Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:19]O)[CH:7]=1)[CH3:2].P(Br)(Br)[Br:23]>O1CCOCC1>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:19][Br:23])[CH:7]=1)[CH3:2]
Reactant: BrP(Br)Br
Reactant: CCOC(=O)Cc1cccc(Oc2ccccc2CO)c1
Solvent: C1COCCO1
Product: CCOC(=O)Cc1cccc(Oc2ccccc2CBr)c1
Reaction time: 1 h
Yield: 54.7 %

Procedure:
To [3-(2-hydroxymethyl-phenoxy)-phenyl]-acetic acid ethyl ester (0.90 g, 3.14 mmol) in 1,4-dioxane was added phosphorus tribromide (0.38 mL, 4.1 mmol), and the reaction was stirred for 1 hour at mom temperature. After work-up, 0.6 g of the desired product was obtained.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH:11]2[CH2:13][CH2:12]2)[N:5]=[C:4]([NH:14][CH2:15][CH2:16][OH:17])[N:3]=1.Cl.[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[CH:11]1([NH:10][C:6]2[C:7]([C:8]#[N:9])=[C:2]([N:29]3[CH2:30][CH2:31][CH:26]([C:23]4[CH:22]=[CH:21][C:20]([F:19])=[CH:25][CH:24]=4)[CH2:27][CH2:28]3)[N:3]=[C:4]([NH:14][CH2:15][CH2:16][OH:17])[N:5]=2)[CH2:13][CH2:12]1
Reactant: N#Cc1c(Cl)nc(NCCO)nc1NC1CC1
Reactant: Fc1ccc(C2CCNCC2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: N#Cc1c(NC2CC2)nc(NCCO)nc1N1CCC(c2ccc(F)cc2)CC1

Procedure:
In analogy to the procedure described in example 20b, the 4-chloro-6-cyclopropylamino-2-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile was treated with the 4-(4-fluoro-phenyl)-piperidine hydrochloride in dioxane in the presence of N-ethyl-diisopropyl-amine at 90° C. to yield 4-cyclopropylamino-6-[4-(4-fluoro-phenyl)-piperidin-1-yl]-2-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile as an amorphous, light brown solid; MS: [M+H]+=397.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)[CH:12]3[CH2:13][NH:14][CH2:15][CH2:16][N:11]3[C:10](=[O:17])[O:9]2)=[CH:4][CH:3]=1.[F:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[N:33]=[C:34]=[O:35]>O1CCCC1.O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)[CH:12]3[CH2:13][N:14]([C:34]([NH:33][C:27]4[CH:28]=[CH:29][C:30]([F:32])=[CH:31][C:26]=4[F:25])=[O:35])[CH2:15][CH2:16][N:11]3[C:10](=[O:17])[O:9]2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(C2(c3ccc(C)cc3)OC(=O)N3CCNCC32)cc1
Reactant: O=C=Nc1ccc(F)cc1F
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C2(c3ccc(C)cc3)OC(=O)N3CCN(C(=O)Nc4ccc(F)cc4F)CC32)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 67.6 %

Procedure:
To a solution of 1,1-bis(4-methylphenyl)-hexahydro-3H-oxazolo[3,4-a]pyrazin-3-one (0.20 g, 0.62 mmol) in tetrahydrofuran (6 mL) was added 2,4-difluorophenyl isocyanate (0.090 mL, 0.76 mmol) at 0° C., and the mixture was stirred at 0° C. for 1 hour. The reaction solution was diluted with water and then extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. The solid was filtered off, and the filtrate was concentrated. The residue was purified with silica gel column chromatography (hexane:ethyl acetate=98:2 to hexane:ethyl acetate=1:1), and then recrystallized from diisopropyl ether to obtain the title compound (0.20 g, yield 68%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:13])=[C:6]([C:8]2[S:9][CH:10]=[CH:11][N:12]=2)[CH:7]=1.C([Sn](CCCC)(CCCC)[C:19]1[N:23]2[CH:24]=[CH:25][C:26]([C:28]([F:31])([F:30])[F:29])=[N:27][C:22]2=[N:21][CH:20]=1)CCC>>[F:13][C:5]1[CH:4]=[CH:3][C:2]([C:19]2[N:23]3[CH:24]=[CH:25][C:26]([C:28]([F:29])([F:30])[F:31])=[N:27][C:22]3=[N:21][CH:20]=2)=[CH:7][C:6]=1[C:8]1[S:9][CH:10]=[CH:11][N:12]=1
Reactant: Fc1ccc(Br)cc1-c1nccs1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(F)(F)F)ccn12
Product: Fc1ccc(-c2cnc3nc(C(F)(F)F)ccn23)cc1-c1nccs1

Procedure:
2-(5-Bromo-2-fluorophenyl)thiazole (50 mg, 0.2 mmol) was coupled to 3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine (0.3 mmol) by the method of Example 32. Purification by chromatography on silica gel eluting with dichloromethane containing 1% methanol gave 3-[4-fluoro-3-(thiazol-2-yl)phenyl]-7-trifluoromethylimidazo[1,2-α]pyrimidine as a yellow solid: δH (400 MHz, CDCl3) 7.29 (1H, d, J 7), 7.44 (1H, dd, J 11 and 9), 7.56-7.62 (2H, m), 7.97 (1H, dd, J 3 and 2), 8.15 (1H, s), 8.57 (1H, dd, J 7 and 2), 8.86 (1H, d, J 7); m/z (ES+) 364 (M++H).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:5]=[CH:4][CH:3]=1.[NH2:15][C:16]1[S:17][C:18]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[F:30])=[CH:19][C:20]=1[C:21]([NH2:23])=[O:22]>>[F:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:18]1[S:17][C:16]([NH:15][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]([CH2:8][N:9]3[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)[N:7]=2)=[C:20]([C:21]([NH2:23])=[O:22])[CH:19]=1
Reactant: Brc1cccc(CN2CCOCC2)n1
Reactant: NC(=O)c1cc(-c2ccccc2F)sc1N
Product: NC(=O)c1cc(-c2ccccc2F)sc1Nc1cccc(CN2CCOCC2)n1

Procedure:
The title compound was prepared according to the general procedure in Example 1 using 4-[(6-bromopyridin-2-yl)methyl]morpholine (53 mg, 0.206 mmol) and 2-amino-5-(2-fluorophenyl)thiophene-3-carboxamide (49.6 mg, 0.210 mmol) as the starting materials.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[S:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[C:20]([C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25]Br)#[N:21]>>[C:20]([C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][N:7]1[C:8]([S:9][C:10]2[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]1=[O:18])#[N:21]
Reactant: CCc1c(Sc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Reactant: N#Cc1cccc(CBr)c1
Product: CCc1c(Sc2cc(C)cc(C)c2)n(Cc2cccc(C#N)c2)c(=O)[nH]c1=O
Yield: 47.3 %

Procedure:
5-Ethyl-6-(3,5-dimethylphenyl)thio-2,4-pyrimidinedione and 3-cyanobenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (185 mg, yield: 47.3%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[OH:10].CC#N.C([O-])([O-])=O.[K+].[K+].[CH2:20](Cl)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[O:10][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: ClCc1ccccc1
Reactant: COc1ccc(Br)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1ccc(Br)c(OCc2ccccc2)c1
Temperature: 25 °C
Yield: 102.5 %

Procedure:
A 12 L four-necked round-bottomed flask equipped with mechanical stirrer, thermometer and reflux condenser with nitrogen inlet was charged with 2-bromo-5-methoxyphenol (615 g, 2.98 mol), CH3CN (6 L), K2CO3 (671 g, 4.77 mol), benzyl chloride (363 mL, 3.14 mol), and KI (6 g, 0.036 mol). The mixture was heated to reflux for 3 h, cooled to room temperature, and H2O (3 L) added to form a biphasic mixture. The aqueous layer was separated, CH3CN (3 L) removed in vacuo and EtOAc (4 L) added to extract the product. After a wash with H2O (3 L) and 10% NaCl solution (1.8 L), the organic layer was concentrated to dryness to afford 1-bromo-4-methoxy-2-(phenylmethoxy)benzene as a light yellow oil (895.5 g, 99%): bp 110° C. (2.5 mm Hg); 1H NMR δ 7.55-7.25 (m, 6 H), 6.55 (d, J=2.7 Hz, 1 H), 6.35 (dd, J=8.5 Hz, 1.5 Hz, 1 H), 5.1 (s, 2 H), 3.75 (s, 3 H).
Reaction SMILES: [C:1]([CH2:4][N:5]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([C@@H:14]2[CH2:18][C@H:17]([S:19][C:20]3[C@H:21]([CH3:44])[C@@H:22]4[C@@H:39]([C@H:40]([OH:42])[CH3:41])[C:38](=[O:43])[N:23]4[C:24]=3[C:25]([O:27]CC3C=CC([N+]([O-])=O)=CC=3)=[O:26])[CH2:16][N:15]2C(OCC2C=CC([N+]([O-])=O)=CC=2)=O)=[O:13])[CH2:7][CH2:6]1)(=[O:3])[NH2:2].[ClH:58]>O1CCCC1.O>[ClH:58].[C:1]([CH2:4][N:5]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([C@@H:14]2[CH2:18][C@H:17]([S:19][C:20]3[C@H:21]([CH3:44])[C@@H:22]4[C@@H:39]([C@H:40]([OH:42])[CH3:41])[C:38](=[O:43])[N:23]4[C:24]=3[C:25]([OH:27])=[O:26])[CH2:16][NH:15]2)=[O:13])[CH2:7][CH2:6]1)(=[O:3])[NH2:2]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CCCN(CC(N)=O)CC4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](C(=O)N4CCCN(CC(N)=O)CC4)C3)[C@H](C)[C@H]12

Procedure:
200 mg of 4-nitrobenzyl (1R, 5S, 6S)-2-[(2S, 4S)-2-(4-carbamoylmethyl-1-homopiperazinylcarbonyl)-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate [prepared as described in step (a) above] were dissolved in 20 ml of a 1:1 by volume mixture of tetrahydrofuran and water, after which 0.18 ml of 1N aqueous hydrochloric acid were added to the mixture, which was then hydrogenated by bubbling hydrogen through it at room temperature for 2 hours in the presence of 0.3 g of 10% w/w palladium-on-charcoal. The catalyst was then filtered off, and the filtrate was extracted with diethyl ether. The aqueous layer was concentrated by evaporation under reduced pressure, and the resulting residue was purified by column chromatography through a Lobar column (a product of Merck, LiChroprep RP-8, size B), using water as the eluent. Those fractions containing the title compound were combined, concentrated by evaporation under reduced pressure and lyophilized, to give 30 mg of the title compound as a colorless powder.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[N:3]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[NH2:21]>CCOC(C)=O.C1CCCCC1>[CH3:28][O:27][C:23]1[CH:22]=[C:20]([NH:21][C:2]2[CH:7]=[N:6][CH:5]=[C:4]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=3)[N:3]=2)[CH:19]=[C:18]([O:17][CH3:16])[C:24]=1[O:25][CH3:26]
Reactant: Clc1cccc(Oc2cncc(Cl)n2)c1
Reactant: COc1cc(N)cc(OC)c1OC
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: COc1cc(Nc2cncc(Oc3cccc(Cl)c3)n2)cc(OC)c1OC
Yield: 43 %

Procedure:
Using Method EE with 2-chloro-6-(3-chlorophenyloxy)-pyrazine (200 mg, 0.83 mmol) and 3,4,5-trimethoxyaniline (183 mg, 1.00 mmol), and purification by column chromatography (AcOEt:cyclohexane, 1:1), the title compound was obtained (165 mg). Yield: 43%. 1H NMR (250 MHz, DMSO-d6) δ 3.43 (s, 6H, [CH3O]3+5), 3.54 (s, 3H, [CH3O]4), 6.76 (s, 2H, Harom2′+6′), 7.18 (d, 1H, Harom 4, J=6.5 Hz), 7.28 (d, 1H, Harom 6, J=6.7 Hz), 7.36 (s, 1H, Harom 2), 7.43 (t, 1H, Harom 5, J=8.1 Hz), 7.79 (s, 1H, HPz 5), 7.98 (s, 1H, HPz 3), 9.62 (s, 1H, NH).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([NH:14]C(=O)C)[CH:7]=[CH:8][C:9]=1[S:10](=[O:13])(=[O:12])[NH2:11].Cl>O>[NH2:14][C:6]1[CH:7]=[CH:8][C:9]([S:10]([NH2:11])(=[O:12])=[O:13])=[C:4]([F:3])[CH:5]=1
Reactant: CC(=O)Nc1ccc(S(N)(=O)=O)c(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1ccc(S(N)(=O)=O)c(F)c1
Temperature: 25 °C

Procedure:
To a stirred solution of sodium hydroxide (120 g, 3 mol) in water (500 ml) was added N-(3-Fluoro-4-sulfamoyl-phenyl)-acetamide (69.7 g, 300 mmol). The reaction mixture was stirred at reflux temperature for 3 hours. The solution was then cooled to room temperature, and the pH was adjusted to 6 by addition of 5N HCl solution. Most of the solvent was removed in vacuo, and the product precipitated out. The product was collected by filtration and drying under vacuum at 60° C. (32 g, 56%).
Reaction SMILES: CC1(C)[O:38][C@H:5]2[O:6][C@H:7]([CH2:15][N:16]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:18]4([C:36]5[C:27](=[CH:28][C:29]6[O:34][CH2:33][CH2:32][O:31][C:30]=6[CH:35]=5)[O:26][CH2:25]4)[C:17]3=[O:37])[C@@H:8]3[O:12]C(C)(C)[O:10][C@@H:9]3[C@H:4]2[O:3]1>FC(F)(F)C(O)=O>[O:37]=[C:17]1[C:18]2([C:36]3[C:27](=[CH:28][C:29]4[O:34][CH2:33][CH2:32][O:31][C:30]=4[CH:35]=3)[O:26][CH2:25]2)[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:16]1[CH2:15][C@H:7]1[O:6][CH:5]([OH:38])[C@H:4]([OH:3])[C@@H:9]([OH:10])[C@H:8]1[OH:12]
Reactant: CC1(C)O[C@H]2[C@@H](O1)[C@@H](CN1C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc31)O[C@@H]1OC(C)(C)O[C@@H]12
Solvent: O=C(O)C(F)(F)F
Product: O=C1N(C[C@H]2OC(O)[C@H](O)[C@@H](O)[C@H]2O)c2ccccc2C12COc1cc3c(cc12)OCCO3
Temperature: 25 °C
Reaction time: 3 h
Yield: 6.6 %

Procedure:
1′-{[(3aR,5R,5aS,8aS,8bR)-2,2,7,7-tetramethyltetrahydro-3aH-bis[1,3]dioxolo[4,5-b:4′,5′-d]pyran-5-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.45 g, 0.83 mmol) was suspended in 80% v/v aqueous trifluoroacetic acid (40 mL) and the reaction mixture was stirred at ambient temperature for 3 h. The reaction mixture was concentrated in vacuo and the residue recrystallized from ethanol to afford 6-deoxy-6-(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]-benzodioxine-8,3′-indol]-1′(2′H)-yl)-D-galactopyranose (0.025 g, 7%) as an off white solid: mp 122-126° C. (ethanol); 13C NMR (75 MHz, CDCl3) δ178.5, 155.2, 155.2, 155.1, 155.0, 144.5, 142.6, 142.2, 142.1, 138.0, 138.0, 132.3, 132.0, 129.0, 123.5, 123.4, 121.0, 120.9, 111.6, 111.4, 109.9, 109.7 99.2, 92.7, 79.9, 64.4, 63.8, 60.4, 58.0, 21.0, 14.2; MS (ES+) m/z 480.0 (M+23).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]2[CH:17]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:15]3[C:10](=[CH:11][C:12](I)=[CH:13][CH:14]=3)[N:9]2[CH:25]=1)=[O:5])[CH3:2].[SH:26][C:27]1[CH:28]=[C:29]([C:33]2([C:39]#[N:40])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[CH:30]=[CH:31][CH:32]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.CCN(C(C)C)C(C)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]2[CH:17]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:15]3[C:10](=[CH:11][C:12]([S:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]5([C:39]#[N:40])[CH2:34][CH2:35][O:36][CH2:37][CH2:38]5)[CH:28]=4)=[CH:13][CH:14]=3)[N:9]2[CH:25]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn2c(cc(-c3ccccc3)c3ccc(I)cc32)n1
Reactant: N#CC1(c2cccc(S)c2)CCOCC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCOC(=O)c1cn2c(cc(-c3ccccc3)c3ccc(Sc4cccc(C5(C#N)CCOCC5)c4)cc32)n1
Temperature: 60 °C

Procedure:
1v (262 mg, 0.59 mmol), 4-(3-Mercapto-phenyl)-tetrahydro-pyran-4-carbonitrile (1w, 130 mg, 0.59 mmol), Pd2dba3 (14 mg, 0.01 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (17 mg, 0.03 mmol), and iPr2NEt (0.27 mL, 1.9 mmol) were dissolved in 1,4-dioxane (2 mL) and degassed with N2 for 10 minutes. The mixture was heated at 60° C. for 2 hours, then cooled to room temperature and concentrated. The residue was purified by silica gel chromatography to give the desired product, 1z.
Reaction SMILES: C1N=CN([C:6](N2C=NC=C2)=[S:7])C=1.[NH2:13][C:14]1[C:15](=[O:32])[N:16]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)[N:17]=[CH:18][C:19]=1[NH2:20]>O1CCCC1>[SH:7][C:6]1[NH:13][C:14]2[C:15](=[O:32])[N:16]([CH2:21][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=[CH:24][CH:23]=3)[N:17]=[CH:18][C:19]=2[N:20]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Nc1cnn(Cc2cccc3ccccc23)c(=O)c1N
Solvent: C1CCOC1
Product: O=c1c2[nH]c(S)nc2cnn1Cc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4.99 g (28.0 mmol) of N,N′-thiocarbonyldiimidazole were added to a solution of 4.4 g (16.5 mmol) of 4,5-diamino-2-naphthalen-1-ylmethyl-2H-pyridazin-3-one in 100 ml of tetrahydrofuran and stirred overnight at ambient temperature. Then the mixture was concentrated by evaporation in vacuo, the residue was combined with approx. 30 ml of water, made weakly acidic with hydrochloric acid, the product precipitated was suction filtered, washed with water and dried.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH3:7])[C:4]([C:8]([OH:10])=O)=[N:3]1.S(Cl)([Cl:13])=O>>[CH3:1][N:2]1[CH:6]=[C:5]([CH3:7])[C:4]([C:8]([Cl:13])=[O:10])=[N:3]1
Reactant: Cc1cn(C)nc1C(=O)O
Reactant: O=S(Cl)Cl
Product: Cc1cn(C)nc1C(=O)Cl

Procedure:
1,4-Dimethyl-1H-pyrazole-3-carboxylic acid (190 mg) was weighed to a round bottom flask and thionyl chloride (1 ml) was added. The reaction was heated to reflux for 6 h then overnight at RT. After this time thionyl chloride was evaporated and the residue azeotroped with toluene to afford the title compound, 200 mg.
Reaction SMILES: [C:1]([NH:9][CH:10]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]#[N:23])[CH:17]=1)[C:11]([O:13][CH3:14])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24](OC)(=[O:32])[C:25]1[C:26](=[CH:28][CH:29]=[CH:30][CH:31]=1)[SH:27].C(N(CC)CC)C>C1(C)C(C)=CC=CC=1>[C:1]([NH:9][CH:10]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]2[S:27][C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[C:24](=[O:32])[N:23]=2)[CH:17]=1)[C:11]([O:13][CH3:14])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccccc1S
Reactant: COC(=O)C(Cc1cccc(C#N)c1)NC(=O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1C
Product: COC(=O)C(Cc1cccc(-c2nc(=O)c3ccccc3s2)c1)NC(=O)c1ccccc1
Temperature: 145 °C
Reaction time: 15 h
Yield: 17.1 %

Procedure:
A mixture of methyl 2-(benzoylamino)-3-(3-cyanophenyl)propionate (201 mg, 0.652 mmol), methyl thiosalicylate (165 mg, 0.981 mmol), triethylamine (0.18 mL, 1.3 mmol) and xylene (0.65 ml) was stirred at 145° C. for 15 hours under a nitrogen flow. The reaction mixture was applied to silica gel column chromatography (gradient elution with hexane-ethyl acetate from 67:33 to 50:50). The eluate was crystallized from ethyl acetate-diisopropyl ether to give the title compound (49.7 mg, 17%).
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:15]=[C:14]([CH:16]=[O:17])[N:13]=[C:12]([CH3:18])[N:11]=2)=[O:9])=[CH:4][C:3]=1[O:21][CH3:22].[CH3:23][Mg]Br>C1COCC1.CCOCC>[F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:15]=[C:14]([CH:16]([OH:17])[CH3:23])[N:13]=[C:12]([CH3:18])[N:11]=2)=[O:9])=[CH:4][C:3]=1[O:21][CH3:22]
Reactant: COc1cc(CNC(=O)c2cc(C=O)nc(C)n2)ccc1F
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cc(CNC(=O)c2cc(C(C)O)nc(C)n2)ccc1F
Temperature: -78 °C
Reaction time: 4 h
Yield: 47.6 %

Procedure:
A solution of N-(4-fluoro-3-methoxybenzyl)-6-formyl-2-methylpyrimidine-4-carboxamide (2 g, 6.59 mmol, Preparation #8) in THF (200 mL) was cooled to about −78° C. and methyl magnesium bromide was added drop wise (8.79 mL, 26.4 mmol, 3M in ether). Upon completion of addition, the reaction mixture stirred for about 4 h at −78° C. The reaction mixture was quenched with aqueous ammoniumchloride (20 mL) and the product extracted with EtOAc (2×100 mL). The organic layer was washed successively with water (1×50 mL), brine (1×50 mL), dried over sodium sulphate and concentrated under reduced pressure to afford N-(4-fluoro-3-methoxybenzyl)-6-(1-hydroxyethyl)-2-methylpyrimidine-4-carboxamide (1 g, 47.6% yield) as a light yellow solid. 1H NMR (400 MHz, DMSO): δ 9.40 (bs, 1H) 7.95 (s, 1H) 7.17-7.11 (m, 2H) 6.89-6.88 (m, 1H) 5.75-5.71 (m, 1H) 4.49-4.47 (m, 2H) 3.81 (s, 3H) 2.68 (s, 3H) MS m/z=320 (m+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([O:14][CH3:15])[C:12]=1[OH:13])[C:6]([O:8][CH3:9])=[O:7].Cl.Cl[CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[C:11]([O:14][CH3:15])[C:12]([O:13][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COC(=O)c1cc(OC)c(O)c(OC)c1
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OC)c(OCCN2CCOCC2)c(OC)c1
Yield: 105.2 %

Procedure:
To a solution of methyl 3,5-dimethoxy-4-hydroxybenzoate (3.0 g, 14 mmol) in DMF (10 mL) was added 4-(2-chloroethyl)-morpholine hydrochloride (3.99 g, 21 mmol) and solid K2CO3 (8.4 g, 60 mmol). The mixture was heated at 60 C under N2 for 30 h. Diluted with EtOAc (100 mL) and washed with H2O (2×50 mL), back extracted the aqueous phase, and washed combined organics with brine. Dried over Na2SO4, filtered and evaporated to give the product as a brown solid (4.79 g, quantitative). 1H-NMR (CDCl3, 500 MHz7.28 (s, 2H), 4.15 (t, 2H), 3.91 (s, 3H), 3.88 (s, 6H), 3.75-3.71 (m, 4H), 2.78 (t, 2H), 2.59 (br s, 4H) ppm; MS (FIA) 326.17 (M+H)
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:19])[N:4]([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:5]([CH:8]([CH3:10])[CH3:9])=[CH:6][CH:7]=1.CN1CCOCC1.[C:27]1([CH3:37])[CH:32]=[CH:31][CH:30]=[C:29]([S:33](Cl)(=[O:35])=[O:34])[CH:28]=1>C(Cl)Cl>[CH3:37][C:27]1[CH:28]=[C:29]([S:33]([NH:1][C:2]2[C:3](=[O:19])[N:4]([CH2:11][C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[C:5]([CH:8]([CH3:9])[CH3:10])=[CH:6][CH:7]=2)(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Reactant: CC(C)c1ccc(N)c(=O)n1CC(=O)OC(C)(C)C
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: Cc1cccc(S(=O)(=O)Nc2ccc(C(C)C)n(CC(=O)OC(C)(C)C)c2=O)c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 87.5 %

Procedure:
3-Amino-6-isopropyl-1-(tert-butoxycarbonylmethyl)-2-pyridinone (assumed to be 3.37 mmol), as prepared in the preceding step, and N-methylmorpholine (1.0 mL, 9.1 mmol) were dissolved in methylene chloride (20 mL) and cooled to 0° C. A solution of m-toluenesulfonyl chloride (0.67 g, 3.5 mmol) in methylene chloride (5 mL) was added and the reaction stirred at ambient temperature for 16 hours. After evaporation in vacuo, the crude product was dissolved in methylene chloride, washed with 10% aqueous citric acid, saturated NaHCO3, and brine, dried over MgSO4, and filtered. The evaporated filtrate gave the title compound (1.24 g, 88%) as a tan solid. 1H NMR (300 MHz, CDCl3) δ7.65 (m, 2H), 7.58 (br s, 1H), 7.46 (d, 1H, J=7.8 Hz), 7.33 (m, 2H), 6.08 (d, 1H, J=7.9 Hz), 4.69 (s, 2H), 2.67 (m, 1H), 2.38 (s, 3H), 1.41 (s, 9H), 1.22 (s, 3H), 1.19 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[S:12][CH:13]=[C:14]([CH2:16][OH:17])[N:15]=3)[S:10][C:3]=12.[CH:18]1([CH2:21][NH:22][C:23]([C:25]2[C:26]3[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][C:27]=3[S:28][C:29]=2[CH3:30])=[O:24])[CH2:20][CH2:19]1.C([O-])([O-])=O.[Cs+].[Cs+]>>[CH:18]1([CH2:21][NH:22][C:23]([C:25]2[C:26]3[CH:34]=[CH:33][C:32]([O:35][C:2]4[CH:7]=[CH:6][N:5]=[C:4]5[CH:8]=[C:9]([C:11]6[S:12][CH:13]=[C:14]([CH2:16][OH:17])[N:15]=6)[S:10][C:3]=45)=[CH:31][C:27]=3[S:28][C:29]=2[CH3:30])=[O:24])[CH2:20][CH2:19]1
Reactant: Cc1sc2cc(O)ccc2c1C(=O)NCC1CC1
Reactant: OCc1csc(-c2cc3nccc(Cl)c3s2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1sc2cc(Oc3ccnc4cc(-c5nc(CO)cs5)sc34)ccc2c1C(=O)NCC1CC1
Yield: 37.4 %

Procedure:
This material was prepared by reacting [2-(7-chlorothieno[3,2-b]pyridin-2-yl)-1,3-thiazol-4-yl]methanol (85 mg, 0.30 mmole) with 6-hydroxy-2-methylbenzo[b]thiophene-3-carboxylic acid (cyclopropylmethyl)amide 130a (94 mg, 0.36 mmole) and Cs2CO3 (195 mg, 0.60 mmole) in a manner similar to that previously described for example 1 to give a yellow solid (57 mg, 25%). 1H NMR (DMSO-d6, 300 MHz) δ 8.56 (1H, d, J=5.46 Hz), 8.49 (1H, t, J=5.75 Hz), 8.17 (1H, s), 7.98 (1H, d, J=2.26 Hz), 7.84 (1H, d, J=8.67 Hz), 7.65 (1H, s), 7.36 (1H, dd, J=2.35, 8.76 Hz), 6.80 (1H, d, J=5.46 Hz), 4.60 (2H, s), 3.20 (2H, t, J=6.22 Hz), 2.62 (3H, s), 1.07 (1H, m), 0.47 (2H, m), 0.26 (2H, m).