Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:17]4[C:18]([CH3:21])=[N:19][N:20]=[C:16]4[CH:15]([CH3:22])[CH2:14][N:13]([C:23]4[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=4)[C:12]=3[CH:31]=2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([OH:53])C.O>C(OCC)(=O)C.C(O[Pd]OC(=O)C)(=O)C>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:17]4[C:18]([CH3:21])=[N:19][N:20]=[C:16]4[CH:15]([CH3:22])[CH2:14][N:13]([C:23]4[CH:24]=[CH:25][C:26]([C:27]([NH2:28])=[O:53])=[CH:29][CH:30]=4)[C:12]=3[CH:31]=2)=[CH:4][CH:3]=1
Reactant: Cc1nnc2n1-c1ccc(-c3ccc(N)nc3)cc1N(c1ccc(C#N)cc1)CC2C
Reactant: CCO
Agent: CC(=O)O[Pd]OC(C)=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nnc2n1-c1ccc(-c3ccc(N)nc3)cc1N(c1ccc(C(N)=O)cc1)CC2C
Temperature: 60 °C
Yield: 50.8 %

Procedure:
A mixture of 4-(8-(6-aminopyridin-3-yl)-1,4-dimethyl-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepin-6(5H)-yl)benzonitrile (150 mg, 0.37 mmol), triphenylphosphine (194 mg, 0.74 mmol) and diacetoxypalladium (8.3 mg, 0.037 mmol) in mixed solution of ethanol (6 mL) and water (2 mL) was heated at 60° C. for 30 minutes under nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with brine (10 mL*3). The organic phase was separated, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give a crude product, which was purified by column chromatography (silica gel, dichloromethane/methanol=15:1) to afford 4-(8-(6-aminopyridin-3-yl)-1,4-dimethyl-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepin-6(5H)-yl)benzamide as a white solid (80 mg, 50.8%).
Reaction SMILES: C1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]([CH3:18])[C:10](=[O:19])[CH:9]([NH:20][C:21]([O:23]C3C=CC([N+]([O-])=O)=CC=3)=O)[N:8]=2)CCCCC1.C(N([CH2:38][CH3:39])CC)C.[CH:40]([S:43]([NH:46][C:47]([C:49]1[CH:54]=[CH:53][CH:52]=[C:51]([NH2:55])[CH:50]=1)=[O:48])(=[O:45])=[O:44])([CH3:42])[CH3:41]>CN(C)C=O>[CH2:39]1[CH2:38][CH:7]([C:9]2([NH:20][C:21]([NH:55][C:51]3[CH:52]=[CH:53][CH:54]=[C:49]([C:47]([NH:46][S:43]([CH:40]([CH3:42])[CH3:41])(=[O:45])=[O:44])=[O:48])[CH:50]=3)=[O:23])[N:8]=[CH:7][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]([CH3:18])[C:10]2=[O:19])[CH2:13][CH2:12][CH2:17]1
Reactant: CN1C(=O)C(NC(=O)Oc2ccc([N+](=O)[O-])cc2)N=C(C2CCCCC2)c2ccccc21
Reactant: CC(C)S(=O)(=O)NC(=O)c1cccc(N)c1
Reactant: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)S(=O)(=O)NC(=O)c1cccc(NC(=O)NC2(C3CCCCC3)N=Cc3ccccc3N(C)C2=O)c1

Procedure:
The title compound was prepared in the same way as that described in Example 11, Step 4, using 5-cyclohexyl-l,3-dihydro- 1-methyl-3(R,S)-[(4-nitrophenyloxycarbonyl)amino]-2H-1,4-benzodiazepin-2-one (0.3 g, 0.69 mmol), triethylamine (96 μl, 0.69 mmol), dimethylformamide (6 ml) and 1-(isopropylsulphonylaminocarbonyl)-3-aminobenzene (0.175 mg, 0.72 mmol). After recrystallisation from ethanol the title compound (0.24 g, 65%) was afforded as a colourless solid. mp 165° C. (dec.). 1H NMR (360 MHz, D6 -DMSO) δ 0.87-0.98 (1H, m), 1.10-1.64 (7H, m), 1.30 (6H, d, J=6.9 Hz), 1.79 (1H, m), 1.88-1.96 (1H, m), 2.95 (1H, m), 3.33 (3H, s), 3.79 (1H, septet, J=6.9 Hz), 5.07 (1H, d, J=8.2 Hz), 7.37 (3H, m), 7.46 (1H, d, J=7.8 Hz), 7.55 (2H, m), 7.64 (1H, dd, J=7.1 and 7.1 Hz), 7.75 (1H, d, J=7.9 Hz), 7.92 (1H,s), 9.22 (1H,s), 11.93 (1H, brs).
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=[O:4].C([O:15][C:16]1[CH:17]=[C:18]([CH:27]([OH:50])[CH2:28][NH:29][C:30]([CH3:49])([CH3:48])[CH2:31][CH2:32][N:33]2[C:37]([CH3:38])=[N:36][C:35]([C:39]3C=[C:41]([CH:45]=[CH:46][CH:47]=3)C(O)=O)=[N:34]2)[C:19]2[O:24][CH2:23][C:22](=[O:25])[NH:21][C:20]=2[CH:26]=1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:50][CH:27]([C:18]1[C:19]2[O:24][CH2:23][C:22](=[O:25])[NH:21][C:20]=2[CH:26]=[C:16]([OH:15])[CH:17]=1)[CH2:28][NH:29][C:30]([CH3:49])([CH3:48])[CH2:31][CH2:32][N:33]1[C:37]([CH3:38])=[N:36][C:35]([C:39]2[CH:47]=[CH:46][CH:45]=[CH:41][C:2]=2[C:3]([OH:5])=[O:4])=[N:34]1
Reactant: Cc1nc(-c2cccc(C(=O)O)c2)nn1CCC(C)(C)NCC(O)c1cc(OCc2ccccc2)cc2c1OCC(=O)N2
Reactant: O=C(O)C(F)(F)F
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1nc(-c2ccccc2C(=O)O)nn1CCC(C)(C)NCC(O)c1cc(O)cc2c1OCC(=O)N2

Procedure:
250 mg (0.36 mmol) 3-(1-{3-[2-(6-benzyloxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-2-hydroxy-ethylamino]-3-methyl-butyl}-5-methyl-1H-[1,2,4]triazol-3-yl)-benzoic acid trifluoroacetate are dissolved in 5 mL methanol and hydrogenated at ambient temperature and 2.5 bar hydrogen pressure in the presence of palladium on charcoal (10%). The catalyst is suction filtered, the filtrate is evaporated down and the residue is purified by chromatography (reverse phase, acetonitrile/water gradient with 0.1% trifluoroacetic acid). Yellow solid. Yield: 62 mg (28%, trifluoroacetate); mass spectroscopy [M+H]+=496.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([C:10]([O:12][CH3:13])=[O:11])[CH2:7][C:6]=2[CH:14]=1.Cl[C:16]1[N:21]=[C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[C:19]([F:30])=[CH:18][N:17]=1>>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([NH:22][C:20]2[C:19]([F:30])=[CH:18][N:17]=[C:16]([NH:1][C:2]3[CH:3]=[CH:4][C:5]4[O:9][CH:8]([C:10]([O:12][CH3:13])=[O:11])[CH2:7][C:6]=4[CH:14]=3)[N:21]=2)=[CH:28][CH:27]=1
Reactant: Fc1cnc(Cl)nc1Nc1ccc(Cl)cc1
Reactant: COC(=O)C1Cc2cc(N)ccc2O1
Product: COC(=O)C1Cc2cc(Nc3ncc(F)c(Nc4ccc(Cl)cc4)n3)ccc2O1

Procedure:
In like manner to the preparation of (±)-N4-(3,4-difluorophenyl)-N2-(2,3-dihydro-2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediamine, the reaction of (±)-5-amino-2,3-dihydro-2-methoxycarbonylbenzofuran with 2-chloro-N4-(4-chlorophenyl)-5-fluoro-4-pyrimidineamine gave (±)-N4-(4-chlorophenyl)-N2-(2,3-dihydro-2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 10.29 (bs, 1H), 9.89 (bs, 1H), 8.21 (d, 1H, J=4.8 Hz), 7.69 (m, 2H), 7.38 (m, 3H), 7.13 (bd, 1H, J=8.1 Hz), 6.83 (d, 1H, J=8.4 Hz), 5.36 (dd, 1H, J=6.3 and 5.7 Hz), 3.70 (s, 3H), 3.52 (dd, 1H, J=10.5 Hz), 3.20 (dd, 1H, J=5.4 and 5.7 Hz); LCMS: purity: 98%; MS (m/e): 415 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH2:8][OH:9])[CH:6]=1.[F:17][C:18]1[CH:19]=[C:20]([CH2:25][C:26]([NH:28][C@@H:29]([CH2:33][CH2:34][CH3:35])[C:30](O)=[O:31])=[O:27])[CH:21]=[C:22]([F:24])[CH:23]=1>>[F:16][C:13]1[CH:14]=[CH:15][C:10]([CH:7]([N:5]2[CH:6]=[C:2]([NH:1][C:30](=[O:31])[C@@H:29]([NH:28][C:26](=[O:27])[CH2:25][C:20]3[CH:21]=[C:22]([F:24])[CH:23]=[C:18]([F:17])[CH:19]=3)[CH2:33][CH2:34][CH3:35])[N:3]=[CH:4]2)[CH2:8][OH:9])=[CH:11][CH:12]=1
Reactant: Nc1cn(C(CO)c2ccc(F)cc2)cn1
Reactant: CCC[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Product: CCC[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(C(CO)c2ccc(F)cc2)cn1

Procedure:
2-(4-amino-1H-imidazol-1-yl)-2-(4-fluorophenyl)ethanol was reduced and coupled with (S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid (U.S. Ser. No. 11/078,898 filed Mar. 11, 2005) to afford the title compound: MS 475 m/z (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9](=O)[CH2:10][C:11]#[N:12])[CH:6]=[CH:7][CH:8]=1.[NH2:14][NH2:15]>CCO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]([NH2:12])[NH:14][N:15]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: NN
Reactant: COc1cccc(C(=O)CC#N)c1
Solvent: CCO
Product: COc1cccc(-c2cc(N)[nH]n2)c1

Procedure:
3-(3-Methoxy-phenyl)-3-oxo-propionitrile (2.0202 gms.) is then suspended in 55 mL of anhydrous EtOH. This suspension is treated with 0.73 mL of anhydrous hydrazine and subsequently heated to refluxing temperature for 1 day. The reaction mixture is concentrated in vacuo. The residue is then triturated with isopropanol to precipitate out the 5-(3-methoxy-phenyl)-2H-pyrazol-3-ylamine as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:15]2[CH2:16][CH2:17][C:18](=[O:21])[NH:19][N:20]=2)[CH:5]=[CH:6][C:7]=1[NH:8][CH2:9][CH2:10][NH:11][C:12](=[O:14])[CH3:13].[C:22](N1C=CN=C1)(N1C=CN=C1)=[O:23]>CN(C)C=O>[NH:11]([CH2:10][CH2:9][N:8]1[C:7]2[CH:6]=[CH:5][C:4]([C:15]3[CH2:16][CH2:17][C:18](=[O:21])[NH:19][N:20]=3)=[CH:3][C:2]=2[N:1]=[C:22]1[OH:23])[C:12]([CH3:13])=[O:14]
Reactant: CC(=O)NCCNc1ccc(C2=NNC(=O)CC2)cc1N
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CC(=O)NCCn1c(O)nc2cc(C3=NNC(=O)CC3)ccc21

Procedure:
To a solution of 580 mg (2.0 mmol) of 6-(3-amino-4-acetylaminoethylamino-phenyl)-4,5-dihydro-3(2H)-pyridazinone in 50 ml of dimethylformamide, 325 mg (2.0 mmol) of carbonyldiimidazole are added at 50° C. After 45 minutes at 50° C. the mixture is evaporated to dryness and the residue is mixed with 10 ml of water. The product precipitated is suction filtered, washed with 5 ml of water and dried.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[N:23]=[N:24][N:25](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:26]=3)=[CH:12][CH:11]=2)[C:7]2[CH:46]=[C:47]([C:51]3O[C:53]([CH3:57])=[C:54]([CH3:56])[N:55]=3)[CH:48]=[C:49]([CH3:50])[C:6]=2[N:5]=1)[CH2:2][CH3:3].[CH2:58]([NH:60]C=O)[CH3:59].C(N)C>>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:26][N:25]=[N:24][N:23]=3)=[CH:12][CH:11]=2)[C:7]2[CH:46]=[C:47]([C:51]3[N:60]([CH2:58][CH3:59])[C:53]([CH3:57])=[C:54]([CH3:56])[N:55]=3)[CH:48]=[C:49]([CH3:50])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(-c3nc(C)c(C)o3)cc2n1Cc1ccc(-c2ccccc2-c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1
Reactant: CCNC=O
Agent: CCN
Product: CCCc1nc2c(C)cc(-c3nc(C)c(C)n3CC)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Prepared analogously to Example 146 from 4'-[[2-n-propyl-4-methyl-6-(4,5-dimethyl-oxazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-2-(2-triphenylmethyl-tetrazol-5-yl)-biphenyl and N-ethyl-formamide/ethylamine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][S:23]([CH3:22])(=[O:25])=[O:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Yield: 98.7 %

Procedure:
To a solution of 1.00 g (4.97 mmol) of N-t-butoxycarbonyl-4-hydroxypiperidine and 0.83 ml (5.96 mmol) of triethylamine in 50 ml of methylene chloride was added 0.46 ml (5.96 mmol) of methanesulfonylchloride under ice-cooling and stirring and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with an aqueous saturated sodium bicarbonate solution and water and dried. The solvent was distilled off. The residue was washed with hexane to obtain 1.37 g of the desired compound (98.6%, colorless powder), mp: 87.0°-88.0° C.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[CH2:10][C@@H:11]([C:20](O)=[O:21])[NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[BH4-].[Na+]>C(COC)OC.O>[C:16]([O:15][C:13]([NH:12][C@H:11]([CH2:20][OH:21])[CH2:10][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:23])=[O:14])([CH3:18])([CH3:19])[CH3:17]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](CO)CC(=O)OCc1ccccc1
Temperature: -7.5 °C
Reaction time: 0.5 h

Procedure:
N-(tert-butoxycarbonyl)-L-aspartic acid 4-benzyl ester (1.23 g, 3.80 mmol) was dissolved in dimethoxyethane (3.6 mL) in a flame-dried flask. The solution was cooled to −5 to −10° C. N-methylmorpholine (0.422 mL, 3.84 mmol) was then added dropwise, followed by a slow addition of isobutyl chloroformate (0.525 mL, 3.9 mmol) while the reaction temperature was maintained below −10° C. The mixture was aged for 30 minutes. The solids were quickly filtered and washed with dimethoxyethane (3.6 mL). The filtrate was cooled to −50° C. and a solution of sodium borohydride (0.18 g, 4.76 mmol) in water (1.8 mL) was added slowly while the reaction temperature was maintained between −30° C. and −15° C. Water (20 mL) was then added such that the reaction mixture temperature was maintained below −15° C. The reaction mixture was extracted with ethyl acetate (3×5 mL), washed with cold 0.1N HCl, then saturated sodium bicarbonate solution and then brine. The organic phase was dried with magnesium sulfate. Evaporated to dryness to yield an oil that crystallizes upon standing. LC-MS m/z=332 (M+Na+).
Reaction SMILES: [N+:1]1([O-])[C:2]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.C[Si]([C:19]#[N:20])(C)C.CN(C)C(Cl)=O>[N+](CC)([O-])=O>[C:19]([C:6]1[N:1]=[C:2]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH:3]=[CH:4][CH:5]=1)#[N:20]
Reactant: C[Si](C)(C)C#N
Reactant: CC(C)(C)OC(=O)c1cccc[n+]1[O-]
Agent: CN(C)C(=O)Cl
Solvent: CC[N+](=O)[O-]
Product: CC(C)(C)OC(=O)c1cccc(C#N)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 86.3 %

Procedure:
A mixture of tert-butyl 2-pyridinecarboxylate N-oxide (12.4 g, 63 mmol), trimethylsilyl cyanide (9.6 g, 96 mmol), N,N-dimethylcarbamoyl chloride (10.3 g, 95 mmol) and nitroethane (80 ml) was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure. The residue was subjected to a silica gel column chromatography, eluted with hexane-ethyl acetate (3;1, v/v) and recrystallized from tetrahydrofuran-hexane to give the titled compound (11.1 g, 85%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[CH:22](O)[C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O=S(Cl)[Cl:32]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[CH:22]([Cl:32])[C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(O)c2ccncc2)cc1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(Cl)c2ccncc2)cc1
Temperature: 80 °C

Procedure:
4-tert-Butyl-N-[4-chloro-2-(hydroxy-pyridin-4-yl-methyl)-phenyl]-benzenesulfonamide (1.1 g, 2.5 mmol) was dissolved in SOCl2 and heated at 80° C. overnight. Excess SOCl2 was removed by rotary evaporation. The residue suspended in 50 mL DCM was washed with saturated sodium bicarbonate solution (50 mL) and dried over MgSO4. Evaporation of solvent gave white crystalline solid. MS: (M+H)=450.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]3[N:13]([C:15]([CH3:18])=[N:16][N:17]=3)[N:14]=2)[CH:4]=1.[CH2:19]=[C:20]1[O:24][C:22](=[O:23])[CH2:21]1>C1(C)C=CC=CC=1>[CH3:1][N:2]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]3[N:13]([C:15]([CH3:18])=[N:16][N:17]=3)[N:14]=2)[CH:4]=1)[C:22](=[O:23])[CH2:21][C:20](=[O:24])[CH3:19]
Reactant: CNc1cccc(-c2ccc3nnc(C)n3n2)c1
Reactant: C=C1CC(=O)O1
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)N(C)c1cccc(-c2ccc3nnc(C)n3n2)c1

Procedure:
A mixture of 2.0 g of N-methyl-3-(3-methyl-1,2,4-triazolo-[4,3-b]pyridazin-6-yl)benzenamine and 2.14 ml of diketene in 250 ml of dry toluene was heated to reflux for 2 days. The solution was concentrated in vacuo and the residue partitioned between 300 ml dichloromethane and 200 ml of water. The aqueous layer was extracted with 150 ml portions of dichloromethane. The organic layer and extracts were combined, dried and concentrated in vacuo. The residue was chromatographed on 300 g of silica gel with dichloromethane-methanol (97:3). The fractions containing product were combined, evaporated in vacuo and the solid recrystalized from dichloromethane-hexane to give 1.15 g of tan crystals, mp 138°-141° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.C1(C)C=CC=CC=1.C(O)C.O.B([O-])([O-])O[C:46]1[CH:51]=[CH:50][CH:49]=[C:48]([O:52][CH2:53][CH2:54][CH3:55])[CH:47]=1.C(=O)([O-])[O-].[K+].[K+]>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>[CH3:31][N:24]([CH2:23][C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:14]([C:8]2[CH2:9][CH2:10][S:11](=[O:13])(=[O:12])[C:5]3[CH:4]=[CH:3][C:2]([C:46]4[CH:51]=[CH:50][CH:49]=[C:48]([O:52][CH2:53][CH2:54][CH3:55])[CH:47]=4)=[CH:32][C:6]=3[CH:7]=2)=[O:15])=[CH:18][CH:19]=1)[CH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: CCCOc1cccc(OB([O-])[O-])c1
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
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: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCOc1cccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
To 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg) was added toluene/ethanol/water (20/1/1, 13.9 ml) and then were added 3-propoxyphenyl borate (125 mg) and potassium carbonate (175 mg), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (27 mg), and the mixture was refluxed for 8 hours and cooled to room temperature. The mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/ethanol=5/2) and recrystallized from ethanol to give N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-7-(3-propoxyphenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 109) (282 mg).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@@H:4]([CH2:17][O:18][C:19](=[O:37])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:5][N:6]1[CH:14]=[N:13][C:12]2[C:11](=[O:15])[NH:10][C:9]([NH2:16])=[N:8][C:7]1=2.[C:38]([NH:45][C@H:46]([C:51](O)=[O:52])[C@H:47]([CH2:49][CH3:50])[CH3:48])([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.CN(C=O)C>[C:38]([NH:45][C@H:46]([C:51]([O:1][CH2:2][CH2:3][C@@H:4]([CH2:17][O:18][C:19](=[O:37])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:5][N:6]1[CH:14]=[N:13][C:12]2[C:11](=[O:15])[NH:10][C:9]([NH2:16])=[N:8][C:7]1=2)=[O:52])[C@H:47]([CH2:49][CH3:50])[CH3:48])([O:40][C:41]([CH3:43])([CH3:44])[CH3:42])=[O:39]
Reactant: CCCCCCCCCCCCCCCCCC(=O)OC[C@H](CCO)Cn1cnc2c(=O)[nH]c(N)nc21
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCC(=O)OC[C@H](CCOC(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)CC)Cn1cnc2c(=O)[nH]c(N)nc21

Procedure:
(R)-9-[4-Hydroxy-2-(stearoyloxymethyl)butyl]guanine (135 mg, 0.26 mmole) and N-BOC-L-isoleucine (180 mg, 0.78 mmole) were coevaporated with dry DMF twice and dissolved in the same solvent (3.5 ml). To the solution was added 1,3-dicyclohexylcarbodiimide (160 mg, 0.78 mmole) and 4-dimethylaminopyridine (4.8 mg, 0.039 mmole). After reaction for 18 hours, the reaction mixture was filtered through Celite and worked up in a conventional manner. The product was isolated by silica gel column chromatography, eluting at 5% MeOH in CH2Cl2. (Yield 160 mg).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[S:5][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12](Cl)=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1)=[O:8].[CH2:33]([CH2:35][NH2:36])[OH:34].C(N(CC)C(C)C)(C)C>C(O)CCC>[NH2:1][C:2]1[N:3]=[C:4]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[S:5][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([NH:36][CH2:35][CH2:33][OH:34])=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1)=[O:8]
Reactant: CN1CCN(c2ccc(Nc3nc(N)c(C(=O)c4ccc(Cl)c([N+](=O)[O-])c4)s3)cc2)CC1
Reactant: NCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CN1CCN(c2ccc(Nc3nc(N)c(C(=O)c4ccc(NCCO)c([N+](=O)[O-])c4)s3)cc2)CC1
Temperature: 100 °C
Yield: 27.7 %

Procedure:
A mixture of [4-amino-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl](4-chloro-3-nitrophenyl)methanone (of Example 15; 0.25 g, 0.53 mmol), ethanolamine (0.13 mL, 2.12 mmol), N,N-diisopropylethylamine (Aldrich) (0.37 mL, 2.12 mmol) in n-butanol (10 mL) was heated at 100° C. overnight. The solvent was evaporated in vacuo and the residue was chromatographed on silica gel using MeOH/CH2Cl2 (1/9) as the eluent to afford 73 mg (28% yield) of the title compound. Mass spectrum (ES) MH+=498.
Reaction SMILES: Cl.[NH:2]1[CH:6]=[C:5]([CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])[N:4]=[CH:3]1.C(N(CC)CC)C.[C:20]1([C:26](Cl)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)(Cl)Cl>[C:20]1([C:26]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:2]2[CH:6]=[C:5]([CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])[N:4]=[CH:3]2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)CCc1c[nH]cn1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of methyl 3-(imidazol-4-yl)propionate hydrochloride, as described above in Step B, (20.2 g, 106 mmol) in dry CHCl3 (500 mL) were added triethylamine (44 mL, 318 mmol), then a solution of triphenylmethyl chloride (29.5 g, 106 mmol) in CHCl3 (100 mL). The mixture was stirred at ambient temperature for 18 hours, then washed with H2O (250 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to yield the product as a pale solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[CH2:15][C@@H:14]([CH2:16][O:17][CH3:18])[N:13]([CH:19]3[CH2:24][CH2:23][N:22]([CH:25]([CH3:29])[CH2:26][CH2:27][NH2:28])[CH2:21][CH2:20]3)[C:12]2=[O:30])=[CH:6][CH:5]=1.[Cl:32][C:33]1[CH:41]=[C:40]([CH3:42])[C:36]([C:37](O)=[O:38])=[C:35]([CH3:43])[N:34]=1>>[CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:5]=[CH:6][C:7]([CH2:10][N:11]2[CH2:15][C@@H:14]([CH2:16][O:17][CH3:18])[N:13]([CH:19]3[CH2:24][CH2:23][N:22]([CH:25]([CH3:29])[CH2:26][CH2:27][NH:28][C:37]([C:36]4[C:35]([CH3:43])=[N:34][C:33]([Cl:32])=[CH:41][C:40]=4[CH3:42])=[O:38])[CH2:21][CH2:20]3)[C:12]2=[O:30])=[CH:8][CH:9]=1
Reactant: Cc1cc(Cl)nc(C)c1C(=O)O
Reactant: COC[C@@H]1CN(Cc2ccc(C(=O)OC)cc2)C(=O)N1C1CCN(C(C)CCN)CC1
Product: COC[C@@H]1CN(Cc2ccc(C(=O)OC)cc2)C(=O)N1C1CCN(C(C)CCNC(=O)c2c(C)cc(Cl)nc2C)CC1
Yield: 60 %

Procedure:
According to general procedure E, 4-{(S)-3-[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-4-methoxymethyl-2-oxo-imidazolidin-1-ylmethyl}-benzoic acid methyl ester (40 mg) and 6-chloro-2,4-dimethyl-nicotinic acid gave 4-[(S)-3-(1-{3-[(6-chloro-2,4-dimethyl-pyridine-3-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-4-methoxymethyl-2-oxo-imidazolidin-1-ylmethyl]-benzoic acid methyl ester (32 mg, 60%).