Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[O:6][C:7]1[N:12]=[C:11]([O:13][C:14]2[CH:15]=[C:16]([CH:22]=[C:23]([OH:25])[CH:24]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:10]([F:26])=[C:9]([CH3:27])[C:8]=1[F:28])#[N:2].[C:32](=O)([O-])[O-].[Cs+].[Cs+].IC>C(#N)C>[C:1]([C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[O:6][C:7]1[N:12]=[C:11]([O:13][C:14]2[CH:15]=[C:16]([CH:22]=[C:23]([O:25][CH3:32])[CH:24]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:10]([F:26])=[C:9]([CH3:27])[C:8]=1[F:28])#[N:2]
Reactant: CCOC(=O)c1cc(O)cc(Oc2nc(Oc3cccc(C#N)c3)c(F)c(C)c2F)c1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CC#N
Product: CCOC(=O)c1cc(OC)cc(Oc2nc(Oc3cccc(C#N)c3)c(F)c(C)c2F)c1
Reaction time: 15 h

Procedure:
To acetonitrile (5 mL) was added 3-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]-5-hydroxybenzoic acid, ethyl ester (0.20 g, 0.47 mmol), cesium carbonate (0.31 g, 0.94 mmol), and iodomethane (0.13 g, 0.94 mmol). After stirring for 15 hours the mixture was partitioned with ethyl acetate and water. The organic layer was dried (MgSO4) and the solvent was removed in vacuo to give 3-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]-5-methoxybenzoic acid, ethyl ester; NMR (CDCl3) 7.3 (m,6), 6.8 (s,1), 4.4 (q,2), 3.8 (s,3), 2.4 (s,3), 1.4 (t,3) ppm.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:6](=[O:15])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:14])[CH3:3].Cl[C:23]1[C:24]2[C:31]([C:32]#[N:33])=[CH:30][NH:29][C:25]=2[N:26]=[CH:27][N:28]=1.CCN(CC)CC>CCCCO>[CH3:14][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]=1[C:6](=[O:15])[N:5]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:4]([C@@H:2]([NH:1][C:23]1[C:24]3[C:31]([C:32]#[N:33])=[CH:30][NH:29][C:25]=3[N:26]=[CH:27][N:28]=1)[CH3:3])=[CH:13]2
Reactant: Cc1cccc2cc([C@H](C)N)n(-c3ccccc3)c(=O)c12
Reactant: N#Cc1c[nH]c2ncnc(Cl)c12
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: Cc1cccc2cc([C@H](C)Nc3ncnc4[nH]cc(C#N)c34)n(-c3ccccc3)c(=O)c12
Temperature: 150 °C
Reaction time: 16 h
Yield: 23.8 %

Procedure:
(S)-3-(1-Aminoethyl)-8-methyl-2-phenylisoquinolin-1(2H)-one (compound 4704) (208 mg, 0.75 mol), 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (compound 5505) (160 mg, 0.90 mmol) and Et3N (228 mg, 2.25 mmol) were dissolved in n-BuOH (20 mL) in a sealed tube, and the resulting mixture stirred at 150° C. for 16 h. The reaction mixture was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with 50% Hex/EA) to afford the desired product, (S)-4-(1-(8-methyl-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethylamino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (5506, compound 264 in Table 4) (90 mg, 28% yield) as a white solid.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3([CH3:17])[O:16]CCO3)=[CH:9][CH:10]=2)[CH:5]([C:18]([O:20]CC)=O)[C:4]1=[O:23])[CH3:2].[NH2:24][C:25]1[S:26][C:27]([CH3:30])=[CH:28][N:29]=1>>[CH3:30][C:27]1[S:26][C:25]([NH:24][C:18]([CH:5]2[C:6]3[C:11](=[CH:10][CH:9]=[C:8]([C:12](=[O:16])[CH3:17])[CH:7]=3)[N:3]([CH2:1][CH3:2])[C:4]2=[O:23])=[O:20])=[N:29][CH:28]=1
Reactant: CCOC(=O)C1C(=O)N(CC)c2ccc(C3(C)OCCO3)cc21
Reactant: Cc1cnc(N)s1
Product: CCN1C(=O)C(C(=O)Nc2ncc(C)s2)c2cc(C(C)=O)ccc21
Yield: 63 %

Procedure:
Starting with 500 mg. (1.57 mmoles) of ethyl 1-ethyl-5-(2-methyl-4,5-dihydro-1,3-dioxol-2-yl)oxindole-3-carboxylate and 357 mg. (3.1 mmoles) of 2-amino-5-methylthiazole and employing the procedure of Example 17 gave 342 mg. (63% yield) of the desired product, m.p. 215° C. (dec.).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([C:10]2[NH:11][C:12](=[O:22])[C:13]3[C:14](=[C:16]([CH2:20][CH3:21])[N:17]([CH3:19])[N:18]=3)[N:15]=2)=[CH:8][C:7]([S:23]([N:26]2[CH2:31][CH2:30][N:29]([CH2:32][CH3:33])[CH2:28][CH2:27]2)(=[O:25])=[O:24])=[CH:6][N:5]=1)C>N.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[CH2:20]([C:16]1[N:17]([CH3:19])[N:18]=[C:13]2[C:12](=[O:22])[NH:11][C:10]([C:9]3[C:4]([O:3][CH3:1])=[N:5][CH:6]=[C:7]([S:23]([N:26]4[CH2:27][CH2:28][N:29]([CH2:32][CH3:33])[CH2:30][CH2:31]4)(=[O:24])=[O:25])[CH:8]=3)=[N:15][C:14]=12)[CH3:21]
Reactant: CCOc1ncc(S(=O)(=O)N2CCN(CC)CC2)cc1-c1nc2c(CC)n(C)nc2c(=O)[nH]1
Agent: [Cu+2]
Agent: N
Agent: O=S(=O)([O-])[O-]
Solvent: O
Product: CCc1c2nc(-c3cc(S(=O)(=O)N4CCN(CC)CC4)cnc3OC)[nH]c(=O)c2nn1C
Temperature: 100 °C
Yield: 23.7 %

Procedure:
A mixture of the title compound of Example 78 (100 mg, 0.21 mmol), and copper (II) sulphate heptahydrate (75 mg, 0.3 mmol) in saturated methanolic ammonia (20 ml) was heated at 100° C. for 4 hours in a sealed vessel. The cooled mixture was evaporated under reduced pressure and the residue suspended in aqueous sodium carbonate solution (20 ml) and extracted with dichloromethane (3×20 ml). The combined organic extracts were washed with brine (3×20 ml), dried (Na2SO4) and evaporated under reduced pressure to give a green solid. The crude product was purified by column chromatography on silica gel, using an elution gradient of dichloromethane:methanol (100:0 to 97:3) and recrystallised from hexane/ethyl acetate/methanol to afford the title compound (23 mg, 24%) as a white solid. Found : C, 51.22; H, 5.81; N, 20.61. C20H27N7O4S; 0.5H2O requires C, 51.05; H, 6.00; N, 20.84%; δ (CDCl3): 1.07 (3H, t), 1.40 (3H, t), 2.40-2.65 (6H, m), 3.04 (2H, q), 3.19 (4H, m), 4.09 (3H, s), 4.24 (3H, s), 8.65 (1H, s), 9.05 (1H, s), 10.58 (1H, s). LRMS: m/z 462 (M+1)+.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:15])=[N:4][C:5]2[C:10]([C:11]=1C(O)=O)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH:16]1[C:21]([C:22]([OH:24])=[O:23])=[CH:20][C:19]2[C:25]([O:27][C:28](=O)[C:18]=2[CH:17]=1)=[O:26].ClC1C=CC(Cl)=CC=1Cl>>[OH:1][C:2]1[C:3]([CH:15]2[C:25](=[O:26])[C:19]3[C:18](=[CH:17][CH:16]=[C:21]([C:22]([OH:24])=[O:23])[CH:20]=3)[C:28]2=[O:27])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Reactant: Cc1nc2ccccc2c(C(=O)O)c1O
Solvent: Clc1ccc(Cl)c(Cl)c1
Product: O=C(O)c1ccc2c(c1)C(=O)C(c1nc3ccccc3cc1O)C2=O
Temperature: 25 °C
Yield: 48 %

Procedure:
To a 250-mL round-bottom-flask, 3-hydroxy-2-methylquinoline-4-carboxylic acid (4.0 g, 0.02 mol), 1,2,4-benzenetricarboxylic anhydride (3.8 g, 0.02 mol) and 1,2,4-trichlorobenzene were added and the mixture was refluxed for 2 hours under nitrogen. After the mixture was cooled to room temperature, a yellow precipitate formed and was collected by filtration. The solid was washed with methanol, refluxed with water and collected by hot filtration to give 2-(3-hydroxy-quinolin-2-yl)-1,3-dioxo-indan-5-carboxylic acid as yellow powder (3.2 g, 0.009) in 48% yield. m.p.>350°. UV-Vis (DMSO) λmax: 424 (32,200), 442 (39,600). In order to convert the acid form into the corresponding tetrabutyl ammonium salt, 2 g of the acid was suspended in methanol (100 mL) and tetrabutyl ammonium hydroxide (1.0 M, 6.0 mL) was added slowly. Because the deprotonation of the first proton (carboxylic acid proton) of the yellow dye does not change its absorption spectrum while the deprotonation of the second proton (hydroxy group) shifts its absorption significantly, the addition of base can be followed easily by UV-Vis spectroscopy. After most of the yellow solid went into the solution, the mixture was filtered and the filtrate was collected. The solvent was removed under vacuum and the resulting residue was washed with ether to give the title compound (3.2 g). UV-Vis (CH2Cl2) λmax: 424 (32,400), 442 (40,000).
Reaction SMILES: [CH2:1]([C@@:4]1([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]2[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]2)[CH2:6][CH2:5]1)[CH:2]=[CH2:3].CCN(CC)CC.[C:31](Cl)([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32]>C(Cl)Cl>[CH2:1]([C@@:4]1([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]2[CH2:16][CH2:15][CH2:14][N:13]([C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:32])[CH2:12]2)[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@H]2CCCNC2)C(=O)O1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC[C@]1(c2ccc(F)cc2)CCN([C@H]2CCCN(C(=O)OCc3ccccc3)C2)C(=O)O1
Temperature: 25 °C
Yield: 49.2 %

Procedure:
To a solution of (R)-6-allyl-6-(4-fluorophenyl)-3-((S)-piperidin-3-yl)-1,3-oxazinan-2-one (112 mg, 0.35 mmol) and Et3N (71 mg, 0.70 mmol) in CH2Cl2 (10 mL) was added CbzCl (71 mg, 0.7 mmol) at 0° C. Then the mixture was stirred at rt till the reaction was over. The reaction was quenched with H2O. The mixture was extracted with EtOAc, and the organic phase was washed with brine, dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by preparative TLC to afford (S)-benzyl 3-((R)-6-allyl-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-3-yl)piperidine-1-carboxylate (78 mg, 49%). 1H NMR (CDCl3): 1.63 (m, 3H), 2.07-2.26 (m, 2H), 2.54 (m, 3H), 2.21 (m, 2H), 3.09 (m, 1H), 3.68 (m, 1H), 3.99 (m, 1H), 4.93-5.09 (m, 4H), 5.09-5.18 (m, 1H), 6.87-7.03 (m, 2H), 7.14 (m, 1H), 7.31 (m, 6H).
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[O:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27]Cl>>[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][N:8]1[C:9]([O:10][C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]1=[O:19]
Reactant: ClCc1ccccn1
Reactant: Cc1cc(C)cc(Oc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Product: Cc1cc(C)cc(Oc2c(C(C)C)c(=O)[nH]c(=O)n2Cc2ccccn2)c1
Yield: 37.2 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and 2-picolyl chloride were reacted by the same way with the example 1 to obtain the titled compound (136 mg, yield: 37.2%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][S:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23]([O:25]C)=[O:24])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].CC(C)([O-])C.[K+]>>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:18][CH2:19][S:20][CH2:21][CH2:22]3)=[O:16])[CH2:12][CH:11]([C:23]([OH:25])=[O:24])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(C2CC(C(=O)OC)CN(C(=O)N3CCSCC3)C2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCSCC3)C2)cc1

Procedure:
According to General Method 5A, 3.00 g (7.97 mmol) of the compound from Example 6A and 8.94 g (79.7 mmol) of potassium tert-butoxide were reacted. The reaction led selectively to the cis isomer. Yield: 2.74 g (93% of theory)
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[Br:13])[N:6]([CH3:14])[C:5]=1[C:15]([O:17]C)=O)(=O)[CH3:2].[C:19]1([NH:25][NH2:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)(=O)C>[Br:13][C:11]1[C:12]2[C:4]3[C:1]([CH3:2])=[N:26][N:25]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:15](=[O:17])[C:5]=3[N:6]([CH3:14])[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: NNc1ccccc1
Reactant: COC(=O)c1c(C(C)=O)c2c(Br)cccc2n1C
Solvent: CC(=O)O
Product: Cc1nn(-c2ccccc2)c(=O)c2c1c1c(Br)cccc1n2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.3 %

Procedure:
22 g (71 mmol) of methyl 3-acetyl-4-bromo-1-methyl-1H-indole-2-carboxylate are dissolved with heating in 350 ml of acetic acid. 30 ml (300 mmol) of phenylhydrazine are added, stirring is carried out for 1 h at room temperature and the reaction mixture is heated at reflux for 5 h, at room temperature for 15 h and then again at reflux for 7 h. 28 ml of phenylhydrazine are added and the process is repeated. The mixture is concentrated under reduced pressure, the residue is taken up in water and the precipitate is collected by filtration, washed with water and dried under reduced pressure. It is purified by chromatography on a column of silica gel. 11.1 g (30 mmol) of product are isolated.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:18])[N:8]([CH2:11][CH2:12][N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:19]=O.[F:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][C:30]=1[NH:31][C:32](=[O:37])[C:33]([OH:36])([CH3:35])[CH3:34])[NH:27][C:26](=[O:38])[CH2:25]2>>[F:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][C:30]=1[NH:31][C:32](=[O:37])[C:33]([OH:36])([CH3:35])[CH3:34])[NH:27][C:26](=[O:38])[C:25]2=[CH:19][C:3]1[NH:4][C:5]2[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][CH2:16][CH2:17]3)[C:7](=[O:18])[C:6]=2[C:2]=1[CH3:1]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCC1)CC2
Reactant: CC(C)(O)C(=O)Nc1cc2c(cc1F)CC(=O)N2
Product: Cc1c(C=C2C(=O)Nc3cc(NC(=O)C(C)(C)O)c(F)cc32)[nH]c2c1C(=O)N(CCN1CCCC1)CC2
Yield: 43 %

Procedure:
The title compound was prepared under the same conditions as described in Example 13 with 3-methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-hydroxy-2-methyl-propionamide as starting materials to give N-{5-fluoro-3-[3-methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-hydroxy-2-methyl-propionamide (40 mg, 43%) as a yellow solid.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1>CN(C)C1C=CN=CC=1.O1CCCC1>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:4]
Reactant: C1CCNC1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: Nc1ccccc1C(=O)N1CCCC1

Procedure:
17.5 g isatoic anhydride and 2.66 g 4-dimethylaminopyridine are combined in 500 ml tetrahydrofuran. 9.32 g of pyrrolidine is added and the mixture is heated at reflux overnight. The mixture is concentrated in vacuo, the residue taken into ethyl acetate and the organic solution washed with citric acid solution, water and brine and dried over magnesium sulfate. The solution is filtered, evaporated and the residue triturated in ether/hexane (1:5) to give N-(2-aminobenzoyl)pyrrolidine, m.p. 79°-81° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([CH:22]=1)[CH2:7][CH:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:19])[CH:15]=2)[O:10][C:9]1([CH3:21])[CH3:20].[H-].[Na+].Cl[CH2:28][C:29]1[S:30][C:31]2[CH:37]=[C:36]([F:38])[C:35]([F:39])=[CH:34][C:32]=2[N:33]=1.O>CN(C=O)C.C(OCC)(=O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([CH:22]=1)[CH2:7][CH:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH2:28][C:29]3[S:30][C:31]4[CH:37]=[C:36]([F:38])[C:35]([F:39])=[CH:34][C:32]=4[N:33]=3)[CH:15]=2)[O:10][C:9]1([CH3:20])[CH3:21]
Reactant: Fc1cc2nc(CCl)sc2cc1F
Reactant: COc1ccc(N)cc1CC1C(=O)c2cc(O)ccc2OC1(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(N)cc1CC1C(=O)c2cc(OCc3nc4cc(F)c(F)cc4s3)ccc2OC1(C)C
Temperature: 0 °C
Yield: 62 %

Procedure:
To a stirred solution of 2.36 (7.21 mmole) of the product of Example 102 in 25 mL DMF at 0° C. was added 332 mg (8.29 mmole) 60% sodium hydride. The mixture was stirred at 0° C. then a solution of 2.06 g (9.37 mmole) 2-(chloromethyl)-5,6-difluorobenzothiazole in 15 mL DMF was added dropwise. The mixture was slowly warmed to room temperature and stirred for 18 hours. The mixture was poured into water and then extracted with ethyl acetate. The ethyl acetate extract was washed successively with 1N KOH, water and brine and then dried (MgSO4) and concentrated to give an oil. Flash chromatography on silica gel eluting with 50% ethyl acetate in hexanes gave 2.3 g (62%) of the title product as a solid. NMR (CDCl3): δ1.45 (d, 6H); 2.90 (m, 3H); 3.69 (s, 3H); 5.39 (s, 2H). MS (Cl, NH3) m/e: 528 (M+ +18), 511 (M+ +1,100).
Reaction SMILES: [CH2:1]([C:11]1[S:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[CH:14][N:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:23](O)(=[O:30])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C1(N=C=NC2CCCCC2)CCCCC1.N1(C2C=CN=CC=2)CCCC1>ClCCl>[CH2:1]([C:11]1[S:12][C:13]([C:16]2[CH:17]=[CH:18][C:19]([O:22][C:23](=[O:30])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:20][CH:21]=2)=[CH:14][N:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCC(=O)O
Reactant: CCCCCCCCCCc1ncc(-c2ccc(O)cc2)s1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: c1cc(N2CCCC2)ccn1
Solvent: ClCCl
Product: CCCCCCCCCCc1ncc(-c2ccc(OC(=O)CCCCCC)cc2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.4 %

Procedure:
In a 50 ml-round-bottomed flask, 0.60 g (1.89 mM) of 2-decyl-5-(4-hydroxyphenyl)thiazole, 0.28 ml (1.97 mM) of heptanoic acid and 15 ml of dichloromethane were placed and mixed. To the solution, 0.39 g (1.89 mM) of N,N'-dicyclohexylcarbodiimide and 0.03 g of 4-pyrrolidinopyridine were successively added under stirring at room temperature, followed by further stirring for 2 hours at room temperature. After stirring, the mixture was left standing overnight at room temperature to precipitate N,N'-dicyclohexylurea. The resultant N,N'-dicyclohexylurea was filtered off and the solvent of the filtrate was distilled-off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: toluene) and recrystallized from acetone to obtain 0.62 g of 2-decyl-5-(4-heptanoyloxyphenyl)thiazole (Yield: 76.4%). ##STR92##
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([I:18])=[CH:15][CH:16]=2)[C:11](=[O:19])[C:10]([C:20](O)=[O:21])=[CH:9]1)[CH2:5][O:6][CH3:7].[N:23]1([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.OC1C2N=NNC=2C=CC=1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[CH3:7][O:6][CH2:5][CH:4]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([I:18])=[CH:15][CH:16]=2)[C:11](=[O:19])[C:10]([C:20]([N:26]2[CH2:27][CH2:28][N:23]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24][CH2:25]2)=[O:21])=[CH:9]1)[CH2:3][O:2][CH3:1]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COCC(COC)n1cc(C(=O)O)c(=O)c2cc(I)ccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COCC(COC)n1cc(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c(=O)c2cc(I)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
To a solution of 1-(1,3-dimethoxypropan-2-yl)-6-iodo-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Intermediate 78, 500 mg, 1.12 mmol) and tert-butyl piperazine-1-carboxylate (312 mg, 1.67 mmol) in dichloromethane (50 mL) was added hydroxybenzotriazole (HOBT) (183 mg, 1.12 mmol) and N-methyl morpholine (484 mg, 4.79 mmol). The reaction mixture was stirred for 1 h at room temperature and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI HCl) (390. mg, 2.15 mmol) was added. The resulting reaction mixture was stirred for room temperature overnight. The reaction mixture was quenched with dilute hydrochloric acid (2N, 30 mL) and the layers were separated. The organic layer was washed with saturated sodium bicarbonate solution (40 mL), water (60 mL) and finally with brine successively and dried over anhydrous sodium sulphate, filtered, concentrated under vacuum to afford tert-butyl 4-{[1-(1,3-dimethoxypropan-2-yl)-6-iodo-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}piperazine-1-carboxylate 400 mg (57%) as thick oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:11][CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])=[N:4][CH:5]=[N:6][C:7]=1[CH:8](Cl)[CH3:9].[CH3:20][OH:21].C[O-].[Na+]>CO>[Cl:1][C:2]1[C:3]([NH:11][CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])=[N:4][CH:5]=[N:6][C:7]=1[CH:8]([O:21][CH3:20])[CH3:9]
Reactant: CO
Reactant: CC(Cl)c1ncnc(NC(C)c2ccccc2)c1Cl
Agent: C[O-]
Agent: [Na+]
Product: COC(C)c1ncnc(NC(C)c2ccccc2)c1Cl
Temperature: 60 °C
Reaction time: 13 h

Procedure:
In 20 ml of methanol was dissolved 1.11 g of 5-chloro-6-(1-chloroethyl)-4-(1-phenylethylamino)pyrimidine, and to the mixture was added 1.3 g of a 28% sodium methoxide methanol solution. The mixture was stirred at 60° C. for 13 hours.
Reaction SMILES: [CH:1]1([CH2:6][C@@H:7]([C:20]([NH:22][NH:23][C:24]2[C:29]([F:30])=[C:28]([N:31]3[CH2:36][CH2:35][N:34]([CH3:37])[C@H:33]([CH3:38])[CH2:32]3)[N:27]=[C:26]([CH3:39])[N:25]=2)=[O:21])[CH2:8][N:9]([O:12]CC2C=CC=CC=2)[CH:10]=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1>CO>[CH:1]1([CH2:6][C@@H:7]([C:20]([NH:22][NH:23][C:24]2[C:29]([F:30])=[C:28]([N:31]3[CH2:36][CH2:35][N:34]([CH3:37])[C@H:33]([CH3:38])[CH2:32]3)[N:27]=[C:26]([CH3:39])[N:25]=2)=[O:21])[CH2:8][N:9]([OH:12])[CH:10]=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1nc(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OCc2ccccc2)c(F)c(N2CCN(C)[C@H](C)C2)n1
Solvent: CO
Product: Cc1nc(NNC(=O)[C@H](CC2CCCC2)CN(O)C=O)c(F)c(N2CCN(C)[C@H](C)C2)n1
Yield: 98.9 %

Procedure:
A solution of [(2R)-2-(cyclopentylmethyl)-3-(2-{6-[(3R)-3,4-dimethyl-1-piperazinyl]-5-fluoro-2-methyl-4-pyrimidinyl}hydrazino)-3-oxopropyl][(phenylmethyl)oxy]formamide (0.082 g, 0.15 mmol), and Pd(C) (0.016 g) in MeOH (10 mL) was run under standard hydrogenation conditions as in General Procedure A, Part C, to provide [(2R)-2-(cyclopentylmethyl)-3-(2-{6-[(3R)-3,4-dimethyl-1-piperazinyl]-5-fluoro-2-methyl-4-pyrimidinyl}hydrazino)-3-oxopropyl]hydroxyformamide as a white solid (0.067 g, 99%). LCMS: (M+H)+=452.4.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[C:3]=1[C:15]([NH2:17])=[O:16].[F:18][C:19]([F:36])([F:35])[C:20]1[CH:21]=[CH:22][C:23]([O:26][C:27]2[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=2)=[N:24][CH:25]=1.[BH4-].[Na+]>CCO.N1CCCCC1>[Cl:14][C:10]1[CH:9]=[C:8]([NH:7][C:4]2[C:3]([C:15]([NH2:17])=[O:16])=[C:2]([NH:1][CH2:31][C:30]3[CH:29]=[CH:28][C:27]([O:26][C:23]4[CH:22]=[CH:21][C:20]([C:19]([F:36])([F:18])[F:35])=[CH:25][N:24]=4)=[CH:34][CH:33]=3)[NH:6][N:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: NC(=O)c1c(Nc2cccc(Cl)c2)n[nH]c1N
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCNCC1
Product: NC(=O)c1c(Nc2cccc(Cl)c2)n[nH]c1NCc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Yield: 42.6 %

Procedure:
5-amino-3-((3-chlorophenyl)amino)-1H-pyrazole-4-carboxamide (300 mg) was suspended in EtOH (5 mL) and 4-[{5-(Trifluoromethyl)pyridin-2-yl}oxy]benzaldehyde (318 mg, 1 eq.) and piperidine (3 drops) were added. Stirred at reflux until intermediate was absent (HPLC). After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain product as a yellow powder. Powder was washed with EtOH. Product was allowed to dry under vacuum for 1 hr (360 mg, 60% yield). Resulting imine (360 mg) was suspended in 10 mL MeOH and sodium borohydride (10 eq., 272 mg) was added. HPLC confirmed reaction was complete (absence of imine). After completion (1 hr), precipitate was filtered to obtain D33 as a light yellow powder. Product was washed with deionized water to remove excess sodium borohydride. Product was allowed to dry under vacuum for 18 hrs. 255 mg (70% yield) of final product was obtained.