Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:11](=[O:12])[C:10]([C:13]3[CH:18]=[CH:17][C:16]([C:19]4([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:22][CH2:21][CH2:20]4)=[CH:15][CH:14]=3)=[C:9]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[O:8][C:7]=12.[NH:37]1[CH:41]=[CH:40][N:39]=[CH:38]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.[Cu](I)I>[N:37]1([C:2]2[N:3]=[CH:4][CH:5]=[C:6]3[C:11](=[O:12])[C:10]([C:13]4[CH:14]=[CH:15][C:16]([C:19]5([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[CH2:22][CH2:21][CH2:20]5)=[CH:17][CH:18]=4)=[C:9]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[O:8][C:7]=23)[CH:41]=[CH:40][N:39]=[CH:38]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(Cl)nccc4c3=O)cc2)CCC1
Reactant: c1c[nH]cn1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(-n5ccnc5)nccc4c3=O)cc2)CCC1
Temperature: 120 °C
Yield: 32.5 %

Procedure:
tert-Butyl (1-(4-(8-chloro-4-oxo-2-phenyl-4H-pyrano[2,3-c]pyridin-3-yl)phenyl)cyclobutyl)carbamate (63 mg, 0.115 mmol), imidazole (11 mg, 0.161 mmol), cesium carbonate (75 mg, 0.23 mmol) and copper (II) iodide (5 mg, 0.023 mmol) were dissolved in DMF (1 mL) in a microwave vial. The vial was sealed, evacuated and flushed twice with nitrogen. The reaction mixture was heated conventionally at 120° C. for 72 h. After cooling to RT, the resultant mixture was diluted with EtOAc, washed with water, dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, 1:1 ethyl acetate/hexane) to give the title compound (20 mg, 24%). LCMS (Method I): RT=5.89 min, [M+H]+=535.
Reaction SMILES: C[C@@H]1[C@H:20](O)[C@@H:19](C)[C:17](=[O:18])[C:16]([CH3:24])([CH3:23])[C@@H:15]([OH:25])[CH2:14][C:12](=[O:13])[O:11][C@H](/C(/C)=C/C2N=C(C)SC=2)C[C@@H]2O[C@]2(C)CCC1.N1CCCCC1.C(Cl)Cl.CC(C)=O>C(Cl)Cl>[CH3:24][C:16]([CH3:23])([C:17](=[O:18])[CH2:19][CH3:20])[C@@H:15]([OH:25])[CH2:14][C:12]([OH:13])=[O:11]
Reactant: C/C(=C\c1csc(C)n1)[C@@H]1C[C@@H]2O[C@]2(C)CCC[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: C1CCNCC1
Product: CCC(=O)C(C)(C)[C@@H](O)CC(=O)O
Reaction time: 16 h

Procedure:
0.5 g (0.99 mmol) of epothilone B are dissolved in 84 mL of CH2Cl2. After adding 43 μL (0.44 mmol) of piperidine and 127 μL (0.44 mmol) of titanium tetra-isopropylate, the reaction solution is strirred for 16 h at RT. After concentration In vacuo, the product is purified by FC (150 g of silica gel, CH2Cl2→CH2Cl2/acetone=4:1) giving a colorless oil: Rf (CH2Cl2/acetone=85:15): 0.57; M+H=508; 1H-NMR (500 MHz, DMSO-d6; δ/ppm): 9.56 (d, 1.5 Hz, 1H CHO), 7.37 (s, 1H, H19), 6.45 (s, 1H, H17), 5.31 (m, 1H, H15), 5.10 (d, 5.5 Hz, 1H, 3-OH), 4.13 (m, 1H, H3), 2.74 (m, 1H, H13), 2.64 (s, 3H, 20-Me), 2.53 (t, 7.5 Hz, 2H, H6), 2.36 (m, 1H, H8), 2.4/2.21 (m/m, 2H, H2), 2.06 (s, 3H, 16-Me), 1.98/1.77 (m/m, 2H, H14), 1.67/1.34 (m/m, 2H, H9), 1.45 (m, 2H, H10), 1.18 (s, 3H, 4-Me), 1 (s/s/s, 9H, 4-Me, 8-Me, 12-Me), 0.87 (t, 7.5 Hz, 3H, 6-Me).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].N1C2C(=CC=CC=2)[C:25]2([CH2:35][O:34][C:33]3[CH:36]=C4C(=C[C:32]2=3)CCO4)C1=O.CC1C=CC(S(OC[C@H]2CCCO2)(=O)=O)=CC=1.BrCC1CCCCO1>>[O:34]1[CH2:35][CH2:25][CH2:32][C@@H:33]1[CH2:36][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: BrCC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)OC[C@H]2CCCO2)cc1
Product: O=C1N(C[C@H]2CCCO2)c2ccccc2C12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and (R)-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate to replace 2-(bromomethyl)tetrahydro-2H-pyran, 1′-[(2R)-tetrahydrofuran-2-ylmethyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (55%) as a colorless solid: mp 174-176° C. (hexanes); 1H NMR (300 MHz, CDCl3) (diastereomers) δ7.32-7.25 (m, 1H), 7.16-7.00 (m, 3H), 6.49 (s, 1H), 6.24 (s, 1H), 4.88 (d, J=8.7 Hz, 1H), 4.63 (d, J=8.7 Hz, 1H), 4.31-4.22 (m, 1H), 4.21-4.17 (m, 2H), 4.14-4.09 (m, 2H), 3.99-3.67 (m, 4H), 2.09-1.82 (m, 3H), 1.78-1.66 (m, 1H); 13C NMR (75 MHz, CDCl3) (diastereomers) δ178.1, 177.9, 155.3, 144.6, 143.0, 142.9, 138.4, 132.4, 132.3, 128.9, 128.8, 123.8, 123.7, 123.3, 121.4, 121.3, 111.7, 111.6, 109.8, 109.5, 99.4, 80.29, 80.26, 77.1, 76.8, 68.4, 68.3, 64.6, 64.0, 58.10, 58.08, 44.7, 29.4, 29.1, 25.9, 25.7; MS (ES+) m/z 380.2 (M+1).
Reaction SMILES: [CH3:1][C:2]([CH3:6])([CH3:5])[C:3]#N.[Cl:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][CH:9]=1.[Mg].[OH:16]S(O)(=O)=O>O1CCCC1.[Na].O>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:3]([C:2]([CH3:6])([CH3:5])[CH3:1])=[O:16])=[CH:10][CH:9]=1
Reactant: Clc1ccc(I)cc1
Reactant: O=S(=O)(O)O
Reactant: CC(C)(C)C#N
Agent: [Mg]
Agent: [Na]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 40 %

Procedure:
Trimethyl acetonitrile (0.1 mol) in dry tetrahydrofuran (50 ml) was added dropwise with stirring to the Grignard reagent prepared form 4-chloro-iodobenzene (0.11 mol) and magnesium turnings (0.11 g atoms) in sodium dry ether (50 ml) at such a rate as to retain gentle reflux. The solution was refluxed for 4 hours, cooled to room temperature, and water (40 ml) added carefully. 2N H2SO4 (50 ml) was added and the ether solution washed with water (3×100 ml) and dried over anhydrous magnesium sulphate. Removal of the solvent gave a yellow oil which was distilled at the water pump to give tertiary butyl 4-chlorophenyl ketone (40%) as a colourless liquid b.p. 116°-128°/15 mm Hg.
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[C:9]([F:10])=[CH:8][C:7]([OH:11])=[CH:6][C:5]=1[F:12].Cl.Cl[CH2:16][C:17]1[N:18]=[CH:19][S:20][CH:21]=1.[CH3:22][C@@H:23]1[CH2:27][CH2:26][CH2:25][N:24]1[CH2:28][C@@H:29]1[CH2:33][CH2:32][CH2:31][NH:30]1>>[F:10][C:9]1[CH:8]=[C:7]([O:11][CH2:16][C:17]2[N:18]=[CH:19][S:20][CH:21]=2)[CH:6]=[C:5]([F:12])[C:4]=1[C:3]([N:30]1[CH2:31][CH2:32][CH2:33][C@H:29]1[CH2:28][N:24]1[CH2:25][CH2:26][CH2:27][C@H:23]1[CH3:22])=[O:13]
Reactant: COC(=O)c1c(F)cc(O)cc1F
Reactant: C[C@@H]1CCCN1C[C@@H]1CCCN1
Reactant: ClCc1cscn1
Agent: Cl
Product: C[C@@H]1CCCN1C[C@@H]1CCCN1C(=O)c1c(F)cc(OCc2cscn2)cc1F

Procedure:
The title compound is prepared in a manner substantially analogous to Procedures D and E using 2,6-difluoro-4-hydroxy-benzoic acid methyl ester [CAS 194938-88-0], 4-(chloromethyl)thiazole hydrochloride [CAS 7709-58-2], and 2-(R)-methyl-1-(2-(S)-pyrrolidinylmethyl)pyrrolidine. MS (ES+) m/e 422.2
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[C:15]1[CH:16]=[CH:17][C:18]([CH3:29])=[C:19]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH:20]=1.CCOC(C)=O.C(Cl)Cl>C1(C)C=CC=CC=1.C(O[Pd]OC(=O)C)(=O)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>[C:24]([O:23][C:22]([NH:21][C:19]1[CH:20]=[C:15]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)[CH:16]=[CH:17][C:18]=1[CH3:29])=[O:28])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1ccc(Br)cc1NC(=O)OC(C)(C)C
Agent: CC(=O)O[Pd]OC(C)=O
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Cc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1NC(=O)OC(C)(C)C
Temperature: 105 °C
Yield: 65.3 %

Procedure:
A mixture of tert-butyl piperazine-1-carboxylate (5.47 g, 29.4 mmol), tert-butyl 5-bromo-2-methylphenylcarbamate (2.8 g, 9.78 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.233 g, 0.489 mmol), diacetoxypalladium (0.066 g, 0.294 mmol), and Reactant 5 (9.56 g, 29.4 mmol) (Cs2CO3) in Toluene (45 mL) was heated at 100-110° C. for 2 days. After the solvent was removed, the residue was dissolved in ethyl acetate and washed with water. After the EtOAc was removed, the residue was purified by column with DCM, then EtOAc/DCM (2%) to give tert-butyl 4-(3-(tert-butoxycarbonylamino)-4-methylphenyl)piperazine-1-carboxylate (2.5 g, 6.39 mmol, 65.3% yield, white solid). 1H-NMR (CDCl3, 500 MHz): δ 7.57 (1H, s), 7.00 (1H, d, J=8.55 Hz), 6.55 (1H, d, J=8.24 Hz), 6.31 (1H, s), 3.56 (4H, m), 3.09 (4H, m), 2.15 (3H, s), 1.52 (9H, s), 1.48 (9H, s).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[CH2:10]1[O:12][CH2:11]1.[OH-].[Na+]>>[OH:12][CH2:11][CH2:10][N:6]1[C:2]([CH3:9])([CH3:1])[C:3](=[O:8])[NH:4][C:5]1=[O:7]
Reactant: CC1(C)NC(=O)NC1=O
Reactant: C1CO1
Agent: [Na+]
Agent: [OH-]
Product: CC1(C)C(=O)NC(=O)N1CCO

Procedure:
Thus, to make the non-methylolated hydantoin fatty acid ester, or MHEDMH ester (Ia), 5,5-dimethylhydantoin, or DMH (ii) [C5H8O2N2 =128 mol. wt.], is reacted with ethylene oxide in a first step per reaction scheme (1a), e.g. in the presence of a catalyst such as sodium hydroxide, to form monohydroxyethyl dimethylhydantoin, or 1-(2-hydroxyethyl)-5,5-dimethylhydantoin [i.e., 1-(2-hydroxyethyl)-5,5-dimethyl-1,3-diazacyclopentane-2,4-dione], or MHEDMH (vi) [C7H12O3N2 =172 mol. wt⟧
Reaction SMILES: [S:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](Cl)=[O:17])=[CH:11][CH:10]=1>>[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([CH:3]2[C:4](=[O:7])[CH2:5][CH2:6][S:1][CH2:2]2)=[O:17])=[CH:11][CH:10]=1
Reactant: O=C1CCSCC1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Product: O=C1CCSCC1C(=O)Cc1ccc(F)cc1
Yield: 78 %

Procedure:
3-(2-(4-Fluorophenyl)acetyl)dihydro-2H-thiopyran-4(3H)-one (508 mg, 78%) was obtained from tetrahydrothiopyran-4-one and 4-fluorophenylacetyl chloride by the general procedure for the preparation of diketones. MS (ES+) m/z 253.1 (M+H)+
Reaction SMILES: C([O-])(=O)C.[Cu+2:5].C([O-])(=O)C.[CH2:10]([CH:12]([CH2:16][CH2:17][CH2:18][CH3:19])[C:13]([OH:15])=[O:14])[CH3:11]>>[Cu:5].[CH2:10]([CH:12]([CH2:16][CH2:17][CH2:18][CH3:19])[C:13]([O-:15])=[O:14])[CH3:11].[CH2:10]([CH:12]([CH2:16][CH2:17][CH2:18][CH3:19])[C:13]([O-:15])=[O:14])[CH3:11].[Cu+2:5]
Reactant: CCCCC(CC)C(=O)O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Product: CCCCC(CC)C(=O)[O-]
Product: [Cu]

Procedure:
A copper containing solution was prepared by mixing and reacting copper acetate with a stoichiometric excess of 2-ethylhexanoic acid to form copper di(2-ethylhexanoate). This solution contained 6.36 percent by weight copper, based on total weight.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[F:9].[CH3:10][S:11](Cl)(=[O:13])=[O:12]>N1C=CC=CC=1.CCOC(C)=O>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][S:11]([CH3:10])(=[O:13])=[O:12])=[CH:4][C:3]=1[F:9]
Reactant: Nc1ccc(Br)c(F)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(Br)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.5 %

Procedure:
step 1—To a solution of 4-bromo-3-fluoro-aniline (1.00 g, 5.263 mmol) in pyridine (5 mL) at 0° C. was added methanesulfonyl chloride (0.500 mL, 6.424 mmol). The reaction was gradually warmed to RT and stirred overnight then diluted with EtOAc. The organic layer was washed successively with saturated aqueous CuSO4 solution, brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (5 to 20% EtOAc) to afford 1.235 g (88%) of N-(4-bromo-3-fluoro-phenyl)-methanesulfonamide (72) as a white solid.
Reaction SMILES: CO.[OH-].[Na+:4].[CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[C:17]([NH:24][C:25]([C:27]3[CH:28]=[N:29][CH:30]=[C:31]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH:32]=3)=[O:26])[CH:16]=2)=[CH:7][N:6]=1>O1CCOCC1>[CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([O-:21])=[O:20])=[C:17]([NH:24][C:25]([C:27]3[CH:28]=[N:29][CH:30]=[C:31]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH:32]=3)=[O:26])[CH:16]=2)=[CH:7][N:6]=1.[Na+:4]
Reactant: O=C(Nc1cc(-c2cncc3ccccc23)ccc1C(=O)O)c1cncc(-c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: O=C(Nc1cc(-c2cncc3ccccc23)ccc1C(=O)[O-])c1cncc(-c2ccccc2)c1

Procedure:
Methanol (5 mL), dioxane (5 mL), and a 2 mol/L aqueous solution of sodium hydroxide (0.091 mL) were added to the obtained 4-(isoquinolin-4-yl)-2-(5-phenylpyridine-3-carboxamido)benzoic acid (81 mg), and the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the obtained residue, and the solid substance was collected by filtration to obtain 83 mg of sodium 4-(isoquinolin-4-yl)-2-(5-phenylpyridine-3-carboxamido)benzoate as a light yellow solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH:10]([C:13]3[CH:18]=[CH:17][C:16](Cl)=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=3)[N:9]2[C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[CH:4][C:3]=1[N+:30]([O-:32])=[O:31].[CH3:33][O:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39][NH2:40])=[CH:37][CH:36]=1>ClCCl>[F:29][C:26]1[CH:27]=[CH:28][C:23]([N:9]2[CH:10]([C:13]3[CH:18]=[CH:17][C:16]([NH:40][CH2:39][C:38]4[CH:41]=[CH:42][C:35]([O:34][CH3:33])=[CH:36][CH:37]=4)=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=3)[CH2:11][CH2:12][CH:8]2[C:5]2[CH:6]=[CH:7][C:2]([NH:40][CH2:39][C:38]3[CH:41]=[CH:42][C:35]([O:34][CH3:33])=[CH:36][CH:37]=3)=[C:3]([N+:30]([O-:32])=[O:31])[CH:4]=2)=[CH:24][CH:25]=1
Reactant: COc1ccc(CN)cc1
Reactant: O=[N+]([O-])c1cc(C2CCC(c3ccc(Cl)c([N+](=O)[O-])c3)N2c2ccc(F)cc2)ccc1Cl
Solvent: ClCCl
Product: COc1ccc(CNc2ccc(C3CCC(c4ccc(NCc5ccc(OC)cc5)c([N+](=O)[O-])c4)N3c3ccc(F)cc3)cc2[N+](=O)[O-])cc1
Temperature: 145 °C
Yield: 62.7 %

Procedure:
The product from Example 29A (0.88 g, 1.86 mmol) was combined with 4-methoxy benzylamine (3.64 mL, 28.0 mmol) and heated at 145° C. for 1 h in a microwave reactor. The mixture was diluted with dichloromethane and filtered. The filtrate was concentrated and purified by chromatography on silica gel with a 330 g column, eluting with 0-60% ethyl acetate/hexanes to give 0.79 g (62%) of an orange foam solid.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[N:6][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]2)=[N:8][CH:9]=1)[CH2:2][CH3:3].[H-].[Na+].[Br:19][C:20]1[CH:29]=[CH:28][C:23]2[N:24]=[C:25](Cl)[S:26][C:22]=2[CH:21]=1>CN(C=O)C.O>[Br:19][C:20]1[CH:29]=[CH:28][C:23]2[N:24]=[C:25]([O:16][CH:13]3[CH2:14][CH2:15][N:10]([C:7]4[N:8]=[CH:9][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][N:6]=4)[CH2:11][CH2:12]3)[S:26][C:22]=2[CH:21]=1
Reactant: CCCc1cnc(N2CCC(O)CC2)nc1
Reactant: Clc1nc2ccc(Br)cc2s1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1cnc(N2CCC(Oc3nc4ccc(Br)cc4s3)CC2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.2 %

Procedure:
To a solution of 1-(5-propylpyrimidin-2-yl)piperidin-4-ol (160 mg, 0.724 mmol) in DMF (5 mL) was added NaH (36.2 mg, 0.905 mmol) at 0° C. Upon completion of addition, the reaction mixture was allowed to warm to rt and then 6-bromo-2-chlorobenzo[d]thiazole (150 mg, 0.604 mmol) was added. The resulting mixture was heated to 90° C., where it stirred overnight. At the conclusion of this period, the reaction mixture was cooled to rt, diluted with water and then extracted with EtOAc (3×5 mL). The combined organic layers were dried over Na2SO4. The resulting mixture was filtered and concentrated under reduced pressure to yield the crude product. The crude product was purified by column chromatography (silica gel, hexanes-EtOAc gradient 0 to 50% EtOAc) to afford Compound 1C (194 mg, 0.448 mmol, 74.2% yield).
Reaction SMILES: ClC(OCC)=O.[CH3:7][O:8][C:9]([C@H:11]1[CH2:16][CH2:15][C@H:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[N:28]=[C:27]([C:29](O)=[O:30])[CH:26]=[N:25][C:24]=3[CH3:32])=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)=[O:10].C[N:34]1CCOCC1.N>C(Cl)Cl.CO>[NH2:34][C:29]([C:27]1[N:28]=[C:23]([C:20]2[CH:21]=[CH:22][C:17]([C@H:14]3[CH2:13][CH2:12][C@H:11]([C:9]([O:8][CH3:7])=[O:10])[CH2:16][CH2:15]3)=[CH:18][CH:19]=2)[C:24]([CH3:32])=[N:25][CH:26]=1)=[O:30]
Reactant: CN1CCOCC1
Reactant: COC(=O)[C@H]1CC[C@H](c2ccc(-c3nc(C(=O)O)cnc3C)cc2)CC1
Agent: CCOC(=O)Cl
Agent: N
Solvent: ClCCl
Solvent: CO
Product: COC(=O)[C@H]1CC[C@H](c2ccc(-c3nc(C(N)=O)cnc3C)cc2)CC1

Procedure:
Ethyl chloroformate (245 μl, 2.54 mmol) was added dropwise to a stirred solution of 6-{4-[trans-4-(methoxycarbonyl)cyclohexyl]phenyl}-5-methylpyrazine-2-carboxylic acid (Intermediate 65-1, 751 mg, 2.12 mmol) and N-methylmorpholine (350 μl, 3.18 mmol) in DCM (20 mL) at 0° C. Ammonia (5 mL of a 7M solution in MeOH) was added. The reaction mixture was allowed to warm up over 1 h then was concentrated and the residue was purified by chromatography eluting with 0-10% MeOH/DCM to give the title compound (226 mg, 30%) as a solid; 1H NMR δ 9.00 (1H, s), 8.08 (1H, s), 7.74 (1H, s), 7.70 (2H, d), 7.40 (2H, d), 3.63 (3H, s), 2.70-2.55 (1H, m), 2.67 (3H, s), 2.50-2.35 (1H, m), 2.10-1.98 (2H, m), 1.96-1.83 (2H, m), 1.65-1.43 (4H, m); MS 354.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[Br:10][CH:11]([CH:17]([Br:19])[CH3:18])[C:12]([N:14]=[C:15]=[O:16])=[O:13]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:15]([NH:14][C:12](=[O:13])[CH:11]([Br:10])[CH:17]([Br:19])[CH3:18])=[O:16])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: CC(Br)C(Br)C(=O)N=C=O
Reactant: Nc1ccc(Cl)c(Cl)c1
Product: CC(Br)C(Br)C(=O)NC(=O)Nc1ccc(Cl)c(Cl)c1

Procedure:
m.p: 196° - 197° C. (from 3,4-dichloroaniline and 2,3-dibromobutyryl isocyanate)
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5]([NH2:6])=[N:4][C:2]1=[O:3].CN([Si:17]([CH3:20])([CH3:19])[CH3:18])C(=O)C(F)(F)F>ClCCl>[CH3:18][Si:17]([N:6]([Si:17]([CH3:20])([CH3:19])[CH3:18])[C:5]1[CH:7]=[CH:8][NH:1][C:2](=[O:3])[N:4]=1)([CH3:20])[CH3:19]
Reactant: CN(C(=O)C(F)(F)F)[Si](C)(C)C
Reactant: Nc1cc[nH]c(=O)n1
Solvent: ClCCl
Product: C[Si](C)(C)N(c1cc[nH]c(=O)n1)[Si](C)(C)C
Temperature: -30 °C

Procedure:
A bis-trimethylsilylcytosine solution was prepared by suspending 5.78 g of cytosine in 75 ml of dichloromethane and adding 20.57 ml of N-methyl-N-trimethylsilyltrifluoroacetamide and cooling the resulting solution to -30° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:24][C:25](OC(C)=O)=[O:26].CCN(CC)CC>CC#N>[CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:10]2[CH2:15][CH2:14][N:13]([C:25](=[O:26])[CH3:24])[CH2:12][CH2:11]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cccnc1CN(Cc1ncccc1C)C1CCNCC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(N(Cc2ncccc2C)Cc2ncccc2C)CC1
Yield: 55.1 %

Procedure:
Using General Procedure B, to a solution of COMPOUND 249(0.1331 g, 0.43 mmol) in CH3CN (5 mL) was added Ac2O (0.05 mL, 0.51 mmol), Et3N (0.09 mL, 0.65 mmol), and KI (0.0116 g, 0.04 mmol). Purification of the crude material by column chromatography on silica gel (50:1:1 CH2Cl2-MeOH—NH4OH) provided 83.5 mg (53%) of COMPOUND 251 as a white solid. 1H NMR (CDCl3) δ 1.53-1.69 (m, 2H), 1.78-1.85 (m, 2H), 2.08 (s, 9H), 2.35 (t, 1H, J=13.0 Hz), 2.72 (t, 1H, J=12.0 Hz), 2.91 (t, 1H, J=12.0 Hz), 3.73-3.90 (m, 5H), 4.69 (d, 1H, J=24.0 Hz), 7.06-7.11 (m, 2H), 7.36 (d, 2H, J=9.0 Hz), 8.35 (d, 2H, J=3.0 Hz). 13C NMR (CDCl3) δ 18.35, 21.86, 27.09, 28.19, 42.05, 46.79, 54.99, 57.78, 122.82, 133.77, 138.43, 146.31, 157.49, 169.14. ES-MS m/z 353 (M+H). Anal. Calcd. for C21H28N4O.H2O: C, 69.43; H, 8.10; N, 15.42. Found: C, 69.52; H, 7.82; N, 15.28.
Reaction SMILES: CC[O-].[Na+].Cl.[F:6][C:7]([F:17])([F:16])[C:8]1[N:9]=[C:10]([C:13]([NH2:15])=[NH:14])[S:11][CH:12]=1.[C:18](OCC)(=[O:25])[CH2:19][C:20](OCC)=[O:21]>CCO>[F:17][C:7]([F:6])([F:16])[C:8]1[N:9]=[C:10]([C:13]2[N:15]=[C:20]([OH:21])[CH:19]=[C:18]([OH:25])[N:14]=2)[S:11][CH:12]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: N=C(N)c1nc(C(F)(F)F)cs1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Oc1cc(O)nc(-c2nc(C(F)(F)F)cs2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
To a stirred solution of NaOEt (32 g, 5 eq.) in EtOH (200 mL) was slowly added compound 282 (22 g, 1 eq.). The reaction mixture was stirred at room temperature for 30 min and diethyl malonate (11.5 mL, 0.8 eq.) was then added. The suspension was refluxed for 24 hrs. The solvent was removed under reduced pressure. The residue was suspended in H2O (200 mL) and acidified to pH 5 with 2 N aqueous HCl. The resulting solid was filtered, washed with water, and dried under reduced pressure to yield compound 283 as a brown solid in 98% yield. 1H NMR (DMSO-d6, 400 MHz) δ 5.77 (s, 1H), 8.68 (s, 1H).
Reaction SMILES: C([Mg][Cl:5])(C)C.Br[C:7]1[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][N:8]=1.[F:14][C:15]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:16]=1[CH:17]=O.[Cl-].[NH4+]>O1CCCC1>[ClH:5].[Cl:5][CH:17]([C:16]1[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:15]=1[F:14])[C:7]1[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][N:8]=1
Reactant: O=Cc1cc(F)ccc1F
Reactant: Cc1cccnc1Br
Reactant: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cccnc1C(Cl)c1cc(F)ccc1F
Product: Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under an argon atmosphere, a tetrahydrofuran solution (1.5 ml, 3 mmol) of isopropylmagnesium chloride was added dropwise to a tetrahydrofuran (2.0 ml) solution of 2-bromo-3-methylpyridine (510 mg, 3 mmol) under ice cooling. The resulting mixture was stirred at room temperature for 60 minutes. To the resulting brown solution, 2,5-difluorobenzaldehyde (328 μl, 3 mmol) was added dropwise under ice cooling. The temperature of the reaction mixture was then raised to room temperature gradually. After addition of a saturated aqueous solution of ammonium chloride, the resulting mixture was extracted with ethyl acetate. After the solvent was dried, the residue obtained by concentration under reduced pressure was purified by silica gel chromatography (hexane:ethyl acetate=8:1) to give a mixture containing the title compound. Thionyl chloride (2.0 ml) and one drop of dimethylformamide were added to the mixture. The resulting mixture was stirred at room temperature for 14 hours. Excess thionyl chloride was distilled off under reduced pressure to yield a white precipitate. The resulting precipitate was triturated with hexane and diethyl ether to give the title compound (101 mg, 12%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][N:7]=1.Br[CH:10]([C:20]1[CH:25]=[CH:24][N:23]=[C:22]([S:26][CH3:27])[N:21]=1)[C:11]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)=O>CN1CCCC1=O.C(Cl)Cl>[Cl:1][C:2]1[C:3]2[N:4]([C:10]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([S:26][CH3:27])[N:21]=3)=[C:11]([C:13]3[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=3)[N:8]=2)[CH:5]=[CH:6][N:7]=1
Reactant: CSc1nccc(C(Br)C(=O)c2ccc(F)cc2)n1
Reactant: Nc1nccnc1Cl
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: CSc1nccc(-c2c(-c3ccc(F)cc3)nc3c(Cl)nccn23)n1
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 5.1 %

Procedure:
To a solution of 3-chloropyrazin-2-ylamine (1.3 g, 10 mmol) in 1-methyl-2-pyrrolidinone (1 mL) heated to about 150° C. was added dropwise over about 15 min a solution of 2-bromo-1-(4-fluorophenyl)-2-(2-methylsulfanylpyrimidin-4-yl)ethanone (prepared according to WO2003000682; 0.34 g, 1 mmol) in 1-methyl-2-pyrrolidinone (1 mL). After about 30 min of stirring at about 150° C., the mixture was cooled to ambient temperature, diluted with DCM, extracted three times with 1N HCl and six times with 2N NaOH. The organic layer was dried over Na2SO4 and concentrated. The crude material was purified by silica gel chromatography with heptane/EtOAc (stepwise gradient, 5:1, 3:1) to give 0.019 g (5%) of the title compound: LC/MS (Table 1, Method b) Rt=2.28 min; MS m/z: 372.2 (M+H)+.