Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[N:19]=[CH:18][N:17]=[C:16]3[N:20]([C:23]4[CH:28]=[CH:27][C:26](I)=[CH:25][C:24]=4[F:30])[N:21]=[CH:22][C:15]=23)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[CH:31]([NH2:34])([CH3:33])[CH3:32].N1CCC[C@H]1C(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu](I)I>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[N:19]=[CH:18][N:17]=[C:16]3[N:20]([C:23]4[CH:28]=[CH:27][C:26]([NH:34][CH:31]([CH3:33])[CH3:32])=[CH:25][C:24]=4[F:30])[N:21]=[CH:22][C:15]=23)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)N
Reactant: CC(C)OC(=O)N1CCC(Oc2ncnc3c2cnn3-c2ccc(I)cc2F)CC1
Agent: I[Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: CC(C)Nc1ccc(-n2ncc3c(OC4CCN(C(=O)OC(C)C)CC4)ncnc32)c(F)c1
Temperature: 100 °C
Yield: 35 %

Procedure:
A mixture of 4-[1-(2-fluoro-4-iodo-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester (263 mg, 0.50 mmol), isopropylamine (450 μL, 5.0 mmol), L-proline (86 mg, 0.75 mmol), copper iodide (95 mg, 0.50 mmol) and potassium carbonate (207 mg, 1.50 mmol) in DMSO (4.0 mL) was heated under microwave irradiation for 50 min at 100° C. The crude mixture was concentrated in vacuo and purified by HPLC to provide Compound A230 as a white solid (80 mg, 35%). 1H NMR (CDCl3, 400 MHz) δ 1.20 (d, 6H), 1.26 (d, 6H), 1.75-1.88 (m, 2H), 1.98-2.09 (m, 2H), 3.28-3.37 (m, 2H), 3.55-3.63 (m, 1H), 3.78-3.87 (m, 2H), 4.88 (h, 1H), 5.55 (h, 1H), 6.90-7.08 (m, 2H), 7.44-7.50 (m, 1H), 8.17 (s, 1H), 8.53 (s, 1H). Exact mass calculated for C23H29FN6O3 456.51, found 457.3 (MH+).
Reaction SMILES: [C:1]12([C:18]([O:20]C(C)(C)C)=[O:19])[N:7]([C:8]([O:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:9])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2>C(O)(C(F)(F)F)=O.C(Cl)Cl.O>[CH2:11]([O:10][C:8]([N:7]1[CH:4]2[CH2:3][CH2:2][C:1]1([C:18]([OH:20])=[O:19])[CH2:6][CH2:5]2)=[O:9])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)C12CCC(CC1)N2C(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: O=C(OCc1ccccc1)N1C2CCC1(C(=O)O)CC2

Procedure:
7-benzyl 1-tert-butyl 7-azabicyclo[2.2.1]heptane-1,7-dicarboxylate (C-34)(synthesized following the procedure reported in J.O.C, 1996, 61, 6313-6325) was stirred in TFA/DCM/H2O (95/5/5, 0.3 M) for 10 minutes. Evaporation of the solvent afforded the titled compound (C-35).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[S:7][C:6](=[O:8])[NH:5][N:4]=[CH:3]1.[H-].[Na+].[CH2:12](I)[CH3:13]>CN(C)C=O>[CH2:12]([N:5]1[N:4]=[CH:3][C:2]([CH3:9])([CH3:1])[S:7][C:6]1=[O:8])[CH3:13]
Reactant: CC1(C)C=NNC(=O)S1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1N=CC(C)(C)SC1=O
Reaction time: 1 h

Procedure:
A solution of 2.8 g of 5-[1-N-ethyl-3,4-dimethoxybenzimidoyl)-1,2,3,4-tetrahydroquinolin-6-yl]-6,6-dimethyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (m.p. 188°) in 40 ml of dimethylformamide is treated with ice-cooling with 0.3 g of NaH and the mixture is stirred for 1 hour. 1.5 ml of ethyl iodide are then added, the mixture is stirred fur a further 2 hours and, after customary working up, 5-[1-N-ethyl-3,4-dimethoxybenzimidoyl)-1,2,3,4-tetrahydroquinolin-6-yl]-3-ethyl-6,6-dimethyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one is obtained.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:21]=[C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:23]=1[OH:24])[C:8]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][C:18]=1[O:19]C)[CH2:15][CH2:14][CH2:13]2)=[O:9])([CH3:4])([CH3:3])[CH3:2].B(Br)(Br)Br.ClCCl.C(O)C>ClCCl>[C:25]([C:22]1[CH:21]=[C:7]([CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:23]=1[OH:24])[C:8]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][C:18]=1[OH:19])[CH2:15][CH2:14][CH2:13]2)=[O:9])([CH3:28])([CH3:27])[CH3:26]
Reactant: COc1cc2c(cc1C(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)CCC2
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCO
Product: CC(C)(C)c1cc(C(=O)c2cc3c(cc2O)CCC3)cc(C(C)(C)C)c1O
Yield: 83.6 %

Procedure:
To a solution of 5-(3,5-di-tert-butyl-4-hydroxybenzoyl)-6-methoxyindan (3.8 g) in dichloromethane (30 ml) was added boron tribromide-dichloromethane (1:2, 3 ml) dropwise with ice-cooling and stirring. The mixture was stirred under ice-cooling for 15 minutes, after which ethanol (5 ml) was added dropwise. The mixture was then washed with water and dried (MgSO4) and the solvent was distilled off. To the residue was added hexane to give crystals of 5-(3,5-di -tert-butyl-4-hydroxybenzoyl)-6-hydroxyindan (3.06 g, 83.6% ) . Recrystallization from ethanol gave light yellow prisms, m.p. 155°-156° C.
Reaction SMILES: Cl.[CH:2]([N:5]1[C:9]([C:10]2[S:11][C:12]3[CH2:13][CH2:14][O:15][C:16]4[CH:23]=[C:22]([CH:24]5[CH2:28][CH2:27][NH:26][CH2:25]5)[CH:21]=[CH:20][C:17]=4[C:18]=3[N:19]=2)=[N:8][CH:7]=[N:6]1)([CH3:4])[CH3:3].[CH3:29][S:30](Cl)(=[O:32])=[O:31]>>[CH:2]([N:5]1[C:9]([C:10]2[S:11][C:12]3[CH2:13][CH2:14][O:15][C:16]4[CH:23]=[C:22]([CH:24]5[CH2:28][CH2:27][N:26]([S:30]([CH3:29])(=[O:32])=[O:31])[CH2:25]5)[CH:21]=[CH:20][C:17]=4[C:18]=3[N:19]=2)=[N:8][CH:7]=[N:6]1)([CH3:4])[CH3:3]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CCNC3)ccc1-2
Reactant: CS(=O)(=O)Cl
Agent: Cl
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CCN(S(C)(=O)=O)C3)ccc1-2

Procedure:
Following the procedure for 395, 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-pyrrolidin-3-yl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene hydrochloride salt and methanesulfonyl chloride gave 396 isolated as a pale orange solid (28 mg, 48%). LCMS: RT=11.27 min, [M+H]+=460. 1H NMR δ (ppm) (CDCl3): 8.33 (1H, d, J=8.21 Hz), 7.90 (1H, s), 7.05 (1H, dd, J=8.24, 1.91 Hz), 6.94 (1H, d, J=1.87 Hz), 5.93-5.83 (1H, m), 4.42-4.36 (2H, m), 3.79 (1H, dd, J=9.53, 7.31 Hz), 3.61 (1H, ddd, J=9.97, 8.27, 3.30 Hz), 3.50-3.31 (5H, m), 2.86 (3H, s), 2.41-2.32 (1H, m), 2.15-2.03 (1H, m), 1.61 (6H, d, J=6.63 Hz)
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]1[C@H:11]([CH3:12])[C@@H:10]([C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([N+:23]([O-:25])=[O:24])[C:14]=2I)[O:9][C:8]1=[O:27].[F:37][C:38]1[C:43]([CH:44]([CH3:46])[CH3:45])=[CH:42][C:41](B(O)O)=[C:40]([O:50][CH3:51])[CH:39]=1>>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]1[C@H:11]([CH3:12])[C@@H:10]([C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([N+:23]([O-:25])=[O:24])[C:14]=2[C:41]2[CH:42]=[C:43]([CH:44]([CH3:46])[CH3:45])[C:38]([F:37])=[CH:39][C:40]=2[O:50][CH3:51])[O:9][C:8]1=[O:27]
Reactant: C[C@@H]1[C@@H](c2cc(C(F)(F)F)cc([N+](=O)[O-])c2I)OC(=O)N1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COc1cc(F)c(C(C)C)cc1B(O)O
Product: COc1cc(F)c(C(C)C)cc1-c1c([C@H]2OC(=O)N(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)cc(C(F)(F)F)cc1[N+](=O)[O-]

Procedure:
Following the procedure described in EXAMPLE 81, 48 mg of (4R,5R)-3-[3,5-bis(trifluoromethyl)benzyl]-5-[2-iodo-3-nitro-5-(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one and 48 mg of (4-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid (EXAMPLE 78) provided two atroposiomers, which were separable by flash chromatography on a Biotage Horizon, 25S column, eluting with 1 CV of 5% EtOAc in hexanes followed by a linear gradient of 5→100% EtOAc in hexanes over 10 CV, providing atropoisomer A [mass spectrum (ESI) 683.4 (M+1)] and atropoisomer B [mass spectrum (ESI) 683.3 (M+1)].
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([F:16])[CH:3]=1.[F:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][C:23]=1[F:24]>>[F:17][C:18]1[CH:19]=[C:20]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([F:16])[CH:3]=2)[CH:21]=[CH:22][C:23]=1[F:24]
Reactant: O=C1NCCn2c1cc1cc(F)cc(Br)c12
Reactant: OB(O)c1ccc(F)c(F)c1
Product: O=C1NCCn2c1cc1cc(F)cc(-c3ccc(F)c(F)c3)c12

Procedure:
The title compound, light grey solid (72 mg, 91%), MS (ISP) m/z=317.1 [(M+H)+], mp 289.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 1) (70.8 mg, 0.25 mmol) and commercially available 3,4-difluoro-phenylboronic acid (51.3 mg, 0.325 mmol).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[C:12]1[CH:11]=[C:10]([F:18])[CH:9]=[CH:8][C:7]=1[S:6]2(=[O:20])=[O:19])#[N:2].[CH2:21](N)[CH2:22][NH2:23].C[O-].[Na+]>CO>[NH:2]1[CH2:21][CH2:22][N:23]=[C:1]1[C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[C:12]1[CH:11]=[C:10]([F:18])[CH:9]=[CH:8][C:7]=1[S:6]2(=[O:20])=[O:19]
Reactant: NCCN
Reactant: N#Cc1ccc2c(c1)S(=O)(=O)c1ccc(F)cc1C2=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C1c2cc(F)ccc2S(=O)(=O)c2cc(C3=NCCN3)ccc21
Reaction time: 120 h

Procedure:
A mixture of 6-cyano-2-fluorothioxanthen-9-one 10,10-dioxide, 5.2 g (0.02 mol), ethylenediamine, 1.2 g (0.02 mol), and sodium methoxide, 0.08 g (0.0015 mol), in methanol, 76 ml, was refluxed for 4 days. Additional ethylenediamine, 1.2 g (0.02 mol), was added and reflux continued for 5 days. The mixture was poured into ice and the precipitate was filtered, dried and recrystallised from ethanol, DMSO and H2O; affording 2.6 g of 6-(2-imidazolin-2-yl)-2-fluorothioxanthen-9-one 10,10-dioxide, m.p. 248°-249° C.; TLC on silica gel (triethylamine; ethanol; hexane/1:1:2), Rf =0.8.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][N:6]1[C:20](=[O:21])[C:15]2=[CH:16][C:17]([NH2:19])=[CH:18][C:13]3[C:14]2=[C:9]([CH:10]=[CH:11][CH:12]=3)[C:7]1=[O:8])[CH3:3].[C:22]([O-:30])(=[O:29])[C@H:23]([CH2:25][C:26]([O-:28])=[O:27])[OH:24]>>[CH3:3][N:2]([CH2:4][CH2:5][N:6]1[C:20](=[O:21])[C:15]2=[CH:16][C:17]([NH2:19])=[CH:18][C:13]3[C:14]2=[C:9]([CH:10]=[CH:11][CH:12]=3)[C:7]1=[O:8])[CH3:1].[CH2:25]([C:26]([OH:28])=[O:27])[C@H:23]([OH:24])[C:22]([OH:30])=[O:29]
Reactant: O=C([O-])C[C@H](O)C(=O)[O-]
Agent: CN(C)CCN1C(=O)c2cccc3cc(N)cc(c23)C1=O
Product: O=C(O)C[C@H](O)C(=O)O

Procedure:
A batch of amonafide L-malate was prepared in accordance with the method of Example I. The material so obtained was 99.4% chromatographically pure on a 10 gram synthetic scale, consistent with previous findings on the larger scale. The material was then converted to the free base amonafide, as follows: 10 grams of the L-malate salt were dissolved in 100 ml distilled water and titrated with vigorous stirring to pH 7 by the addition of ¼ concentrated ammonium hydroxide. The large mass of yellow needles that formed was filtered by suction, washed with water, and recrystalized from ethanol to afford 5.8 gr. Of 99.8% chromatographically pure amonafide free base, mp 172° C. (MW 283.3, 93% yield).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:3]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][CH3:26])=[CH:21][CH:20]=1>>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:3]=2)[CH3:26])=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1nc(Cl)c2ccccc2n1
Reactant: CNc1ccc(OC)cc1
Product: CCOC(=O)c1nc(N(C)c2ccc(OC)cc2)c2ccccc2n1

Procedure:
The title compound was prepared from ethyl 4-chloroquinazoline-2-carboxylate and (4-methoxy-phenyl)-methylamine by using the procedure described for Example 1b. 1H NMR (CDCl3): 7.98-8.02 (m, 1H), 7.61 (ddd, J=1H, 8.1, 6.9, 1.5), 7.08-7.17 (m, 3H), 7.01-7.05 (m, 1H), 6.91-6.96 (m, 2H), 4.56 (q, J=2H, 7.2), 3.84 (s, 3H), 3.71 (s, 3H), 1.50 (t, J=2H, 7.2).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Br:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:14][CH:13]=1.[CH2:26]([O:33][C:34](=[O:37])[CH2:35]Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[Cl-].[NH4+]>C1COCC1>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([CH:18]([CH2:35][C:34]([O:33][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:37])[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)Cc1ccc(Br)cc1
Reactant: O=C(CBr)OCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(CC(=O)OCc1ccccc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.5 %

Procedure:
Lithium bis(trimethylsilyl)amide (1.06 M in THF; 18.1 mL, 19.2 mmol) was added dropwise over 10 min to a stirred solution of tert-butyl (4-bromophenyl)acetate (4.92 g, 18.1 mmol) in THF (50 mL) at −78 ° C. under nitrogen. On completion of addition stirring was continued at −78 ° C. for 30 min then benzyl-2-bromoacteate (4.97 g, 3.44 mL, 21.7 mmol) was added dropwise over 5 min. The reaction was allowed to warm slowly to room temperature over 4 h then saturated ammonium chloride solution (50 mL) was added and the resulting suspension extracted with ethyl acetate (3×100 mL). The organic phases were combined, dried (magnesium sulfate) and evaporated to dryness. The residue was chromatographed on silica gel (10% diethyl ether: cyclohexane) to give the title compound as a colourless oil (6.26 g, 82%). LC/MS: 4.02 min; z/e 419 and 421, calcd (M+1) 419 and 421. 1H NMR (400 MHz: CDCl3): 7.40 (2H), 7.30 (5H), 7.10 (2H), 5.10 (2H), 3.90 (1H), 3.15 (1H), 2.65 (1H), 1.35 (9H).
Reaction SMILES: [CH3:1][N:2]([CH2:18][C:19]([OH:21])=O)[NH:3][C:4](=[O:17])[NH:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1.[NH2:22][C@H:23]([C:36]([N:38]([C@@H:50]([CH3:58])[CH:51]([O:55][CH2:56][CH3:57])[O:52][CH2:53][CH3:54])[CH2:39][C:40]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:43]=[CH:42][CH:41]=1)=[O:37])[CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32]>>[CH2:56]([O:55][CH:51]([O:52][CH2:53][CH3:54])[C@@H:50]([N:38]([CH2:39][C:40]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:43]=[CH:42][CH:41]=1)[C:36](=[O:37])[C@@H:23]([NH:22][C:19](=[O:21])[CH2:18][N:2]([CH3:1])[NH:3][C:4](=[O:17])[NH:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1)[CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:34])[CH3:32])[CH3:58])[CH3:57]
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@@H](N)CCCCNC(=O)OC(C)(C)C
Reactant: CN(CC(=O)O)NC(=O)NCc1cccc2ccccc12
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)CN(C)NC(=O)NCc1cccc2ccccc12

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(1-methyl-2-(naphthalen-1-ylmethylcarbamoyl)hydrazinyl)acetic acid (Compound VI-8) 84 mg (0.29 mmol) was coupled with tert-butyl (S)-5-amino-6-(((S)-1,1-diethoxypropan-2-yl)(naphthalen-1-ylmethyl)amino)-6-oxohexylcarbamate (Compound IV-13) 100 mg (0.19 mmol) to obtain the title compound.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([CH:23]=[CH:24][CH:25]=1)[O:8][CH2:9][CH2:10][CH2:11][N:12]1C(=O)C2C(=CC=CC=2)C1=O)[CH3:3].CN>CCOCC>[NH2:12][CH2:11][CH2:10][CH2:9][O:8][C:7]1[CH:6]=[C:5]([CH2:4][N:2]([CH3:1])[CH3:3])[CH:25]=[CH:24][CH:23]=1
Reactant: CN(C)Cc1cccc(OCCCN2C(=O)c3ccccc3C2=O)c1
Agent: CN
Solvent: CCOCC
Product: CN(C)Cc1cccc(OCCCN)c1
Yield: 79.9 %

Procedure:
2-[3-[3-(N,N-Dimethylaminomethyl)phenoxy]propyl]-1H-isoindole-1,3(2H)-dione (25 g) was treated with 30% ethanolic methylamine (150 ml). After 24 hr at room temperature ether (100 ml) was added and a solid was filtered off. The filtrate was distilled to give the title compound as a yellow oil (12.3 g) b.p. 102°-112° (0.2 mm). TLC silica; ethyl acetate:isopropanol:water:0.88 ammonia Rf 0.25.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3[CH:18]=[C:17]([CH2:19]Cl)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1.[F:23][C:24]1[CH:25]=[C:26](O)[CH:27]=[CH:28][CH:29]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3[CH:18]=[C:17]([CH2:19][C:28]4[CH:27]=[CH:26][CH:25]=[C:24]([F:23])[CH:29]=4)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1
Reactant: CCN1c2ncc(CCl)cc2C(=O)N(C)c2ccc(Cl)nc21
Reactant: Oc1cccc(F)c1
Product: CCN1c2ncc(Cc3cccc(F)c3)cc2C(=O)N(C)c2ccc(Cl)nc21
Yield: 70 %

Procedure:
Using a procedure analogous to that described in Example 98, the title compound, m.p. 104°-105° C., was prepared from 2-chloro-8-chloromethyl-5,11-dihydro-11-ethyl-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one and 3-fluorophenol. The yield was 70% of theory.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]2[CH:25]=[CH:24][C:18]3=[N:19][CH:20]=[C:21](Cl)[CH:22]=[C:17]3[C:16](=[O:26])[C:15]=2[CH:27]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:28][N:29]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[N:30]1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Si:1]([O:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]2[CH:25]=[CH:24][C:18]3=[N:19][CH:20]=[C:21]([C:32]4[CH:31]=[N:30][N:29]([CH3:28])[CH:33]=4)[CH:22]=[C:17]3[C:16](=[O:26])[C:15]=2[CH:27]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCc1ccc2ccc3ncc(Cl)cc3c(=O)c2c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cn1cc(-c2cnc3ccc4ccc(CCO[Si](C)(C)C(C)(C)C)cc4c(=O)c3c2)cn1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A test tube fitted with a teflon septum was charged with 7-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3-chloro-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (9 mg, 0.023 mmol), PdCl2(PPh3)2 (2 mg, 0.002 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (14 mg, 0.068 mmol), and sodium carbonate (7 mg, 0.068 mmol). The tube was evacuated and backfilled with argon three times. Fully degassed dioxane (0.5 mL) was added and the mixture was stirred at 100° C. overnight. The solution was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate, concentrated in vacuo, and purified via flash chromatography (silica, 20-100% ethyl acetate/hexanes) to afford the title compound. LRMS (APCI) calc'd for (C26H32N3O2Si) [M+H]+, 446.2; found 446.2.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1.[NH2:13][C@H:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C@H:15]1[NH:20][C:21]1[N:22]=[N:23][C:24]([C:40]([NH2:42])=[O:41])=[C:25](NC2C=CC=C(C3N=CC=CN=3)C=2)[N:26]=1>>[NH2:13][C@H:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C@H:15]1[NH:20][C:21]1[N:22]=[N:23][C:24]([C:40]([NH2:42])=[O:41])=[C:25]([NH:10][C:9]2[CH:11]=[CH:12][C:6]([C:2]3[O:1][CH:5]=[CH:4][N:3]=3)=[CH:7][CH:8]=2)[N:26]=1
Reactant: NC(=O)c1nnc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1cccc(-c2ncccn2)c1
Reactant: Nc1ccc(-c2ncco2)cc1
Product: NC(=O)c1nnc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1ccc(-c2ncco2)cc1

Procedure:
The title compound was prepared with 4-(oxazol-2-yl)aniline using the similar procedure described in Example 3-((1R,2S)-2-aminocyclohexylamino)-5-(3-(pyrimidin-2-yl)phenylamino)-1,2,4-triazine-6-carboxamide. MS found for C19H22N8O2 as (M+H)+ 395.6. UV: λ=240, 297 nm. Proton NMR: (CD3OD) δ 8.13 (2H, m), 8.03 (1H, s), 7.90 (2H, m), 7.34 (1H, s), 4.45 (1H, m), 3.72 (1H, m), 1.90-1.63 (8H, m) ppm.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]2=[N:7][O:8][N:9]=[C:5]2[C:4]=1[CH3:12])=[CH2:2].C1C=C(Cl)C=C(C(OO)=[O:21])C=1>C(Cl)Cl>[CH3:12][C:4]1[C:5]2[C:6](=[N:7][O:8][N:9]=2)[CH:10]=[CH:11][C:3]=1[CH:1]1[CH2:2][O:21]1
Reactant: C=Cc1ccc2nonc2c1C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1c(C2CO2)ccc2nonc12
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of 5-ethenyl-4-methyl-2,1,3-benzoxadiazole (1.4 g, 8.4 mmol) and mCPBA (85%, 2.57 g, 12.6 mmol) in 200 mL of DCM was stirred at room temperature for 96 hours. The reaction mixture was cooled to 0° C. and was washed subsequently with saturated NaHCO3 (50 mL), saturated Na2SO3 (50 mL), 5% NaOH (50 mL×2) and brine (50 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica column chromatography (PE:EtOAc=5:1) to afford the title compound.
Reaction SMILES: C(OC(=O)[NH:10][C@H:11]([CH2:17][OH:18])[C:12]([N:14]([CH3:16])[CH3:15])=[O:13])C1C=CC=CC=1>CO.[C].[Pd]>[CH3:15][N:14]([CH3:16])[C:12](=[O:13])[C@@H:11]([CH2:17][OH:18])[NH2:10]
Reactant: CN(C)C(=O)[C@@H](CO)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CN(C)C(=O)[C@H](N)CO
Yield: 104.3 %

Procedure:
A solution of (R)-benzyl[1-(dimethylamino)-3-hydroxy-1-oxopropan-2-yl]carbamate (1.30 g) and 10% palladium carbon (130 mg) in methanol (30 mL) was stirred at room temperature for 7 hr under a hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (673 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][CH:5]([NH2:21])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([F:15])[F:14])=[C:8]([O:16][CH2:17][CH:18]2[CH2:20][CH2:19]2)[CH:7]=1.C(N(CC)CC)C.C([O:32][C:33](=O)[C:34]1[C:39]([N+:40]([O-:42])=[O:41])=[CH:38][CH:37]=[CH:36][C:35]=1[CH2:43]Br)C>CN(C=O)C>[CH3:1][O:2][C:3](=[O:22])[CH2:4][CH:5]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([F:14])[F:15])=[C:8]([O:16][CH2:17][CH:18]2[CH2:19][CH2:20]2)[CH:7]=1)[N:21]1[CH2:43][C:35]2[C:34](=[C:39]([N+:40]([O-:42])=[O:41])[CH:38]=[CH:37][CH:36]=2)[C:33]1=[O:32]
Reactant: CCOC(=O)c1c(CBr)cccc1[N+](=O)[O-]
Reactant: COC(=O)CC(N)c1ccc(OC(F)F)c(OCC2CC2)c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)CC(c1ccc(OC(F)F)c(OCC2CC2)c1)N1Cc2cccc([N+](=O)[O-])c2C1=O
Temperature: 90 °C
Yield: 77 %

Procedure:
To a solution of 3-amino-3-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-propionic acid methyl ester (490 mg, 1.5 mmol) and triethyl amine (0.43 ml, 3.1 mmol) in DMF (10 ml) was added 2-bromomethyl-6-nitro-benzoic acid ethyl ester (460 mg, 1.6 mmol). The mixture was heated at 90° C. under nitrogen atmosphere overnight. The solvent was removed in vacuo. The resulted oil was extracted with ethyl acetate (50 ml) and 1N HCl (50 ml). The organic layer was washed with water (30 ml), brine (30 ml) and dried over magnesium sulfate. The solvent was removed in vacuo and the resulted oil was purified by silica gel chromatography (hexane:ethyl acetate=2:1) to give 3-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-3-(7-nitro-1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid methyl ester as a yellowish solid (550 mg, 75%). 1H NMR (CDCl3): δ 0.31-0.37 (m, 2H), 0.59-0.67 (m, 2H), 1.22-1.28 (m, 1H), 3.09 (dd, J=7, 15 Hz, 1H), 3.28 (dd, J=9, 15 Hz, 1H), 3.65 (s, 3H), 3.79-3.91 (m, 2H), 4.18 (d, J=17 Hz, 1H), 4.46 (d, J=17 Hz, 1H), 5.83 (dd, J=7, 9 Hz, 1H), 6.61 (t, JH-F=75 Hz, 1H), 7.04-7.05 (m, 3H), 7.58-7.76 (m, 3H).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[CH:8]([NH2:12])([CH2:10][CH3:11])[CH3:9]>C(OCC)C>[CH:8]([NH:12][C:1]([CH:2]=[CH:3][C:4]([OH:6])=[O:5])=[O:7])([CH2:10][CH3:11])[CH3:9]
Reactant: O=C1C=CC(=O)O1
Reactant: CCC(C)N
Solvent: CCOCC
Product: CCC(C)NC(=O)C=CC(=O)O

Procedure:
To a stirred solution of maleic anhydride, 95% (42.1 g, 0.4 mol) in 500 mL diethyl ether at 0° C. was added drop wise sec-butyl amine (29.25 g, 0.4 mol) in 50 mL diethyl ether. The resulting mixture was stirred while a solid formed, which was recovered by filtration. The residue was washed with 2×100 mL diethyl ether and dried to yield 51.76 g of the desired compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:3][CH:2]=1.F[C:14]1[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:8][CH2:9][N:10]([C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)[CH2:11][CH2:12]2)=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: c1cc(N2CCNCC2)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(N2CCN(c3ccncc3)CC2)cc1
Reaction time: 0.5 h

Procedure:
A solution of 4-(4-pyridyl)piperazine (9.78 g), ethyl 4-fluorobenzoate (9.7 ml) and powdered potassium carbonate (9.9 g) in dried dimethylsulphoxide (60 ml) was heated at 95° C. for 18 hours. The mixture was poured into water (1200 ml) and stirred for 30 minutes. The precipitate was filtered off, washed with water and dried. The solid was purified by flash column chromatography on alumina (ICN alumina N32-63) using 1% methanol/dichloromethane as eluent, to give ethyl 4-[4-(4-pyridyl)-1-piperazinyl]benzoate (4.85 g) as a cream solid, mp 162-164° C.