquinone (0.02 mol) in warm anhydrous ethanol (250 cm3). The mixture was refluxed until thin layer chromatography indicated that no 4-(4-pyrrolidinophenyl)-1,2-naphthoquinone remained. The mixture was cooled in ice, diluted with water and the brown precipitate was collected by vacuum filtration and washed with water and air dried. Yield=84%, m.p.=278-300° C. (decomp.).
Reaction SMILES: [O:1]=[C:2]([C:9]1[C:10]([C:15]([F:18])([F:17])[F:16])=[N:11][CH:12]=[CH:13][CH:14]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].Br[CH2:20][C:21]([C:23]1[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[C:26]([O:32][CH3:33])=[C:25]([O:34][CH3:35])[CH:24]=1)=O.Cl>N1C=CC=CC=1>[CH3:35][O:34][C:25]1[CH:24]=[C:23]([C:21]2[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:2]([C:9]3[C:10]([C:15]([F:18])([F:16])[F:17])=[N:11][CH:12]=[CH:13][CH:14]=3)[O:1][CH:20]=2)[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[C:26]=1[O:32][CH3:33]
Reactant: CCOC(=O)CC(=O)c1cccnc1C(F)(F)F
Reactant: COc1cc(C(=O)CBr)cc([N+](=O)[O-])c1OC
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1c(-c2cc(OC)c(OC)c([N+](=O)[O-])c2)coc1-c1cccnc1C(F)(F)F
Temperature: 70 °C
Reaction time: 5 h

Procedure:
To a stirred solution of ethyl 3-oxo-3-(2-(trifluoromethyl)pyridin-3-yl)propanoate (1.305 g, 5 mmol) in pyridine (25 mL) was added 2-bromo-1-(3,4-dimethoxy-5-nitrophenyl)ethanone (1.67 g, 5.5 mmol). The reaction mixture was heated to 70° C. and to stirred for 5 hours, then cooled to room temperature and poured onto 6 N aqueous HCl (100 mL). The precipitate was filtered off, washed with water and dried over P2O5 under vacuum. The solid was recrystallised from dichloromethane/isopropanol to give crude ethyl 4-(3,4-dimethoxy-5-nitrophenyl)-2-(2-(trifluoromethyl)pyridin-3-yl)furan-3-carboxylate, 1.00 g (43%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].[Na].[CH3:21][OH:22]>ClCCl.CO>[N+:17]([C:3]1[CH:4]=[C:5]([NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:7][C:2]=1[O:22][CH3:21])([O-:19])=[O:18]
Reactant: CO
Reactant: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)c1ccccc1
Agent: [Na]
Solvent: ClCCl
Product: COc1ccc(NC(=O)c2ccccc2)cc1[N+](=O)[O-]

Procedure:
Prepared according to the procedure described for Example 10, Step A from N-(4-fluoro-3-nitrophenyl)-benzamide (5.2 g, 20 mmol) and sodium (1.3 g, 57 mmol) using methanol in place of ethanol to afford the product (3.7 g) after chromatography on silica gel in dichloromethane/methanol 99:1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][C:23]=2[C:25]2[C:26]([CH3:30])=[N:27][NH:28][CH:29]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[C:23]([C:25]5[C:26]([CH3:30])=[N:27][NH:28][CH:29]=5)[CH:22]=[CH:21][CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: Cc1n[nH]cc1-c1cccc2c1C(C)NCC2
Product: Cc1n[nH]cc1-c1cccc2c1C(C)N(C(=O)c1cc3ncc(Br)cn3n1)CC2

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-8-(3-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10](O)=O.C[NH2:14]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][NH2:14]
Reactant: CN
Reactant: COc1ccccc1CC(=O)O
Product: COc1ccccc1CCN

Procedure:
Synthesized according to typical procedures C and D from 2-methoxyphenylacetic acid and methylamine.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([O:23][CH3:24])[NH:20]3)=[C:16]([NH2:25])[N:15]=2)[CH2:10][CH2:9]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][CH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>CN(C=O)C>[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]3[CH2:33][CH:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[C:16]([NH2:25])[N:15]=2)[CH2:10][CH2:9]1
Reactant: COc1nc2c(N)nc(OCCC3CC3)nc2[nH]1
Reactant: BrCC1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: COc1nc2c(N)nc(OCCC3CC3)nc2n1CC1CCOCC1
Temperature: 50 °C
Yield: 44.6 %

Procedure:
2-[(2-Cyclopropylethyl)oxy]-8-methoxy-9H-purin-6-amine trifluoroacetic acid salt (0.30 g) was heated with potassium carbonate (anhydrous, 0.46 g) in anhydrous DMF (5 mL) at 60° C. for 1 hour. The reaction was cooled to room temperature before 4-(bromomethyl) tetrahydro-2H-pyran (0.16 g) in anhydrous DMF (1 mL) was added. The reaction mixture was then heated to 50° C. overnight. The reaction was quenched into water (50 mL) and extracted with ethyl acetate (50 mL, 3 times). The organic layer was combined and washed with brine (50 mL). The organic layer was separated and dried by passing through a hydrophobic frit before being evaporated under reduced pressure to give oil). This material was purified by C18 reverse phase chromatography using water (containing 0.1% formic acid)-acetonitrile (containing 0.05% formic acid) as eluent (20-60%). This material was purified by reverse phase chromatography (20-60% acetonitrile: water). This gave the title compound as a white solid (0.1279 g).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[N:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Cl.[NH2:11][OH:12].C([O-])([O-])=O.[Na+].[Na+]>CCO>[OH:12][NH:11][C:4](=[NH:5])[C:3]1[CH:6]=[CH:7][N:8]=[CH:9][C:2]=1[CH3:1]
Reactant: NO
Reactant: Cc1cnccc1C#N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cnccc1C(=N)NO
Temperature: 85 °C
Yield: 74 %

Procedure:
Prepared using General Procedure 1. To 3-methylisonicotinonitrile (0.500 g, 4.2 mmol) in EtOH (7 mL) was added hydroxylamine hydrochloride (0.588 g, 8.5 mmol) and Na2CO3 (1.34 g, 12.7 mmol) and the reaction mixture was heated at 85° C. for 4 h. Once cooled to room temperature, the reaction mixture was filtered using EtOH to rinse the filter cake. The filtrate was concentrated under reduced pressure. The resulting pale yellow solid was triturated with ice water (50 mL), filtered, and the solid was washed with ice water (5 mL). The solid was dried under reduced pressure to yield 0.47 g (74%) of N-hydroxy-3-methylisonicotinimidamide INT-69 as a white powder. LCMS-ESI (m/z) calculated for C7H9N3O: 151.2; found 152.1 [M+H]+, tR=0.56 min. 1H NMR (400 MHz, CD3OD) δ 8.43-8.32 (m, 2H), 7.34 (d, J=5.0, 1H), 2.39 (s, 3H).
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.P(=O)(O)(O)O.[CH3:20][O:21][C:22]1[CH:36]=[CH:35][C:25]([C:26]([NH:28][CH2:29][CH2:30][CH2:31][C:32](O)=[O:33])=[O:27])=[CH:24][CH:23]=1>>[CH3:20][O:21][C:22]1[CH:36]=[CH:35][C:25]([C:26]([N:28]2[CH2:29][CH2:30][CH2:31][C:32]2=[O:33])=[O:27])=[CH:24][CH:23]=1
Reactant: COc1ccc(C(=O)NCCCC(=O)O)cc1
Agent: O=P(O)(O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: COc1ccc(C(=O)N2CCCC2=O)cc1
Temperature: 50 °C

Procedure:
10 g. of phosphorus pentoxide and 6 ml. of orthophosphoric acid (at least 85%) are warmed with one another. 2.0 g. of 4-(p-methoxybenzoylamino)butyric acid are added at room temperature to the resulting solution. The mixture is warmed to 50° C. for 60 minutes, subsequently treated with ice and extracted with ethyl acetate. The organic phase is washed first with cold water, then with cold sodium bicarbonate solution and finally again with water and dried over sodium sulfate. The residue is triturated with diethyl ether and there is obtained 1-(p-methoxybenzoyl)-2-pyrrolidinone having a melting point of 120°-122° C.
Reaction SMILES: [C:1](/[CH:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14](=O)[CH3:15])=[CH:9][CH:8]=1)([O:3][CH3:4])=[O:2].[OH:17][CH:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:19][NH2:20].O>C1C=CC=CC=1>[C:1](/[CH:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([NH:20][CH2:19][CH:18]([OH:17])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH3:15])=[CH:9][CH:8]=1)([O:3][CH3:4])=[O:2]
Reactant: NCC(O)c1ccccc1
Reactant: COC(=O)/C=C/c1ccc(CC(C)=O)cc1
Solvent: O
Solvent: c1ccccc1
Product: COC(=O)/C=C/c1ccc(CC(C)NCC(O)c2ccccc2)cc1
Reaction time: 0.5 h

Procedure:
A mixture of 4-(E)-(2-carbomethoxyethenyl)phenylpropan-2-one (2.18 g) and 2-hydroxy-2-phenylethanamine (1.37 g) was refluxed in benzene under a Dean and Stark apparatus until the theoretical amount of water had been collected. The solvent was evaporated, methanol added, and sodium borohydride (1.0 g) added portionwise at room temperature. The solution was left to stir for 0.5 h, and solvent removed. Water was added, the mixture extracted with ether and the combined ether layers dried (MgSO4). Removal of the solvent gave the title compound, isolated as a 1:1 mixture of diastereoisomers, as the hemi-fumarate hemihydrate mp 99°-100.5° (ethyl acetate). τ (DMSO) 8.95 (3H, d, J=6 Hz), 6.4-7.5 (5H, m), 6.31 (3H, s), 5.2-4.9 (1H, m), 3.45 (1H, d, J=16 Hz+2H, s), 2.15-2.9 (10H, m), 1.6 (4H, s, disappears with D2O).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH3:9].[C:10](OC(=O)C)(=[O:12])[CH3:11]>C(Cl)Cl>[F:8][C:4]1[C:3]([CH3:9])=[C:2]([NH:1][C:10](=[O:12])[CH3:11])[CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(N)cccc1F
Solvent: ClCCl
Product: CC(=O)Nc1cccc(F)c1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1-amino-3-fluoro-2-methylbenzene (1 equivalent) was dissolved in CH2Cl2 and acetic anhydride (2.0 equivalents) was added slowly. The solution was stirred at room temperature for 4 hours. The reaction mixture was then quenched with water, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with H2O, a 10% HCl solution, H2O, and brine. It was then dried over Na2SO4 and concentrated in vacuo, to yield N-(3-fluoro-2-methylphenyl)acetamide as a pink solid. LC/MS (m/z) 168.2 (MH+), Rt 1.91 minutes.