Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:12]([OH:14])=[O:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.Cl[C:16]([O:18][CH2:19][CH3:20])=O>N1C=CC=CC=1>[CH2:19]([O:18][C:16]1[O:13][C:12](=[O:14])[C:3]2[CH:4]=[C:5]3[C:10]([CH:9]=[CH:8][CH:7]=[CH:6]3)=[CH:11][C:2]=2[N:1]=1)[CH3:20]
Reactant: Nc1cc2ccccc2cc1C(=O)O
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Product: CCOc1nc2cc3ccccc3cc2c(=O)o1
Reaction time: 20 h

Procedure:
To a solution of 3-amino-2-naphthoic acid (3.74 g, 20.0 mmol, 1 equiv.) in pyridine (40 ml) at −10° C. under nitrogen was added ethyl chloroformate (7.6 ml, 8.63 g, 79.5 mmol, 4.0 equiv) dropwise over an hour. The reaction was stirred from −10° C. to room temperature over 20 hours. The solvent was evaporated under reduced pressure, water (100 ml) was added to the solid residue, and the mixture was stirred at room temperature for 1 hour. The precipitate was filtered, washed with water and dried to yield 2-ethoxy-4H-naphtho[2,3-d][1,3]oxazin-4-one (1-2) as a tan solid. LRMS m/z (M+H) 242.2 found, 242.1 required.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:10]2[C:5](=[CH:6][C:7]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:8][CH:9]=2)[NH:4][CH2:3]1.Cl[C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][C:27]=2[F:29])[N:22]=[C:21]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[C:20]=1[CH3:36].[H-].[Na+]>CN(C=O)C>[CH3:1][C:2]1([CH3:17])[C:10]2[C:5](=[CH:6][C:7]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:8][CH:9]=2)[N:4]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][C:27]=3[F:29])[N:22]=[C:21]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)[C:20]=2[CH3:36])[CH2:3]1
Reactant: Cc1c(-c2ccccn2)nc2cccc(F)c2c1Cl
Reactant: CC1(C)CNc2cc(N3CCOCC3)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(-c2ccccn2)nc2cccc(F)c2c1N1CC(C)(C)c2ccc(N3CCOCC3)cc21
Temperature: 130 °C

Procedure:
Prepared according to procedure M using 3,3-dimethyl-6-morpholinoindoline (348 mg, 1496 μmol), 4-chloro-5-fluoro-3-methyl-2-(pyridin-2-yl)quinoline (340 mg, 1247 μmol) in DMF (12 mL), and sodium hydride (72 mg, 2992 μmol) and heating at 130° C. overnight. After purification 4-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-indol-1-yl)-5-fluoro-3-methyl-2-(2-pyridinyl)quinoline was obtained as a yellow film. 1H NMR (400 MHz, chloroform-d) δ ppm 8.76 (1H, dd, J=3.5, 1.2 Hz), 8.02 (1H, d, J=8.2 Hz), 7.83-7.96 (2H, m), 7.60 (1H, td, J=8.1, 5.3 Hz), 7.40 (1H, ddd, J=7.0, 5.1, 2.0 Hz), 7.08-7.17 (1H, m), 7.04 (1H, d, J=8.2 Hz), 6.26 (1H, dd, J=8.0, 2.2 Hz), 5.50 (1H, d, J=2.3 Hz), 3.76-3.85 (1H, m), 3.60-3.76 (5H, m), 2.86-3.02 (4H, m), 2.42 (3H, s), 1.50 (3H, s), 1.44 (3H, s). Mass Spectrum (ESI) m/e=469 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]2[CH2:15][CH2:14][N:13]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH:17]3[OH:22])[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35]Br)=[CH:33][CH:32]=1>C(Cl)Cl>[F:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][N:19]2[CH2:20][CH2:21][CH:16]([N:13]3[CH2:14][CH2:15][CH:10]([C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)=[O:9])[CH2:11][CH2:12]3)[CH:17]([OH:22])[CH2:18]2)=[CH:33][CH:32]=1
Reactant: O=C(c1ccc(F)cc1)C1CCN(C2CCNCC2O)CC1
Reactant: Fc1ccc(CBr)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc(F)cc1)C1CCN(C2CCN(Cc3ccc(F)cc3)CC2O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.3 %

Procedure:
Into a solution of 13a (132 mg, 0.42 mmol) and triethylamine (17.1 mg, 1.69 mmol) in CH2Cl2 (15 mL), a solution of 4-fluorobenzyl bromide (80 mg, 0.42 mmol) in CH2Cl2(5 mL) was slowly added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with water (20 mL×2) and brine solution (20 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel column chromatograph using triethylamine/ethyl acetate (1/50, v/v) as mobile phase to afford free base 14a as pale yellow oil (78.9 mg, 45%). 1H NMR (CDCl3): δ 1.53-2.04 (m, 9H), 2.20-2.32 (m, 2H), 2.71-2.76 (m, 2H), 2.91-3.01 (m, 2H), 3.17-3.22 (m, 2H), 3.51-3.63 (m, 3H), 6.96-7.02 (m, 2H), 7.10-7.17 (m, 2H), 7.23-7.27 (m, 2H), 7.93-7.98 (m, 2H). Free base was converted to the oxalate salt by dissolving it in acetone and mixing with 1 equivalent of oxalic acid in acetone. mp: 234° C. (decomposed). Anal. (C24H28F2N2O2.H2C2O4.0.25H2O) C, H, N.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][NH:7][C:8](=[O:28])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:18]=[CH:17][C:16]=2[NH2:27])[CH:10]=1.[CH3:34][N:35]([CH2:47][CH2:48][N:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1)[C:36]([C:38]1[CH:39]=[C:40]([CH:44]=[CH:45][CH:46]=1)[C:41](O)=[O:42])=[O:37].CCN=C=NCCCN(C)C.[ClH:66]>ClCCl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[ClH:66].[F:33][C:2]([F:1])([F:32])[C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][NH:7][C:8]([C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:18]=[CH:17][C:16]=2[NH:27][C:41](=[O:42])[C:40]2[CH:44]=[CH:45][CH:46]=[C:38]([C:36]([N:35]([CH3:34])[CH2:47][CH2:48][N:49]3[CH2:50][CH2:51][O:52][CH2:53][CH2:54]3)=[O:37])[CH:39]=2)[CH:10]=1)=[O:28]
Reactant: Nc1ccc(N2CCCCC2)cc1-c1cc(C(=O)NCc2cccc(C(F)(F)F)c2)ccn1
Reactant: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.5 %

Procedure:
Into a 250-mL round bottom flask, was placed a solution of N-(3-(trifluoromethyl)benzyl)-2-(2-amino-5-(piperidin-1-yl)phenyl)isonicotinamide (1 g, 2.09 mmol, 1.00 equiv, 95%) in dichloromethane (30 mL), 3-(methyl(2-morpholinoethyl)carbamoyl)benzoic acid (960 mg, 3.12 mmol, 1.50 equiv, 95%), EDC HCl (840 mg, 4.38 mmol, 2.00 equiv), and 4-dimethylaminopyridine (540 mg, 4.43 mmol, 2.00 equiv). The resulting solution was stirred for 3 h at 25° C. The resulting solution was diluted with 200 mL of ethyl acetate. The resulting mixture was washed with 2×30 mL of NH4Cl (aq), 1×30 mL of 10% sodium bicarbonate, and 1×30 mL of brine. The mixture was dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate:methanol (20:1). This resulted in 1.30 g of N1-(2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-(piperidin-1-yl)phenyl)-N3-methyl-N3-(2-morpholinoethyl)isophthalamide as a brown oil. The brown oil was dissolved in 40 mL of methanol. HCl gas was added at 0° C. The mixture was stirred for 20 min at 0° C. The mixture was concentrated under vacuum. The product was obtained as 1.40 g (86%) of a yellow solid. 1H-NMR (300 MHz, DMSO-d6+D2O, ppm): δ 9.96 (m, 1H), 8.94 (d, J=6 Hz, 1H), 8.59 (m, 2H), 8.49 (s, 1H), 7.93-8.07 (m, 2H), 7.87-8.03 (m, 2H), 7.54-7.80 (m, 7H), 4.59 (s, 2H), 4.12 (m, 1H), 3.99-4.03 (m, 2H), 3.88 (m, 2H), 3.76-3.79 (m, 2H), 3.58 (m, 2H), 3.43 (m, 2H), 3.15-3.17 (m, 3H), 2.96 (s, 3H), 1.97 (m, 4H), 1.71 (m, 2H). MS (ES, m/z): 729 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:10]=[C:11]([CH:13]=[CH:14][C:15]=2[CH3:16])[NH2:12])[CH:4]=1.[C:17]([O:21][C:22]([NH:24][C:25]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=S)=[O:23])([CH3:20])([CH3:19])[CH3:18].C(N(C(C)C)CC)(C)C.[I-].C[N+]1C=CC=CC=1Cl>ClCCl>[C:31]([O:30][C:28]([NH:27][C:25]([NH:24][C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:23])=[N:12][C:11]1[CH:13]=[CH:14][C:15]([CH3:16])=[C:9]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][N:6]=2)[CH:10]=1)=[O:29])([CH3:34])([CH3:33])[CH3:32]
Reactant: COc1ccnc(-c2cc(N)ccc2C)c1
Reactant: CC(C)(C)OC(=O)NC(=S)NC(=O)OC(C)(C)C
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccnc(-c2cc(N=C(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)ccc2C)c1
Reaction time: 2 h
Yield: 92.9 %

Procedure:
To a suspension of 3-(4-methoxypyridin-2-yl)-4-methylaniline (238 mg), N,N′-bis(tert-butoxycarbonyl)thiourea (368 mg) and diisopropylethylamine (0.445 ml) in dichloromethane (10 ml) was added 1-methyl-2-chloropyridinium iodide (369 mg), and the mixture was stirred for 2 hours. The mixture was diluted with dichloromethane, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 25 g, n-hexane:ethyl acetate=3:1) to give N,N′-bis(tert-butoxycarbonyl)-N″-(3-(4-methoxypyridin-2-yl)-4-methylphenyl)guanidine (471 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[C:18]2[O:20][CH2:21][CH2:22][O:23][C:17]2=[CH:16][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=1)=O.[Cl:24][CH2:25][C:26](=O)[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].S(=O)(=O)(O)O>C(O)(=O)C>[CH2:31]([O:30][C:28]([C:27]1[C:26]([CH2:25][Cl:24])=[N:1][C:2]2[C:3]([C:4]=1[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=1)=[CH:16][C:17]1[O:23][CH2:22][CH2:21][O:20][C:18]=1[CH:19]=2)=[O:29])[CH3:32]
Reactant: CCOC(=O)CC(=O)CCl
Reactant: COc1ccc(C(=O)c2cc3c(cc2N)OCCO3)cc1OC
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CCOC(=O)c1c(CCl)nc2cc3c(cc2c1-c1ccc(OC)c(OC)c1)OCCO3
Temperature: 100 °C
Reaction time: 3 h
Yield: 60.1 %

Procedure:
To a mixture of 2-amino-3',4'-dimethoxy-4,5-ethylenedioxybenzo-phenone (6.5 g), ethyl 4-chloroacetoacetate (3.7 g) and acetic acid (60 ml), concentrated sulfuric acid (0.3 ml) was added, followed by stirring at 100° C. for 3 hours. After the reaction mixture was concentrated under reduced pressure, the residue was poured over water and alkalinized with 2 N NaOH and then extracted with chloroform. The chloroform layer was washed with water and dried (MgSO4), after which the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with chloroform-ethyl acetate (7:3, v/v) to yield 2-chloromethyl-4-(3,4-dimethoxyphenyl)-6,7-ethylenedioxyquinoline-3-carboxylic acid ethyl ester (5.5 g, 60%), which was then recrystallized from acetone to yield a colorless prismatic crystal having a melting point of 197 to 198° C.
Reaction SMILES: [OH:1][CH:2]([CH3:9])[CH2:3][NH:4][C:5](=[O:8])[O:6][CH3:7].[Br:10][CH:11]([CH3:15])[C:12](Br)=[O:13]>>[Br:10][CH:11]([CH3:15])[C:12]([O:1][CH:2]([CH3:9])[CH2:3][NH:4][C:5](=[O:8])[O:6][CH3:7])=[O:13]
Reactant: COC(=O)NCC(C)O
Reactant: CC(Br)C(=O)Br
Product: COC(=O)NCC(C)OC(=O)C(C)Br

Procedure:
by using methyl 2-hydroxypropylcarbamate and 2-bromopropionyl bromide there is obtained methyl 2-(2-bromopropionyloxy)-propylcarbamate, nD20 1.4764;
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]1[CH2:13][CH:12]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:11][NH:10][C@@H:9]1[C:19]([OH:21])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.[C:49]1([CH:55]2[CH2:59][CH2:58][NH:57][CH2:56]2)[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:18][O:17][C:15](=[O:16])[CH2:14][CH:12]1[CH2:11][NH:10][C@H:9]([C:19]([N:57]2[CH2:58][CH2:59][CH:55]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[CH2:56]2)=[O:21])[C@@H:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13]1
Reactant: c1ccc(C2CCNC2)cc1
Reactant: COC(=O)CC1CN[C@H](C(=O)O)[C@@H](C(=O)OC(C)(C)C)C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)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: COC(=O)CC1CN[C@H](C(=O)N2CCC(c3ccccc3)C2)[C@@H](C(=O)OC(C)(C)C)C1
Reaction time: 8 h
Yield: 104.9 %

Procedure:
To an oven-dried 5 mL conical vial equipped with a magnetic stir bar and under a nitrogen gas atmosphere was placed sequentially: (2S,3S)-3-(tert-butoxycarbonyl)-5-(2-methoxy-2-oxoethyl)piperidine-2-carboxylic acid (50 mg, 0.166 mmol), anhydrous DMF (2 mL), BOP reagent (100 mg, 0.226 mmol), 3-phenyl-pyrrolidine (25 mg, 0.17 mmol), and N,N-diisopropyl ethylamine (0.086 mL, 0.49 mmol). After stirring the reaction mixture overnight, the reaction was quenched with 5% citric acid (1 mL) and the reaction mixture was diluted with ethyl acetate (15 mL) and water (4 mL). The aqueous layer was extracted with ethyl acetate (3×3 mL) and the combined organic phases were washed with saturated sodium bicarbonate (3×5 mL), brine (5 mL), dried (NaSO4), and concentrated in-vacuo to afford 75 mg of crude product that was used directly in the following hydrolysis. LCMS (ESI): 431 (M+H), 375 (M−t-Bu+2H+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:18]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([N+:31]([O-])=O)[C:24]=3[N+:28]([O-])=O)[C:19]2=[O:34])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:18]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([NH2:31])[C:24]=3[NH2:28])[C:19]2=[O:34])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: CCOc1cc(C(CS(C)(=O)=O)N2C(=O)c3ccc([N+](=O)[O-])c([N+](=O)[O-])c3C2=O)ccc1OC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOc1cc(C(CS(C)(=O)=O)N2C(=O)c3ccc(N)c(N)c3C2=O)ccc1OC
Reaction time: 16 h
Yield: 73.1 %

Procedure:
A mixture of 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4,5-dinitroisoindoline-1,3-dione (4.35 g, 8.81 mmol) and Pd/C (800 mg) in ethyl acetate (200 mL) was shaken under hydrogen (50-60 psi) in a Parr bottle for 16 hours. The suspension was filtered through a pad of Celite filter material. The Celite filter material was washed with acetone (200 mL). The solvent was removed in vacuo to give a solid. The solid was stirred in ethyl acetate (10 mL) for 2 hours. The suspension was filtered to give 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4,5-diaminoisoindoline-1,3-dione as a yellow solid (2.79 g, 73% yield): mp, 205-207° C.; 1H NMR (DMSO-d6) δ1.32 (t, J=6.9 Hz, 3H, CH3), 2.99 (s, 3H, CH3), 3.73 (s, 3H, CH3), 3.95-4.07 (m, 3H, CHH), 4.37 (dd, J=10.4, 14.0 Hz, 1H, CHH), 5.67 (dd, J=3.9, 10.2 Hz, 1H, NCH), 5.90-6.00 (m, 4H, 2NH2), 6.64 (d, J=7.7 Hz, 1 H, Ar), 6.88-6.92 (m, 3H, Ar), 7.06 (s, 1H, Ar); 13C NMR (CDCl3) δ14.64, 40.94, 46.65, 53.53, 55.46, 63.79, 109.36, 111.74, 112.29, 114.42, 117.04, 119.55, 130.68, 133.98, 134.06, 142.38, 147.74, 148.63, 167.16, 169.38; Anal Calcd for C20H23N3O6S: C, 55.42; H, 5.35; N, 9.69. Found: C, 55.71; H, 5.30; N, 9.29. MS: 434 (M++1), 456 (M++23 Na).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:18]=[C:17]([C:19]#[N:20])[S:16][CH:15]=2)[C:9]1=[O:21])(C)(C)C.[ClH:23]>CCOC(C)=O>[ClH:23].[NH2:7][C@H:8]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:18]=[C:17]([C:19]#[N:20])[S:16][CH:15]=2)[C:9]1=[O:21]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(Cc2csc(C#N)c2)C1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: N#Cc1cc(CN2CC[C@H](N)C2=O)cs1
Reaction time: 3 h

Procedure:
[1-(5-Cyanothiophen-3-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-carbamic acid tert-butyl ester (4.0 g, 13.8 mmol) is added to a solution of 100 mL of EtOAc saturated with HCl gas at 0° C. After 3 hours, the solution is concentrated. The title compound (3.3 g, 13.5 mmol) is obtained as a white solid.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][NH2:10].C(O[CH:14]=[C:15]([C:18]#[N:19])[C:16]#[N:17])C.C(N(CC)CC)C>CO>[NH2:19][C:18]1[N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH3:2])[N:10]=[CH:14][C:15]=1[C:16]#[N:17]
Reactant: CCOC=C(C#N)C#N
Reactant: Cc1ccccc1NN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: Cc1ccccc1-n1ncc(C#N)c1N

Procedure:
10.2 g (64.4 mmol) of 2-methylphenylhydrazine hydrochloride are suspended with 7.8 g (64.4 mmol) of ethoxymethylenemalononitrile in 100 ml of methanol, and 26.9 ml (193.3 mmol) of triethylamine are added. The reaction mixture is heated to reflux overnight, during which a clear solution forms. The solution is subsequently distilled off under reduced pressure, and the crude product is purified by column chromatography (silica gel, mobile phase dichloromethane). 10.8 g (85% of theory) of the desired product are obtained.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([N:13]2[C:17]([OH:18])=[CH:16][C:15]([C:19]([O:21][CH3:22])=[O:20])=[N:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[H-].[Na+].[N+:27]([C:30]1[CH:35]=[C:34]([S:36]([C:39]([F:42])([F:41])[F:40])(=[O:38])=[O:37])[CH:33]=[CH:32][C:31]=1Cl)([O-:29])=[O:28]>>[CH3:22][O:21][C:19]([C:15]1[CH:16]=[C:17]([O:18][C:31]2[CH:32]=[CH:33][C:34]([S:36]([C:39]([F:41])([F:42])[F:40])(=[O:38])=[O:37])=[CH:35][C:30]=2[N+:27]([O-:29])=[O:28])[N:13]([C:5]2[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=[C:3]([C:2]([F:1])([F:23])[F:24])[CH:4]=2)[N:14]=1)=[O:20]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)C(F)(F)F)ccc1Cl
Reactant: COC(=O)c1cc(O)n(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1cc(Oc2ccc(S(=O)(=O)C(F)(F)F)cc2[N+](=O)[O-])n(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1

Procedure:
Using procedure as in example 10, a reaction of methyl 1-[3,5-di(trifluoromethyl)phenyl]-5-hydroxy-1H-pyrazole-3-carboxylate (100 mg, 0.282 mmol), NaH (12 mg, 1.1 equiv.) and 2-nitro-4-(trifluoromethylsulfonyl)chlorobenzene (82 mg, 1 equiv.) afforded 1-(3,5-bis-trifluoromethyl-phenyl)-5-(2-nitro-4-trifluoromethanesulfonyl-phenoxy)-1H-pyrazole-3-carboxylic acidmethyl ester. 1HNMR (300 MHz, DMSO-d6) δ 8.76 (d, J=2.1 Hz, 1H), 8.58 (dd, J=2.1 & 8.2 Hz, 1H), 8.42 (s, 2H), 8.30 (s, 1H), 8.13 (d, J=8.2 Hz, 1H), 6.76 (m, 1H), 3.7 (s, 3H, OCH3). MS-EI m/z 607 [M+].
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[N:15]([CH2:27][CH2:28][OH:29])[CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[C:21]([CH3:26])[CH:20]=4)[N:18]=3)[CH2:10][CH2:9]2)[C:3]=1Br.[C:31]([O:35][C:36]([N:38]1[CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:40]=[N:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32].C([O-])([O-])=O.[Cs+].[Cs+]>O>[NH2:1][C:2]1[C:3]([C:41]2[CH:40]=[N:39][N:38]([C:36]([O:35][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:37])[CH:42]=2)=[C:4]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[N:15]([CH2:27][CH2:28][OH:29])[CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[C:21]([CH3:26])[CH:20]=4)[N:18]=3)[CH2:10][CH2:9]2)[N:5]=[CH:6][N:7]=1
Reactant: Cc1cc(-c2cn(CCO)c(C3CCN(c4ncnc(N)c4Br)CC3)n2)ccc1F
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Product: Cc1cc(-c2cn(CCO)c(C3CCN(c4ncnc(N)c4-c4cnn(C(=O)OC(C)(C)C)c4)CC3)n2)ccc1F
Temperature: 50 °C
Reaction time: 8 h

Procedure:
a mixture of 2-[2-[1-(6-amino-5-bromo-pyrimidin-4-yl)-piperidin-4-yl]-4-(4-fluoro-3-methyl-phenyl)-imidazol-1-yl]-ethanol (1333.00 mg; 2.80 mmol; 1.00 eq.), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazole-1-carboxylic acid tert-butyl ester (1237.31 mg; 4.21 mmol; 1.50 eq.), Cs2CO3 (548 mg, 1.68 mmol) in doxane 10 ml and water 1 ml, purged with argon, added Pd(0) (tBu3)2 (143 mg, 0.28 mmol) stirred at 50° C. for overnight. LC-MS showed desired as major product, removed off solvent, purified by prep HPLC (Basic), collected title compound 400 mg, 25.4%
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[C:12]([O-])([O-])=O.[K+].[K+].COS(OC)(=O)=O>CC(C)=O>[CH3:12][O:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: Cc1ccc(C(N)=O)c(O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: COc1cc(C)ccc1C(N)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 617.5 %

Procedure:
A mixture of 2-hydroxy-4-methyl-benzamide (15.1 g, 0.1 mol) and K2CO3 (41.7 g, 0.3 mol) in 1000 mL of acetone was heated to reflux for 1 hour before Me2SO4 was added at that temperature. The resulting mixture was refluxed overnight. The reaction mixture was then filtered and the filtrate was concentrated. The resulting residue was dissolved in 1000 mL of methanol/ammonia (1:1) and stirred at room temperature for 3 hours. After removal of the solvent, the residue was recrystallized from EtOAc/PE to afford 102 g of 2-methoxy-4-methyl-benzamide (yield 61%). 1H NMR (400 MHz, DMSO-d6): δ 7.72 (d, J=7.6 Hz, 1H), 7.57 (br s, 1H), 7.46 (br s, 1H), 6.92 (s, 1H), 6.81 (d, J=7.6 Hz, 1H), 3.85 (s, 3H), 2.31 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:8])([CH2:5][CH2:6][OH:7])[CH2:3][OH:4].N1C=CC=CC=1.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>ClCCl>[CH3:15][S:16]([O:4][CH2:3][C:2]([F:8])([F:1])[CH2:5][CH2:6][O:7][S:16]([CH3:15])(=[O:18])=[O:17])(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: OCCC(F)(F)CO
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)OCCC(F)(F)COS(C)(=O)=O
Reaction time: 8 h

Procedure:
To a stirred mixture of 2,2-difluoro-1,4-butanediol (12.97 g, 103 mM), dry pyridine (65 mL) and dichloromethane (200 mL) is slowly added a solution of methanesulfonylchloride (23.6 g) in dichloromethane (50 mL). Stirring is continued overnight. The reaction mixture is washed with 2N HCl (twice), followed by 10% aqueous NaHCO3 until neutral, and then with water. The organic layer is dried (MgSO4) and upon evaporation of the solvents, a slightly yellow oil is obtained. Crystallization is induced by scratching the oil with dry ether, to yield the compound 1,4-bis-methanesulfonyloxy-2,2-difluorobutane as white crystals: 22.3 g (77%).
Reaction SMILES: [C:1]([CH2:4][N:5]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12][N:11]([CH2:17][C:18]([OH:20])=[O:19])[CH2:10][CH2:9][N:8]([CH2:21][C:22]([OH:24])=[O:23])[CH2:7][CH2:6]1)([OH:3])=[O:2].[O:25]1[CH2:41][CH:26]1[CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36]([O:38]CC)=[O:37])=[CH:31][CH:30]=1.[OH-].[K+].Cl>O1CCOCC1.O>[OH:25][CH:26]([CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36]([OH:38])=[O:37])=[CH:31][CH:30]=1)[CH2:41][N:14]1[CH2:13][CH2:12][N:11]([CH2:17][C:18]([OH:20])=[O:19])[CH2:10][CH2:9][N:8]([CH2:21][C:22]([OH:24])=[O:23])[CH2:7][CH2:6][N:5]([CH2:4][C:1]([OH:3])=[O:2])[CH2:16][CH2:15]1
Reactant: CCOC(=O)Cc1ccc(OCC2CO2)cc1
Reactant: O=C(O)CN1CCNCCN(CC(=O)O)CCN(CC(=O)O)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)Cc1ccc(OCC(O)CN2CCN(CC(=O)O)CCN(CC(=O)O)CCN(CC(=O)O)CC2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
10 g (28.87 mmol) of 1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyclododecane (=DO3A) and 12.99 g (51.96 mmol) of 2,3-epoxy-1-[4-(2-ethoxycarbonylmethyl)-phenoxy]-propane are added in 80 ml of dioxane/60 ml of water and adjusted to pH 13 with 6N potassium hydroxide solution. It is stirred for 12 hours at room temperature. Then, it is refluxed for 2 hours. It is adjusted with 5N hydrochloric acid to pH 7 and evaporated to dryness in a vacuum. The residue is absorptively precipitated in 200 ml of ethanol/50 ml of chloroform at 60° C. The precipitated potassium chloride is filtered off and the filtrate is concentrated by evaporation in a vacuum. The residue is purified on a reversed-phase column (RP-18, washing with water, then elution with tetrahydrofuran/water=2:1). The main fractions are concentrated by evaporation in a vacuum.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][C@@H:5]1[CH3:10])(=[O:3])[CH3:2].Cl.[N:12]([O-])=[O:13].[Na+].[OH-].[Na+]>O>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([N:12]=[O:13])[CH2:6][C@@H:5]1[CH3:10])(=[O:3])[CH3:2]
Reactant: O=N[O-]
Reactant: CC(=O)N1CCNC[C@@H]1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)N1CCN(N=O)C[C@@H]1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 68.6 %

Procedure:
To a slurry of (S)-1-acetyl-2-methylpiperazine (424 mg) in water (2.5 ml) was added concentrated hydrochloric acid (0.9 ml) dropwise below 25° C. A solution of sodium nitrite (227 mg) in water (2 ml) was added dropwise at 0° C. The mixture was stirred at 0° C. for 2 hours. A solution of sodium hydroxide (409 mg) in water (6 ml) was added dropwise at 0° C. The mixture was extracted with chloroform, washed with water, dried and evaporated to give (S)-1-acetyl-2-methyl-4-nitrosopiperazine (350 mg). This product was used for next step without purification.