Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([NH:11][C:12](=[O:30])[CH:13]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=2)[CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[S:9][CH:10]=1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[CH:15]1([CH2:14][CH:13]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=2)[C:12]([NH:11][C:8]2[S:9][CH:10]=[C:6]([CH2:4][OH:3])[N:7]=2)=[O:30])[CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: CCOC(=O)c1csc(NC(=O)C(CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2nc(CO)cs2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 46.4 %

Procedure:
A solution of 2-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazole-4-carboxylic acid ethyl ester (prepared in Example 3(B)(b), 130 mg, 0.29 mmol) in diethyl ether (2 mL) was cooled to 0° C. and then slowly treated with lithium aluminum hydride (17 mg, 0.44 mmol). The reaction mixture was allowed to warm to 25° C. where it was stirred for 4 h. After 4 h at 25° C., thin layer chromatography indicated the presence of starting material. An additional amount of lithium aluminum hydride (11 mg, 0.29 mmol) was added to the reaction mixture, and the reaction mixture was allowed to stir at 25° C. for 15 h. The reaction mixture was then slowly quenched by the dropwise addition of water. The resulting mixture was partitioned between water and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, ethyl acetate) afforded 3-cyclopentyl-N-(4-hydroxymethyl-thiazol-2-yl)-2-(4-methanesulfonyl-phenyl)-propionamide (55 mg, 46%) as a white solid: mp 124-126° C.; EI-HRMS m/e calcd for C19H24N2O4S2 (M+) 408.11-78, found 408.1164.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([NH:7][C:8](=[O:18])[C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[O:16][CH3:17])=[N:4][CH:3]=1.Br[CH2:20][C:21]1[N:22]=[CH:23][S:24][CH:25]=1>>[Br:1][C:2]1[S:6]/[C:5](=[N:7]\[C:8](=[O:18])[C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[O:16][CH3:17])/[N:4]([CH2:20][C:21]2[N:22]=[CH:23][S:24][CH:25]=2)[CH:3]=1
Reactant: BrCc1cscn1
Reactant: COc1ccc(Cl)cc1C(=O)Nc1ncc(Br)s1
Product: COc1ccc(Cl)cc1C(=O)/N=c1\sc(Br)cn1Cc1cscn1
Yield: 52 %

Procedure:
A mixture of Example 84A (1001 mg, 3.33 mmol) and commercially available 4-(bromomethyl)thiazole were processed using the method described for Example 83B to afford the title compound (660 mg, 52% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 3.78 (s, 3H), 5.54 (s, 2H), 7.12 (d, J=9.2 Hz, 1H), 7.49 (dd, J=8.8, 2.7 Hz, 1H), 7.69 (dd, J=15.9, 2.4 Hz, 2H), 7.93 (s, 1H), 9.10 (d, J=2.0 Hz, 1H) MS (DCI) m/z 445 (M+H); Anal. Calculated for C15H11BrClN3O2S2: C, 40.51; H, 2.49; N, 9.45. Found: C, 40.85; H, 2.90; N, 9.62.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:10][C:11](=[O:25])[CH:12]([NH2:24])[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([Br:23])[CH:21]=2)[NH:16][CH:15]=1)[CH3:9].[CH2:26]([O:30][C:31]1[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1)[C:27]#[C:28][CH3:29]>O.O1CCOCC1>[CH2:8]([O:10][C:11](=[O:25])[CH:12]([NH:24][S:37]([C:34]1[CH:33]=[CH:32][C:31]([O:30][CH2:26][C:27]#[C:28][CH3:29])=[CH:36][CH:35]=1)(=[O:39])=[O:38])[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([Br:23])[CH:21]=2)[NH:16][CH:15]=1)[CH3:9]
Reactant: CCOC(=O)C(N)Cc1c[nH]c2ccc(Br)cc12
Reactant: CC#CCOc1ccc(S(=O)(=O)Cl)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: O
Product: CC#CCOc1ccc(S(=O)(=O)NC(Cc2c[nH]c3ccc(Br)cc23)C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 61.4 %

Procedure:
Triethylamine (4.81 mL, 34.5 mmol) was added to a mixture of 2-amino-3-(5-bromo-1H-indol-3-yl)-propionic acid ethyl ester (4.00 g, 11.51 mmol) and 4-but-2-ynyloxy-benzenesulfonyl chloride (3.10 g, 12.66 mmol) in H2O-dioxane (40 mL/60 mL) at room temperature. The reaction mixture was stirred for 20 hours at room temperature. The mixture was concentrated and diluted with ethyl acetate. The organic solution was washed with H2O and brine, dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography (silica, 40% ethyl acetate in hexanes) to give 3.67 g of the title compound as a pale yellow solid. 1H NMR (DMSO-d6): 400 MHz δ 11.05 (s, 1H), 8.31 (d, J=8.8 Hz, 1H), 7.56 (d, J=8.8 Hz, 2H), 7.45 (d, J=1.6 Hz, 1H), 7.27 (d, J=8.4 Hz, 1H), 7.14 (m, 2H), 6.99 (d, J=8.8 Hz, 2H), 4.80 (q, J=2.4 Hz, 2H), 3.88 (q, J=7.6 Hz, 1H), 3.75 (q, J=7.2 Hz, 2H), 3.00 (dd J=14.4, 7.2 Hz, 1H), 2.88 (dd J=14.4, 7.6 Hz, 1H), 1.82 (t, J=2.4 Hz, 3H), 0.92 (t, J=7.2 Hz, 3H); HRMS: calcd for C23H24BrN2O5S (ESI+, Br79, [M+H]1+), 519.0584; found 519.0589.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:18][CH:17]=2)(=[O:15])=[O:14])=[N:4][CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH2:10][OH:11].[H-].[Na+].Cl[C:29]1[N:34]=[CH:33][C:32]([S:35][CH3:36])=[CH:31][N:30]=1.Cl.[Cl-].[NH4+]>CC(N(C)C)=O>[Br:1][C:2]1[C:3]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:18][CH:17]=2)(=[O:15])=[O:14])=[N:4][CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH2:10][O:11][C:29]1[N:34]=[CH:33][C:32]([S:35][CH3:36])=[CH:31][N:30]=1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2ncnc(OCCO)c2Br)cc1
Reactant: CSc1cnc(Cl)nc1
Agent: Cl
Agent: [Cl-]
Agent: [H-]
Solvent: CC(=O)N(C)C
Product: CSc1cnc(OCCOc2ncnc(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)c2Br)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.6 %

Procedure:
To a solution of N-[5-bromo-6-(2-hydroxyethoxy)pyrimidin-4-yl]-4-tert-butylbenzenesulfonamide (3.10 g) in dimethylacetamide (30 ml) is added sodium hydride (60% dispersion-type, 720 mg), and the mixture is stirred at room temperature for 30 minutes. To the mixture is added 2-chloro-5-methylthiopyrimidine (1.51 g), and the mixture is stirred at room temperature overnight. The reaction solution is treated with 10% hydrochloric acid and saturated ammonium chloride solution, and extracted with ethyl acetate. The ethyl acetate layer is washed, dried, and evaporated to remove the solvent. The residue is purified by silica gel column chromatography (solvent; chloroform/ethyl acetate=10:1), and recrystallized from hexane/ethyl acetate to give N-{5-bromo-6-[2-(5-methylthiopyrimidin-2-yloxy)ethoxy]pyrimidin-4-yl}-4-tert-butylbenzenesulfonamide (3.34 g).
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[C:5](S(C(F)(F)F)(=O)=O)[CH:4]=1)#[N:2].O1C=C[CH:20]=[C:19]1P(C1OC=CC=1)C1OC=CC=1.[Cl-].[Li+].C([Sn](CCCC)(CCCC)CCCC)=C.[F-].[K+]>CN1CCCC1=O.C(OCC)C>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[C:5]([CH:19]=[CH2:20])[CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C=O)c(S(=O)(=O)C(F)(F)F)c1
Reactant: c1coc(P(c2ccco2)c2ccco2)c1
Agent: C=C[Sn](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: CCOCC
Solvent: CN1CCCC1=O
Product: C=Cc1cc(C#N)ccc1C=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of 4-cyano-2-trifluoromethylsulphonyl-benzaldehyde (0.91 g, 3.26 mmol), tris(dibenzylidenacetone)dipalladium(0) (67 mg, 0.074 mmol), tris(2-furyl)phosphine (34 mg, 0.15 mmol) and anhydrous lithium chloride (0.47 g, 11.04 mmol) in dry N-methylpyrrolidinone (10 ml) was stirred under an atmosphere of nitrogen at room temperature for 5 minutes. Vinyltri-n-butyltin (1.31 g, 4.08 mmol) was added and the solution stirred at room temperature fo 22 hours. A saturated solution of potassium fluoride (15 ml) was then added, followed by diethyl ether (15 ml). After stirring for 5 minutes, the resulting yellow suspension was filtered through celite and the solids washed with diethyl ether. The filtrate layers were separated and the organic phase washed once with a saturated solution of potassium fluoride, dried, filtered and evaporated to give 4-cyano-2-vinylbenzaldehyde as a pale yellow solid.
Reaction SMILES: [CH2:1]([Li])CCC.C(NC(C)C)(C)C.[CH2:13]([O:17][C:18]1[CH:41]=[CH:40][C:21]([C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:35][CH2:34][CH:33]([N:36]([CH3:38])[CH3:37])[CH2:32]3)=[C:27]([F:39])[CH:26]=2)=[O:23])=[C:20]([CH3:42])[CH:19]=1)[CH2:14][CH2:15][CH3:16].Cl>C1COCC1.CN(C=O)C>[CH2:13]([O:17][C:18]1[CH:19]=[C:20]2[C:21](=[CH:40][CH:41]=1)[C:22](=[O:23])[N:24]([C:25]1[CH:30]=[CH:29][C:28]([N:31]3[CH2:35][CH2:34][CH:33]([N:36]([CH3:38])[CH3:37])[CH2:32]3)=[C:27]([F:39])[CH:26]=1)[CH:1]=[CH:42]2)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCOc1ccc(C(=O)Nc2ccc(N3CCC(N(C)C)C3)c(F)c2)c(C)c1
Reactant: [Li]CCCC
Agent: Cl
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCCCOc1ccc2c(=O)n(-c3ccc(N4CCC(N(C)C)C4)c(F)c3)ccc2c1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
n-Butyllithium (2.6M in toluene; 0.70 mL) was added to a solution of N,N-diisopropylamine (184 mg) in THF (30 mL) at −78° C. After 10 minutes, 4-butoxy-N-[4-(3-dimethylaminopyrrolidin-1-yl)-3-fluorophenyl]-2-methylbenzamide (0.30 g) was added, and the mixture was stirred at −78° C. for 30 minutes and then warmed to −20° C. DMF (53 mg) was added, and the reaction mixture was hydrolyzed after a further 30 minutes with hydrochloric acid. The reaction mixture was partitioned between sodium carbonate solution and ethyl acetate. The organic phase was dried over sodium sulfate and concentrated. The residue was purified by preparative HPLC. The product with the molecular weight of 423.54 (C25H30FN3O2) was obtained in this way; MS (ESI): 424 (M+H+).
Reaction SMILES: [NH2:1][C@H:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH:15]([CH3:19])[CH2:16][CH2:17][CH3:18])=[CH:9][CH:8]=1)[C:3]([CH3:6])([OH:5])[CH3:4].C(O)(C(F)(F)F)=O.[C:27]1([C@H:33]([CH3:37])[C:34](O)=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C([O-])(O)=O.[Na+]>ClCCl>[OH:5][C:3]([CH3:6])([CH3:4])[C@H:2]([NH:1][C:34](=[O:35])[C@H:33]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH3:37])[C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH:15]([CH3:19])[CH2:16][CH2:17][CH3:18])=[CH:11][CH:12]=1
Reactant: CCCC(C)COc1ccc([C@@H](N)C(C)(C)O)cc1
Reactant: C[C@H](C(=O)O)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCC(C)COc1ccc([C@@H](NC(=O)[C@@H](C)c2ccccc2)C(C)(C)O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
A solution of (1R)-1-amino-2-methyl-1-(4-(2-methylpentyloxy)phenyl)propan-2-ol.TFA (100 mg, 0.264 mmol) in dichloromethane (4 mL) was cooled to 0° C. To this solution (S)-2-phenylpropanoic acid (0.043 mL, 0.316 mmol), N,N-diisopropylethylamine (0.276 mL, 1.581 mmol) and HATU (120 mg, 0.316 mmol) were added. The ice-water bath was removed and reaction mixture was stirred at room temperature for 3 h. The reaction mixture was transferred to a separatory funnel containing saturated aqueous NaHCO3 solution (60 mL). The aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (20 mL), dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (30%→40% ethyl acetate in hexanes) to afford (2S)-N-((1R)-2-hydroxy-2-methyl-1-(4-(2-methylpentyloxy)phenyl)propyl)-2-phenylpropanamide (73 mg, 70% yield) as a colorless solid: 1H NMR (400 MHz, CDCl3) δ 7.17-7.34 (m, 5H), 6.92 (d, J=8.8 Hz, 2H), 6.74 (d, J=8.8 Hz, 2H), 6.29 (d, J=8.6 Hz, 1H), 4.68 (d, J=8.6 Hz, 1H), 3.75 (dd, J=8.8, 5.8 Hz, 1H), 3.59-3.68 (m, 2H), 1.90 (dq, J=12.9, 6.4 Hz, 1H), 1.74 (s, 1H), 1.47 (d, J=7.1 Hz, 3H), 1.26-1.51 (m, 3H), 1.18 (s, 3H), 1.14-1.26 (m, 1 H), 0.98 (d, J=6.5 Hz, 3H), 0.96 (s, 3H), 0.90 (t, J=7.3 Hz, 3H); LRMS (ESI) m/e 398.2 [(M+H)+, calcd for C25H36NO3 398.3].
Reaction SMILES: N1C2C(=CC(N)=CC=2)C=C1.Br[C:12]1[N:17]=[C:16]2[N:18]([C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][CH:30]=3)[N:27]([CH3:31])[CH:26]=[CH:25]4)[C:19](=[O:21])[NH:20][C:15]2=[N:14][CH:13]=1.C[O:33][C:34]1[CH:35]=[C:36](C2C=C3C(C4C=C5C(=CC=4)NC=C5)=CNC3=NC=2)[CH:37]=[CH:38][C:39]=1OC.OC1C=CC(B(O)O)=CC=1.COC1C=C(B(O)O)C=C(OC)C=1OC.BrC1N=C2N(C3C=C4C(=CC=3)NC=C4)C(=O)NC2=NC=1>>[OH:33][C:34]1[CH:35]=[CH:36][C:37]([C:12]2[N:17]=[C:16]3[N:18]([C:22]4[CH:23]=[C:24]5[C:28](=[CH:29][CH:30]=4)[N:27]([CH3:31])[CH:26]=[CH:25]5)[C:19](=[O:21])[NH:20][C:15]3=[N:14][CH:13]=2)=[CH:38][CH:39]=1
Reactant: Cn1ccc2cc(-n3c(=O)[nH]c4ncc(Br)nc43)ccc21
Reactant: COc1ccc(-c2cnc3[nH]cc(-c4ccc5[nH]ccc5c4)c3c2)cc1OC
Agent: COc1cc(B(O)O)cc(OC)c1OC
Agent: Nc1ccc2[nH]ccc2c1
Agent: O=c1[nH]c2ncc(Br)nc2n1-c1ccc2[nH]ccc2c1
Product: Cn1ccc2cc(-n3c(=O)[nH]c4ncc(-c5ccc(O)cc5)nc43)ccc21

Procedure:
Compound BE was prepared by a method analogous to that described in Example 1 by substituting 1-methyl-1H-indol-5-amine for 1H-indol-5-amine in the reaction with Intermediate BA to prepare 6-bromo-1-(1-methyl-1H-indol-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one. In a procedure similar to that used to synthesize Compound D, 4-hydroxyphenylboronic acid was substituted for 3,4,5-trimethoxyphenylboronic acid and 6-bromo-1-(1-methyl-1H-indol-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one was substituted for 6-bromo-1-(1H-indol-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one to obtain the title compound. 2.2 mg recovered. HPLC retention time: 2.18 minutes. MS ESI (m/z): 358.2 (M+H)+, calc. 357.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23].O>ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:8][CH2:9][CH:10]([O:13][S:22]([CH3:21])(=[O:24])=[O:23])[CH2:11][CH2:12]1
Reactant: OC1CCN(c2ncccn2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)OC1CCN(c2ncccn2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a cooled solution of 1-Pyrimidin-2-yl-piperidin-4-ol (WO2008/8895 A1), (100 mg; 0.55 mmol) and triethylamine (233 μL, 1.67 mmol) in dry dichloromethane (1 mL), was added methanesulfonyl chloride (52 μL, 0.67 mmol). The reaction mixture was stirred at room temperature for 5 hours. Water was added. After extraction with dichloromethane, the combined organic extracts were dried over sodium sulfate and concentrated to afford a crude product that was used in the next step without further purification.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:23]3[C:22]([NH2:24])=[N:21][CH:20]=[N:19][C:18]=3[N:17]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][CH2:33][N:34]4[CH:38]=[CH:37][N:36]=[CH:35]4)[CH:26]=3)[CH:16]=2)=[CH:11][C:10]=1[O:39][CH3:40])C1C=CC=CC=1.[H][H].C(O)C>C1COCC1.[Pd]>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:23]3[C:22]([NH2:24])=[N:21][CH:20]=[N:19][C:18]=3[N:17]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][CH2:33][N:34]4[CH:38]=[CH:37][N:36]=[CH:35]4)[CH:26]=3)[CH:16]=2)=[CH:11][C:10]=1[O:39][CH3:40]
Reactant: [H][H]
Reactant: COc1cc(-c2cn(-c3cccc(OCCn4ccnc4)c3)c3ncnc(N)c23)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(-c2cn(-c3cccc(OCCn4ccnc4)c3)c3ncnc(N)c23)ccc1O

Procedure:
0.6 g of 5-(4-benzyloxy-3-methoxyphenyl)-7-[3-(2-(1-imidazolyl)ethoxy)phenyl]-4-amino-pyrrolo[2,3-d]pyrimidine is hydrogenated in a hydrogen atmosphere at normal pressure and about 50° C. for 6 h in 20 ml of THF and 10 ml of ethanol in the presence of 0.2 g of 5% palladium/carbon. After filtration through Celite and crystallization of the residue from methylene chloride, 5-(4-hydroxy-3-methoxyphenyl)-7-[3-(2-(1-imidazolyl)ethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine having an m.p. of 190° C. is obtained.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:26][C@@H:25]2[C@:20]([CH3:31])([CH2:21][CH2:22][C@H:23]([O:27][CH2:28][CH2:29][OH:30])[CH2:24]2)[C@@H:19]2[C@@H:3]1[C@H:4]1[C@:16]([CH3:33])([C@@H:17]([OH:32])[CH2:18]2)[C@@H:7]([C@H:8]([CH3:15])[CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH2:6][CH2:5]1.[C:34]1([CH3:44])[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1>C(Cl)(Cl)Cl.N1C=CC=CC=1>[OH:1][C@@H:2]1[CH2:26][C@H:25]2[C@:20]([CH3:31])([CH2:21][CH2:22][C@H:23]([O:27][CH2:28][CH2:29][O:30][S:40]([C:37]3[CH:38]=[CH:39][C:34]([CH3:44])=[CH:35][CH:36]=3)(=[O:42])=[O:41])[CH2:24]2)[C@@H:19]2[C@@H:3]1[C@H:4]1[C@:16]([CH3:33])([C@@H:17]([OH:32])[CH2:18]2)[C@@H:7]([C@H:8]([CH3:15])[CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH2:6][CH2:5]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@H]4C[C@@H](OCCO)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@@H](OCCOS(=O)(=O)c5ccc(C)cc5)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Reaction time: 8 h

Procedure:
The compound of Example 1B (1.50 g, 3.2 mmol) was dissolved in 15 ml of chloroform and 15 ml of pyridine; p-toluenesulfonyl chloride (920 mg, 4.83 mmol) was added, and the mixture was stirred overnight. Chloroform (250 ml) was added, the resultant solution was washed with 5% HCI solution and sat. Na2SO4. After solvent removal in vacuo, the crude product was purified by column chromatography on silica gel (40%->60% ethyl acetate/hexanes. The yield of the title compound was 1.40 g (71%).
Reaction SMILES: [C@H]1(NCC2C=C(C(C)(C)C)C=C(C(C)(C)C)C=2O)CCCC[C@@H]1NCC1C=C(C(C)(C)C)C=C(C(C)(C)C)C=1[OH:23].[Cl:41][C:42]1[CH:43]=[C:44]2[C:48](=[CH:49][CH:50]=1)[C:47](=[O:51])[CH:46]([C:52]([O:54][CH3:55])=[O:53])[CH2:45]2.C(OO)(C)(C)C>C1(C)C=CC=CC=1.CC(C)[O-].[Zr+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Cl:41][C:42]1[CH:43]=[C:44]2[C:48](=[CH:49][CH:50]=1)[C:47](=[O:51])[C:46]([OH:23])([C:52]([O:54][CH3:55])=[O:53])[CH2:45]2
Reactant: COC(=O)C1Cc2cc(Cl)ccc2C1=O
Reactant: CC(C)(C)c1cc(CN[C@H]2CCCC[C@@H]2NCc2cc(C(C)(C)C)cc(C(C)(C)C)c2O)c(O)c(C(C)(C)C)c1
Agent: [Zr+4]
Agent: CC(C)(C)OO
Agent: CC(C)[O-]
Solvent: Cc1ccccc1
Product: COC(=O)C1(O)Cc2cc(Cl)ccc2C1=O
Temperature: 55 °C

Procedure:
A chiral zirconium complex was prepared by stirring zirconium(IV) isopropoxide (0.560 g, 1.44 mmol) with 2,2′-[(1S,2S)-1,2-cyclohexanediylbis(iminomethylene)]bis[4,6-bis(1,1-dimethylethyl)phenol] (Formula IIIa wherein R6 is C(CH3)3, 1.00 g, 1.82 mmol) for 30 minutes in toluene (25 mL) at ambient temperature. The homogeneous solution was evaporated to dryness in vacuo, and the residue redissolved in toluene (8.70 g, 10 mL). A toluene solution of methyl 5-chloro-2,3-dihydro-1-oxo-1H-indene-2-carboxylate (1.53 g of a 21.55% by weight toluene solution, 1.47 mmol of methyl 5-chloro-2,3-dihydro-1-oxo-1H-indene-2-carboxylate) was added to the toluene solution of the chiral zirconium complex and the reaction mixture was heated to 55° C. Over the next 47 minutes, a toluene solution of methyl 5-chloro-2,3-dihydro-1-oxo-1H-indene-2-carboxylate (36.71 g of a 21.55% by weight toluene solution, 35.2 mmol of methyl 5-chloro-2,3-dihydro-1-oxo-1H-indene-2-carboxylate) and, simultaneously, an aqueous solution of tert-butyl hydroperoxide (70%, 4.69 g, 36.4 mmol) were co-fed to the reaction mixture at 55° C. After the two solutions were added, the reaction mixture was heated at 55° C. for an additional 6 hours, cooled to 25° C., and then filtered. After drying, 4.64 g (52.5%) of the S-enantiomer of methyl 5-chloro-2,3-dihydro-2-hydroxy-1-oxo-1H-indene-2-carboxylate was obtained as a white solid in ≧98% enantiomeric excess. Quantitative HPLC analysis of the filtrate and solids showed that the overall reaction proceeded with 85% conversion of methyl 5-chloro-2,3-dihydro-1-oxo-1H-indene-2-carboxylate, forming methyl 5-chloro-2,3-dihydro-2-hydroxy-1-oxo-1H-indene-2-carboxylate in 74% yield (87% chemoselectivity) and 75% enantiomeric excess of the S-enantiomer.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:7]([N:21]2[C:33](=[O:34])[C:32]3[S:31][C:30]4[CH2:29][CH2:28][CH2:27][CH2:26][C:25]=4[C:24]=3[CH:23]=[N:22]2)=[N:8][CH:9]=[CH:10][C:11]=1B1OC(C)(C)C(C)(C)O1)(=[O:3])[CH3:2].Br[C:36]1[CH:37]=[C:38]([NH:44][C:45]2[CH:49]=[C:48]([CH3:50])[O:47][N:46]=2)[C:39](=[O:43])[N:40]([CH3:42])[CH:41]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C.O>[C:1]([O:4][CH2:5][C:6]1[C:7]([N:21]2[C:33](=[O:34])[C:32]3[S:31][C:30]4[CH2:29][CH2:28][CH2:27][CH2:26][C:25]=4[C:24]=3[CH:23]=[N:22]2)=[N:8][CH:9]=[CH:10][C:11]=1[C:36]1[CH:37]=[C:38]([NH:44][C:45]2[CH:49]=[C:48]([CH3:50])[O:47][N:46]=2)[C:39](=[O:43])[N:40]([CH3:42])[CH:41]=1)(=[O:3])[CH3:2]
Reactant: Cc1cc(Nc2cc(Br)cn(C)c2=O)no1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1-n1ncc2c3c(sc2c1=O)CCCC3
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CC(=O)OCc1c(-c2cc(Nc3cc(C)on3)c(=O)n(C)c2)ccnc1-n1ncc2c3c(sc2c1=O)CCCC3
Temperature: 100 °C
Reaction time: 3 h
Yield: 60.1 %

Procedure:
A 50-mL round-bottomed flask equipped with a reflux condenser was charged with (2-{6-oxo-8-thia-4,5-diazatricyclo[7.4.0.02,7]trideca-1(9),2(7),3-trien-5-yl}-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)methyl acetate 230i (150 mg, 0.31 mmol), 5-bromo-1-methyl-3-(5-methylisoxazol-3-ylamino)pyridine-2(1H)-one 283a (88 mg, 0.31 mmol), PdCl2(dppf) (24 mg, 0.031 mmol), K3PO4 (131 mg, 0.62 mmol), sodium acetate (61 mg, 0.62 mmol), water (0.2 mL), and acetonitrile (10 mL). The system was subjected to three cycles of vacuum/argon flush and stirred at 100° C. for 3 h. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was partitioned between dichloromethane (20 mL) and water (10 mL). The organic layer was separated and the water layer was extracted with dichloromethane (2×20 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The dark residue was purified by silica-gel column chromatography eluting with 30:1 dichloromethane/methanol to afford 291a (104 mg, 60%) as a yellow solid. MS-ESI: [M+H]+ 559.1
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][NH:9][C:10]([C:12]2[C:13](=[O:31])[N:14]([CH2:27][CH2:28][O:29]C)[C:15]3[C:20]([C:21]=2[CH3:22])=[CH:19][CH:18]=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:16]=3)=[O:11])[CH:5]=[CH:6][CH:7]=1.BrB(Br)Br.CCOC(C)=O.CCCCCC>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][NH:9][C:10]([C:12]2[C:13](=[O:31])[N:14]([CH2:27][CH2:28][OH:29])[C:15]3[C:20]([C:21]=2[CH3:22])=[CH:19][CH:18]=[C:17]([C:23]([F:25])([F:26])[F:24])[CH:16]=3)=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: COCCn1c(=O)c(C(=O)NCc2cccc(F)c2)c(C)c2ccc(C(F)(F)F)cc21
Agent: BrB(Br)Br
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1c(C(=O)NCc2cccc(F)c2)c(=O)n(CCO)c2cc(C(F)(F)F)ccc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 96.7 %

Procedure:
To a solution of 800 mg (1.83 mmol) N-[(3-fluorophenyl)-methyl]-1-(2-methoxy-ethyl)-4-methyl-2-oxo-7-(trifluoromethyl)-1H-quinoline-3-carboxylic acid amide (example 4) in DCM (30 ml) was added 0.26 ml (2.7 mmol) tribromoborane at −78° C. The reaction mixture was stirred at 0° C. for 2 h. Then the reaction mixture was cooled to −78° C. and quenched with a sat. NaHCO3 sol. The reaction mixture was diluted with DCM (20 ml) and washed with a sat. NaHCO3 sol. (20 ml), brine (20 ml), and water (20 ml), dried over Na2SO4 and concentrated in vacuum. After CC (EtOAc/hexane 1:4) of the residue, 750 mg (1.77 mmol, 97%) N-[(3-Fluorophenyl)-methyl]-1-(2-hydroxy-ethyl)-4-methyl-2-oxo-7-(trifluoromethyl)-1H-quinoline-3-carboxylic acid amide (example 38) were obtained. MS: m/z 423.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[C:8]([Br:11])[C:9]=1[OH:10])=[O:4].[C:12](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[C:8]([Br:11])[C:9]=1[O:10][CH3:12])=[O:4]
Reactant: COC(=O)c1scc(Br)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)c1scc(Br)c1OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 129.3 %

Procedure:
Methyl-3-hydroxy-4-bromo-2-thiophenecarboxylate (10.0 g, 42.2 mmol) was dissolved in 250 mL of acetone. Potassium carbonate (30.0 g, 217.4 mmol) was added followed by a solution of iodomethane (14.5 mL, 233.0 mmol). The mixture was heated to reflux and continued for 6 h. After cooled to room temperature, the mixture was filtered, the solid material was rinsed with acetone (˜200 mL). The filtrate and rinsing were concentrated under reduced pressure to a solid, further dried on high vacuum, yielding 13.7 g (100%) of methyl-3-methoxy-4-bromo-2-thiophenecarboxylate (MH+=251.0).