Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[C:19]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:18]=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH2:15][CH3:16])[CH3:14])=[CH:9][CH:8]=1)=[O:5].[OH:25][CH2:26][CH2:27][O:28][C:29]1[C:36]([CH3:37])=[CH:35][C:32]([CH:33]=O)=[CH:31][C:30]=1[CH3:38]>C(O)C.[Cu](Cl)Cl>[CH:13]([C:10]1[CH:9]=[CH:8][C:7]([N:6]2[C:4](=[O:5])[C:3]3[C:2](=[CH:20][C:19]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:18][CH:17]=3)[N:1]=[C:33]2[C:32]2[CH:35]=[C:36]([CH3:37])[C:29]([O:28][CH2:27][CH2:26][OH:25])=[C:30]([CH3:38])[CH:31]=2)=[CH:12][CH:11]=1)([CH2:15][CH3:16])[CH3:14]
Reactant: Cc1cc(C=O)cc(C)c1OCCO
Reactant: CCC(C)c1ccc(NC(=O)c2ccc(S(C)(=O)=O)cc2N)cc1
Agent: Cl[Cu]Cl
Solvent: CCO
Product: CCC(C)c1ccc(-n2c(-c3cc(C)c(OCCO)c(C)c3)nc3cc(S(C)(=O)=O)ccc3c2=O)cc1

Procedure:
To a solution of 2-amino-N-(4-sec-butyl-phenyl)-4-methanesulfonyl-benzamide (0.20 g, 0.55 mmol) and 4-(2-hydroxy-ethoxy)-3,5-dimethyl-benzaldehyde (0.13 g, 0.66 mmol) in ethanol (15 mL) was added anhydrous copper (II) chloride (0.222 g, 1.65 mmol). The resulting mixture was stirred at reflux for 24 hours and the solvent was removed using a rotary evaporator. The residue was then diluted with water (50 mL), extracted with ethyl acetate (2×100 mL), and concentrated on using a rotary evaporator. The crude product was made into a slurry in diethyl ether (20 mL) and filtered to provide the title compound as white solid. Yield: 0.20 g (70%). MP 235-237° C. 1H-NMR (400 MHz, CDCl3): δ 8.53 (d, 1H), 8.41 (d, 1H), 8.00 (dd, 1H), 7.16 (d, 2H), 7.06 (d, 2H), 7.00 (s, 2H), 3.91 (m, 2H), 3.80 (m, 2H), 3.15 (s, 3H), 2.59 (m, 1H), 2.13 (s, 6H), 2.04 (m, 1H), 1.58 (m, 2H), 1.22 (d, 3H), 0.73 (t, 3H). MS (ES+) m/z: 521.22 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH2:6].[C:10]([O:14][C:15]([NH:17][C:18](=[N:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])SC)=[O:16])([CH3:13])([CH3:12])[CH3:11]>CN(C=O)C.O.C([O-])(=O)C.[Ag+]>[C:25]([O:24][C:22]([NH:21][C:18]([NH:17][C:15]([O:14][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:16])=[N:6][CH2:5][C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([OH:1])[CH:3]=1)=[O:23])([CH3:28])([CH3:27])[CH3:26]
Reactant: NCc1cccc(O)c1
Reactant: CSC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Agent: [Ag+]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NC(=NCc1cccc(O)c1)NC(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
3-hydroxybenzylamine, prepared as above (1.23 g) and N,N'-bis(tert-butoxycarbonyl)-S-methylisothiourea (2.90 g) were combined in 100 mL DMF, and silver acetate (2.9 g) was added in three portions over 30 min with mechanical stirring. The mixture became thick and a yellow color developed. After 1 hr, the mixture was diluted with 300 mL water, and the solids collected by filtration, re-suspended in dichloromethane, filtered to remove silver salts, and chromatographed on silica gel with 10% ethyl acetate in dichloromethane. Recrystallization provided the title compound as a white solid, mp 169°-172° C. (dec) (2.2 g, 61%).
Reaction SMILES: [O:1]=[C:2]([N:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1)/[CH:3]=[CH:4]/[C:5]1[C:13]2[C:8](=[CH:9][C:10](/[CH:14]=[CH:15]/[C:16]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[O:17])=[CH:11][CH:12]=2)[N:7]([CH2:23][C:24]2[CH:32]=[CH:31][C:27]([C:28]([OH:30])=O)=[CH:26][C:25]=2[O:33][CH3:34])[CH:6]=1.[Cl:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[S:47]([NH2:50])(=[O:49])=[O:48]>>[Cl:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[S:47]([NH:50][C:28](=[O:30])[C:27]1[CH:31]=[CH:32][C:24]([CH2:23][N:7]2[C:8]3[C:13](=[CH:12][CH:11]=[C:10](/[CH:14]=[CH:15]/[C:16]([N:18]4[CH2:19][CH2:20][CH2:21][CH2:22]4)=[O:17])[CH:9]=3)[C:5](/[CH:4]=[CH:3]/[C:2](=[O:1])[N:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)=[CH:6]2)=[C:25]([O:33][CH3:34])[CH:26]=1)(=[O:49])=[O:48]
Reactant: NS(=O)(=O)c1ccccc1Cl
Reactant: COc1cc(C(=O)O)ccc1Cn1cc(/C=C/C(=O)N2CCCC2)c2ccc(/C=C/C(=O)N3CCCC3)cc21
Product: COc1cc(C(=O)NS(=O)(=O)c2ccccc2Cl)ccc1Cn1cc(/C=C/C(=O)N2CCCC2)c2ccc(/C=C/C(=O)N3CCCC3)cc21

Procedure:
Using a similar procedure to that described in Example 32, except starting from E,E-4-[3,6-di-(3oxo-3-pyrrolidino-1-propenyl)indol-1-ylmethyl]- 3-methoxybenzoic acid, and using 2-chlorobenzenesulfonamide, title compound was obtained (87%) as powder, mp 291°-293°.
Reaction SMILES: [C:1]1([C:7]2[N:11]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[C:10]([C:23]3[CH:24]=[C:25]4[C:30](=[CH:31][CH:32]=3)[CH:29]=[C:28]([O:33][CH2:34][C:35]3[CH:44]=[CH:43][C:38]([C:39]([O:41]C)=[O:40])=[CH:37][C:36]=3[C:45]([O:47]C)=[O:46])[CH:27]=[CH:26]4)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C1COCC1.CO.O>[C:1]1([C:7]2[N:11]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[C:10]([C:23]3[CH:24]=[C:25]4[C:30](=[CH:31][CH:32]=3)[CH:29]=[C:28]([O:33][CH2:34][C:35]3[CH:44]=[CH:43][C:38]([C:39]([OH:41])=[O:40])=[CH:37][C:36]=3[C:45]([OH:47])=[O:46])[CH:27]=[CH:26]4)=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(COc2ccc3cc(-c4ccc(-c5ccccc5)n4Cc4ccc(C(F)(F)F)cc4)ccc3c2)c(C(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(COc2ccc3cc(-c4ccc(-c5ccccc5)n4Cc4ccc(C(F)(F)F)cc4)ccc3c2)c(C(=O)O)c1
Temperature: 25 °C
Yield: 93.7 %

Procedure:
A mixture of dimethyl 4-{[(6-{5-phenyl-1-[4-(trifluoromethyl)benzyl]-1H-pyrrol-2-yl}-2-naphthyl)oxy]methyl}isophthalate (165 mg, 0.254 mmol), prepared in the previous step, and 1 N NaOH (1.52 mL, 1.52 mmol) in 30 mL of THF plus 20 mL of methanol plus 5 mL of water was refluxed under nitrogen for 6 h. The reaction was filtered, cooled to room temperature, acidified by the addition of 5 mL of 1 N HCl and then concentrated under reduced pressure to remove the THF and methanol. The solid present was collected by filtration, rinsed with water and dried under reduced pressure at 60° C. to give the title compound (148 mg, 94%) as a yellow solid, mp 250–252° C. Elemental Analysis for C37H26F3NO5.0.18 C4H8O.0.34 H2O Calc'd: C, 70.71; H, 4.42; N, 2.19. Found: C, 70.65; H, 4.34; N, 2.13.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]3[CH:12]=[N:13][N:14]=[C:7]3[C@@H:6]([CH2:15][CH3:16])[N:5]([CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[C:4]=2[N:3]=1.[NH2:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([NH:29][CH3:30])=[O:28])=[CH:25][C:24]=1[O:33][CH3:34].Cl.C([O-])(O)=O.[Na+]>C(O)C.O>[CH:17]1([N:5]2[C:4]3[N:3]=[C:2]([NH:22][C:23]4[CH:32]=[CH:31][C:26]([C:27]([NH:29][CH3:30])=[O:28])=[CH:25][C:24]=4[O:33][CH3:34])[N:11]=[CH:10][C:9]=3[N:8]3[CH:12]=[N:13][N:14]=[C:7]3[C@H:6]2[CH2:15][CH3:16])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CC[C@@H]1c2nncn2-c2cnc(Cl)nc2N1C1CCCC1
Reactant: CNC(=O)c1ccc(N)c(OC)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC[C@@H]1c2nncn2-c2cnc(Nc3ccc(C(=O)NC)cc3OC)nc2N1C1CCCC1
Temperature: 90 °C
Reaction time: 24 h
Yield: 78 %

Procedure:
To a solution of (R)-7-chloro-5-cyclopentyl-4-ethyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridine (80 mg, 0.263 mmol) in a mixture ethanol/water (1/4, 5 mL) were added 4-amino-3-methoxy-N-methylbenzamide (72 mg, 0.394 mmol) followed by a catalytic amount of concentrated HCl (0.04 mL). The reaction mixture was stirred at 90° C. for 24 hours, then cooled to room temperature and basified with saturated aqueous solution of NaHCO3. The mixture was extracted with ethyl acetate, the organic layer was dried (MgSO4) and the residue purified by flash chromatography to give the title compound as a colourless solid (92 mg, 78% yield); 1H NMR (DMSO D6) 0.75 (3H, t), 1.43-1.60 (4H, m), 1.80-2.07 (6H, m), 2.80 (3H, d), 3.88 (3H, s), 4.19 (1H, m), 5.38 (1H, m), 7.50 (1H, d), 7.59 (1H, s), 7.83 (1H, d), 8.47 (1H, m), 8.67 (1H, s), 9.31 (1H, s), 9.40 (1H, br s); LC/MS M+1 (obs.) 449.3.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([OH:14])=[C:12]([C:15](=O)[CH3:16])[C:11]([CH3:18])=[N:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8].[CH3:19][O:20][C:21]([C:23]1[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=1)[C:26]([NH:28][NH2:29])=[O:27])=[O:22]>>[CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C:12](=[C:15]([NH:29][NH:28][C:26](=[O:27])[C:25]3[CH:30]=[CH:31][CH:32]=[C:23]([C:21]([O:20][CH3:19])=[O:22])[CH:24]=3)[CH3:16])[C:11]([CH3:18])=[N:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CC(=O)c1c(C)nn(-c2ccc(C)c(C)c2)c1O
Reactant: COC(=O)c1cccc(C(=O)NN)c1
Product: COC(=O)c1cccc(C(=O)NNC(C)=C2C(=O)N(c3ccc(C)c(C)c3)N=C2C)c1

Procedure:
From 1-(1-(3,4-dimethylphenyl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl)-ethanone and 3-methoxycarbonylbenzhydrazide, 27.4 mg of the desired product was obtained in the same manner as in Synthetic Example 4 as a pale yellow solid (yield 35%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][NH2:7].C(O[C:11]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]3[N:21]4[C:25]([C:26](=[O:27])[C:14]([C:15]=23)=[CH:13][N:12]=1)=[CH:24][CH:23]=[C:22]4[N+:28]([O-:30])=[O:29])C>CN(C)C=O>[OH:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][NH:7][C:11]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]3[N:21]4[C:25]([C:26](=[O:27])[C:14]([C:15]=23)=[CH:13][N:12]=1)=[CH:24][CH:23]=[C:22]4[N+:28]([O-:30])=[O:29]
Reactant: CCOc1ncc2c(=O)c3ccc([N+](=O)[O-])n3c3cccc1c23
Reactant: NCCNCCO
Solvent: CN(C)C=O
Product: O=c1c2cnc(NCCNCCO)c3cccc(c32)n2c([N+](=O)[O-])ccc12
Yield: 85.5 %

Procedure:
N-(2-Hydroxyethyl)ethylenediamine (1.77 g) is added all at once to a solution, stirred and heated to 70° C., of 4-ethoxy-10-nitro-7-oxo-7H-indolizino[7,6,5-de]isoquinoline (5 g) in dimethylformamide (200 cc). The red solution thus obtained is allowed to return to ambient temperature (about 20° C.) in the course of 2 hours. A suspension of red crystals is thus obtained, to which distilled water (200 cc) is added. The crystals are filtered off and then washed with water (3 × 10 cc). After drying under reduced pressure (1 mm Hg) at 24° C., brick-red crystals of crude 4-[2-(2-hydroxyethylamino)ethylamino]-10-nitro-7-oxo-7H-indolizino[7,6,5-de]isoquinoline (5.08 g) are obtained.
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]1[CH:11]=[CH:10][CH:9]=[CH:8]1.[CH3:12][N:13]1[CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]1>CCCCCC.C(OCC)C>[CH3:12][N:13]1[CH2:18][CH2:17][C:16]([C:8]2[N:7]([CH3:6])[CH:11]=[CH:10][CH:9]=2)([OH:19])[CH2:15][CH2:14]1
Reactant: CN1CCC(=O)CC1
Reactant: Cn1cccc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CN1CCC(O)(c2cccn2C)CC1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
A 1.6 M solution of n-butyllithium in hexane (175 ml) was added dropwise at room temperature to a solution of 24.2 g of N-methylpyrrole in 250 ml of diethyl ether contained in a reaction flask (under a nitrogen blanket). After addition was completed, the resulting mixture was heated at reflux with stirring for 16 hours, then cooled to 0° C. 34 Grams of 1-methyl-4-piperidone was added dropwise from a dropping funnel with the temperature maintained at 0° C. during the addition by cooling the reaction flask with dry ice-acetone bath. The reaction mixture was stirred at room temperature for 3 hours, and then quenched in ice water to yield 26 g of the title compound in a crystalline form; recrystallization from heptane gave white prisms, m.p. 123°-123.5°.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:10](=[O:11])[CH:9]=[C:8]([N:12]2[CH:16]=[C:15](I)[N:14]=[C:13]2[CH3:18])[CH:7]=[N:6]1.[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=1)#[CH:20]>>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:10](=[O:11])[CH:9]=[C:8]([N:12]2[CH:16]=[C:15]([C:20]#[C:19][C:21]3[CH:22]=[C:23]([CH3:27])[CH:24]=[CH:25][CH:26]=3)[N:14]=[C:13]2[CH3:18])[CH:7]=[N:6]1
Reactant: C#Cc1cccc(C)c1
Reactant: COCCn1ncc(-n2cc(I)nc2C)cc1=O
Product: COCCn1ncc(-n2cc(C#Cc3cccc(C)c3)nc2C)cc1=O

Procedure:
The title compound, light yellow viscous oil, MS: m/e=349.4 (M+H+), was prepared in accordance with the general method of example 21a from 2-(2-methoxy-ethyl)-5-(4-iodo-2-methyl-imidazol-1-yl)-2H-pyridazin-3-one and 1-ethynyl-3-methyl-benzene.
Reaction SMILES: [C:1]12([NH:11][C:12]3[NH:16][C:15]4[CH:17]=[C:18]([CH2:21][O:22][Si](C(C)C)(C(C)C)C(C)C)[CH:19]=[CH:20][C:14]=4[N:13]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.F[C:34]1[CH:63]=[CH:62][C:37]([C:38](/N=C2\NC3C=CC(CO)=CC=3N\2[C@@H]2CC[C@H](C(OC)=O)CC2)=[O:39])=[CH:36][CH:35]=1>>[C:1]12([N:11]3[C:15]4[CH:17]=[C:18]([CH2:21][OH:22])[CH:19]=[CH:20][C:14]=4[N:13]=[C:12]3[NH:16][C:38](=[O:39])[C:37]3[CH:62]=[CH:63][CH:34]=[CH:35][CH:36]=3)[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: COC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3ccc(CO)cc32)CC1
Reactant: CC(C)[Si](OCc1ccc2nc(NC34CC5CC(CC(C5)C3)C4)[nH]c2c1)(C(C)C)C(C)C
Product: O=C(Nc1nc2ccc(CO)cc2n1C12CC3CC(CC(C3)C1)C2)c1ccccc1

Procedure:
The title compound was prepared in 2 steps from N-1-adamantyl-6-((triisopropylsilyloxy)methyl)-1H-benzo[d]imidazol-2-amine using a method analogous to the preparation of cis-methyl 4-((E)-2-(4-fluorobenzoylimino)-6-(hydroxymethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate. The yield was 200 mg (37.7%, 2 steps). MS m/z=402.2 [M+H]. Calc'd for C25H27N3O2: 401.2.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][C:7]=1[Cl:18])(=O)C.C(OCC1C=CC(C(=O)C(C)(C)C)=CC=1)(=O)C>>[Cl:18][C:7]1[CH:8]=[C:9]([C:12](=[O:17])[C:13]([CH3:15])([CH3:14])[CH3:16])[CH:10]=[CH:11][C:6]=1[CH2:5][OH:4]
Reactant: CC(=O)OCc1ccc(C(=O)C(C)(C)C)cc1Cl
Agent: CC(=O)OCc1ccc(C(=O)C(C)(C)C)cc1
Product: CC(C)(C)C(=O)c1ccc(CO)c(Cl)c1

Procedure:
Following the above procedure, but using an equivalent amount of α-acetoxy-2-chloro-4-pivaloyl-toluene in plce of the α-acetoxy-p-pivaloyl-toluene, there is obtained 2-chloro-4-pivaloyl-benzyl alcohol.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7](Cl)=[N:6][CH:5]=1.[CH2:12]1[C:17]2[NH:18][C:19]3[C:24]([C:16]=2[CH2:15][CH2:14][NH:13]1)=[CH:23][CH:22]=[CH:21][CH:20]=3.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH2:12]1[C:17]2[NH:18][C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:16]=2[CH2:15][CH2:14][N:13]1[C:7]1[CH:8]=[CH:9][C:4]([C:3]([O:2][CH3:1])=[O:11])=[CH:5][N:6]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: c1ccc2c3c([nH]c2c1)CNCC3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1ccc(N2CCc3c([nH]c4ccccc34)C2)nc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 24.7 %

Procedure:
A mixture of methyl-6-chloronicotinate (170 mg), 1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole (170 mg), potassium carbonate (150 mg) and dioxane (6 mL) was heated in a 100° C. oil bath overnight. Another aliquote of 1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole (170 mg) was added and the heating was continue for five hours. The reaction was cooled and partitioned between water and EtOAc. The organics were washed with water, dried, and the solvent evaporated. The residue was purified by filtration through silica gel eluting with EtOAc to give methyl 6-(1,3,4,9-tetrahydro-2H-b-carbolin-2-yl)nicotinate as a brown solid (75 mg), m/e=308 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:15]([O-:17])=[O:16])[C:5]([NH2:14])=[N:6][C:7]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.C(O)(C(F)(F)F)=O.CCN(C(C)C)C(C)C.[CH3:34][O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[C:42]1[C:46]([C:47](O)=[O:48])=[C:45]([CH3:50])[O:44][N:43]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:14][C:5]1[N:6]=[C:7]([N:8]2[CH2:9][CH2:10][N:11]([C:47]([C:46]3[C:42]([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=4[O:35][CH3:34])=[N:43][O:44][C:45]=3[CH3:50])=[O:48])[CH2:12][CH2:13]2)[C:2]([Cl:1])=[CH:3][C:4]=1[N+:15]([O-:17])=[O:16]
Reactant: Nc1nc(N2CCNCC2)c(Cl)cc1[N+](=O)[O-]
Reactant: COc1ccccc1-c1noc(C)c1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccccc1-c1noc(C)c1C(=O)N1CCN(c2nc(N)c([N+](=O)[O-])cc2Cl)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-chloro-3-nitro-6-(piperazin-1-yl)pyridin-2-amine, TFA (0.192 mmol) in DMF (2 ml) was added DIEA (0.134 ml, 0.768 mmol), 3-(2-methoxyphenyl)-5-methylisoxazole-4-carboxylic acid (44.8 mg, 0.192 mmol) and HATU (73.0 mg, 0.192 mmol). The reaction was stirred at room temperature for 1 h. The reaction mixture was purified by preparative HPLC to afford 69 mg (73.7% for 3 steps) of the title compound. 1H NMR (500 MHz, CDCl3) δ ppm 8.25 (1H, s), 7.58 (1H, dd, J=7.5, 1.7 Hz), 7.52-7.39 (1H, m), 7.08-7.06 (1H, m), 6.97 (1H, d, J=7.9 Hz), 3.79 (3 H, s), 3.72 (2H, br. s.), 3.55 (2H, br. s.), 3.16 (2H, br. s.), 2.98 (2H, br. s.), 2.55 (3H, s).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:9]=[C:10]3[N:16]=[C:15]([C:17]4[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=4[NH2:19])[S:14][C:11]3=[N:12][CH:13]=2)[CH2:3][CH2:2]1.[C:24]1([C:30]2[N:31]=[C:32]([C:35](O)=[O:36])[S:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:9]=[C:10]3[N:16]=[C:15]([C:17]4[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=4[NH:19][C:35]([C:32]4[S:33][CH:34]=[C:30]([C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=5)[N:31]=4)=[O:36])[S:14][C:11]3=[N:12][CH:13]=2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1nc(-c2ccccc2)cs1
Reactant: Nc1ccccc1-c1nc2cc(CN3CCOCC3)cnc2s1
Solvent: O
Product: O=C(Nc1ccccc1-c1nc2cc(CN3CCOCC3)cnc2s1)c1nc(-c2ccccc2)cs1

Procedure:
The title compound was prepared according to amide synthesis general method A, utilizing 2-(6-(morpholinomethyl)thiazolo[5,4-b]pyridin-2-yl)aniline and 4-phenylthiazole-2-carboxylic acid. The product was isolated by precipitation during the addition of water, triturated with hot methanol and purified by silica gel chromatography (gradient 0 to 10% methanol in CH2Cl2). MS Calcd for C27H23N5O2S2: 513.13. Found (M+H)+ m/z=514.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[F:23])[C:4]=2[N:5]=[C:6](S(C)=O)[N:7]=1.[NH2:24][CH:25]([CH2:28][OH:29])[CH2:26][OH:27].CCN(CC)CC>ClCCl.CN(C=O)C>[Cl:1][C:2]1[C:3]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[F:23])[C:4]=2[N:5]=[C:6]([NH:24][CH:25]([CH2:28][OH:29])[CH2:26][OH:27])[N:7]=1
Reactant: CS(=O)c1nc(Cl)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: NC(CO)CO
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=c1ccc2c(Cl)nc(NC(CO)CO)nc2n1-c1c(F)cccc1F
Yield: 42 %

Procedure:
A solution of 4-chloro-2-methylsulfinyl-8-(2,6-difluoro-phenyl)-8H-pyrido[2,3-d]pyrimidin-7-one (0.75 mmol) in dichloromethane (30 mL) was mixed with a solution of serinol (0.075 g, 0.82 mmol) and Et3N (0.21 mL, 1.5 mmol) in DMF (0.75 mL). The resultant mixture was stirred at room temperature for about 1 hour, then concentrated under vacuum. Flash chromatography (EtOAc:Hexane, 3:1) provided the title compound 4-chloro-8-(2,6-difluorophenyl)-2-{[2-hydroxy-1-(hydroxy-methyl)ethyl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one (42%): LC-MS m/z 383 (M+H)+; 1H-NMR (CDCl3) δ 1.95 (s, br, 2H), 3.90 (m, br, 5H), 6.05 (m, br, 1H), 6.56 (d, J=9.6 Hz, 1H), 7.10 (m, 2H), 7.48 (d, J=8.1 Hz, 2H), 7.94 (d, J=9.6 Hz, 1H).
Reaction SMILES: C1[C:6]2[C:7]([O:9][C:10](=O)[C:5]=2[CH:4]=[C:3]2[C:12]([O:14][C:15](=O)C=12)=[O:13])=[O:8].CC(C(OCCN(C)C)=O)=C>>[C:7]([O:9][CH3:10])(=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][C:12]([O:14][CH3:15])=[O:13]
Reactant: O=c1oc(=O)c2cc3c(=O)oc(=O)c3cc12
Agent: C=C(C)C(=O)OCCN(C)C
Product: COC(=O)CCCCC(=O)OC

Procedure:
An adhesive as described in Example 2 was prepared except that 1.0 g. of PMDA, 1.5 g. of E/DMAEMA resin and an additional 4.75 g. of Piccoumaron® 410 HL were added.
Reaction SMILES: [F:1][C:2]1[C:22]([C:23]([OH:26])([CH3:25])[CH3:24])=[CH:21][CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:11](O)=[O:12])[C:7](=[O:18])[CH:6]=1.[CH3:27][N:28]1[CH:32]=[CH:31][C:30]([NH2:33])=[N:29]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>ClCCl>[CH3:27][N:28]1[CH:32]=[CH:31][C:30]([NH:33][C:11](=[O:12])[C@@H:10]([N:8]2[CH2:9][C:5]([O:4][C:3]3[CH:19]=[CH:20][CH:21]=[C:22]([C:23]([OH:26])([CH3:24])[CH3:25])[C:2]=3[F:1])=[CH:6][C:7]2=[O:18])[CH2:14][CH:15]([CH3:16])[CH3:17])=[N:29]1
Reactant: Cn1ccc(N)n1
Reactant: CC(C)C[C@@H](C(=O)O)N1CC(Oc2cccc(C(C)(C)O)c2F)=CC1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)C[C@@H](C(=O)Nc1ccn(C)n1)N1CC(Oc2cccc(C(C)(C)O)c2F)=CC1=O
Temperature: 0 °C
Yield: 92.7 %

Procedure:
To a solution of (S)-2-{4-[2-fluoro-3-(1-hydroxy-1-methyl-ethyl)-phenoxy]-2-oxo-2,5-dihydro-pyrrol-1-yl}-4-methyl-pentanoic acid (0.392 g, 1.07 mmol) in dichloromethane (10 mL) was added 1-methyl-1H-pyrazol-3-ylamine (0.208 g, 2.14 mmol) and benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (0.522 g, 1.18 mmol). The mixture was stirred at 0° C. and N,N-diisopropylethylamine (0.304 g, 2.35 mmol) was added. The mixture was stirred at room temperature overnight and the solvents were evaporated. The residue was treated with ethyl acetate and ammonium chloride solution, and the organic layer separated. The organic layer was washed with brine and dried over sodium sulfate. The solvents were evaporated and the residue was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 112 g, 60% to 100% ethyl acetate/hexanes) which afforded (S)-2-{4-[2-fluoro-3-(1-hydroxy-1-methyl-ethyl)-phenoxy]-2-oxo-2,5-dihydro-pyrrol-1-yl}-4-methyl-pentanoic acid (1-methyl-1H-pyrazol-3-yl)-amide (0.441 g, 92%) as an off-white solid: HR-ES-MS m/z calculated for C23H29FN4O4 [M+H]+ 445.2246, observed 445.2246, 1H NMR (300 MHz, DMSO-d6) δ 1.00 0.90 (d, J=6.4 Hz, 3H), 0.93 (d, J=6.4 Hz, 3H), 1.36-1.47 (m, 1H), 1.49 (s, 6H), 1.52-1.65 (m, 1H), 1.67-1.82 (m, 1H), 3.73 (s, 3H), 4.20 (d, J=18.4 Hz, 1H), 4.58 (d, J=18.4 Hz, 1H), 4.81 (s, 1H), 4.88 (dd, J=10.7, 5.0 Hz, 1H), 5.42 (s, 1H), 6.40 (d, J=2.1 Hz, 1H), 7.23 (t, J=7.8 Hz, 1H), 7.29-7.40 (m, 1H), 7.54 (d, J=2.1 Hz, 1H), 7.51-7.60 (m, 1H), 10.73 (s, 1H).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:13]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@@H:14]([C:22]([OH:24])=O)[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[O:32]1[CH2:37][CH2:36][CH:35]([CH2:38][N:39]2[CH2:44][CH2:43][CH:42]([CH2:45][NH2:46])[CH2:41][CH2:40]2)[CH2:34][CH2:33]1.[OH-].[Na+]>ClCCl>[C:28]([O:27][C:25](=[O:26])[NH:13][C@@H:14]([C:22](=[O:24])[NH:46][CH2:45][CH:42]1[CH2:41][CH2:40][N:39]([CH2:38][CH:35]2[CH2:34][CH2:33][O:32][CH2:37][CH2:36]2)[CH2:44][CH2:43]1)[CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: NCC1CCN(CC2CCOCC2)CC1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)NCC1CCN(CC2CCOCC2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.5 %

Procedure:
6.7 g of carbonyldiimidazole is added to a solution of 10 g of Boc-D-Phe-OH in 80 ml of dichloromethane, cooled to 0° C. The resulting solution is maintained under stirring at 0° C. for 1 hour. A solution consisting of 8.0 g of (11) in 20 ml of dichloromethane is then dripped into the reaction mixture at a rate such that the temperature does not exceed 5° C. The solution is maintained under stirring at 0° C. for 1 hour, and at ambient temperature for 2 hours. 100 ml of 1M NaOH is added to the mixture, the two phases are separated, the organic phase is washed with water (2×), and after a low-pressure solvent change with ethyl acetate, compound (12) is crystallised from ethyl acetate to obtain 14.64 g of white solid. Yield 85%.