Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:11]=[CH:10][C:8]([OH:9])=[C:6]([OH:7])[CH:5]=1.C1C=CC(CCCN2CCN(CCOC(C3C=CC(F)=CC=3)C3C=CC(F)=CC=3)CC2)=CC=1>>[NH2:1][CH2:2][CH2:3][C:4]1[CH2:5][CH:6]([C:8](=[CH:10][CH:11]=1)[OH:9])[OH:7]
Reactant: NCCc1ccc(O)c(O)c1
Agent: Fc1ccc(C(OCCN2CCN(CCCc3ccccc3)CC2)c2ccc(F)cc2)cc1
Product: NCCC1=CC=C(O)C(O)C1
Temperature: 37 °C
Reaction time: 0.25 h

Procedure:
Uptake of tritiated dopamine (3H-DA) is performed in cultures at day 6 or day 7 as described previously (Friedman and Mytilineou (1987) Neurosci. Lett. 79:65-72) with minor modifications, and all the solutions are maintained at 37° C. Briefly, the culture medium is removed, rinsed twice with 0.25 ml of the uptake buffer which consists of Krebs-Ringer's phosphate buffer, pH 7.4, containing 5.6 mM glucose, 1.3 mM EDTA, 0.1 mM ascorbic acid and 0.5 mM pargyline, an inhibitor of monoamine oxidase. The cultures are incubated with 0.25 ml of 50 nM 3H-DA (New England Nuclear, Boston, Mass. sp. act 36-37 Ci/mmol) for 15 minutes at 37° C. 3H-DA uptake is stopped by removing the incubation mixture and cells are then washed twice with 0.5 ml of the uptake buffer. In order to release 3H-DA from the cells, the cultures are incubated with 0.5 ml of 95% ethanol for 30 min at 37° C., and then added to 10 ml of EcoLite (ICN, Irvine, Calif.) and counted on a scintillation counter. Blank values are obtained by adding to the uptake buffer 0.5 mM GBR-12909 (RBI), a specific inhibitor of the high-affinity uptake pump of the dopamine neurons (Heikkila et al. 1984 Euro J. Pharmacol. 103:241-48).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:14]2[C:9](=[CH:10][C:11]([Cl:15])=[CH:12][CH:13]=2)[NH:8][N:7]=1)=[O:4].[NH:16]1[CH:20]=[N:19][CH:18]=[N:17]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:15][C:11]1[CH:10]=[C:9]2[C:14]([C:6]([NH:5][C:3](=[O:4])[CH2:2][N:16]3[CH:20]=[N:19][CH:18]=[N:17]3)=[N:7][NH:8]2)=[CH:13][CH:12]=1
Reactant: c1nc[nH]n1
Reactant: O=C(CCl)Nc1n[nH]c2cc(Cl)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(Cn1cncn1)Nc1n[nH]c2cc(Cl)ccc12
Yield: 21.2 %

Procedure:
The process is performed as in Example 75, starting with 500 mg of 2-chloro-N-(6-chloro-1H-indazol-3-yl)acetamide, 15 cm3 of acetonitrile, 423 mg of 1,2,4-triazole and 283 mg of potassium carbonate. The reaction medium is refluxed for 4 hours and then concentrated to dryness under reduced pressure (2 kPa; 50° C.); the crude product obtained is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 2.5 cm), eluting with ethyl acetate. The fractions containing the expected product are combined, evaporated under reduced pressure (2 kPa; 50° C.) and dried (90 Pa; 45° C.) to give 120 mg of N-(6-chloro-1H-indazol-3-yl)-1H-1,2,4-triazole-1-acetamide in the form of a white powder melting above 260° C.
Reaction SMILES: C(SC1C=C(O)C(=O)NC=1)C1C=CC=CC=1.[Cl:17][C:18]1[CH:35]=[CH:34][CH:33]=[CH:32][C:19]=1[CH2:20][S:21][C:22]1[CH:23]=[C:24]([O:30]C)[C:25]([O:28]C)=[N:26][CH:27]=1>>[Cl:17][C:18]1[CH:35]=[CH:34][CH:33]=[CH:32][C:19]=1[CH2:20][S:21][C:22]1[CH:23]=[C:24]([OH:30])[C:25](=[O:28])[NH:26][CH:27]=1
Reactant: COc1cc(SCc2ccccc2Cl)cnc1OC
Agent: O=c1[nH]cc(SCc2ccccc2)cc1O
Product: O=c1[nH]cc(SCc2ccccc2Cl)cc1O

Procedure:
Prepared as described for 5-(benzylsulfanyl)-3-hydroxypyridin-2(1H)-one (Example 1) from 5-[(2-chlorobenzyl)sulfanyl]-2,3-dimethoxypyridine (Intermediate 10).
Reaction SMILES: C(OC([N:11]1[C@@H:15]([CH3:16])[CH2:14][CH2:13][C@H:12]1[C:17]1[NH:18][C:19]([C:22]2[CH:35]=[C:34]3[O:36][CH2:37][C:31]4[C:32]5[C:33]3=[C:24]([CH2:25][O:26][C:27]=5[CH:28]=[C:29]([C:38]3[NH:42][C:41]([C@@H:43]5[CH2:47][C@H:46]([CH2:48][O:49][CH3:50])[CH2:45][N:44]5[C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])=[N:40][CH:39]=3)[CH:30]=4)[CH:23]=2)=[CH:20][N:21]=1)=O)C1C=CC=CC=1.[CH3:58][O:59][C:60]([NH:62][C@@H:63]([CH:67]([CH3:69])[CH3:68])[C:64](O)=[O:65])=[O:61].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C.CCOC(C)=O.[Pd]>[CH3:58][O:59][C:60]([NH:62][C@@H:63]([CH:67]([CH3:69])[CH3:68])[C:64]([N:11]1[C@@H:15]([CH3:16])[CH2:14][CH2:13][C@H:12]1[C:17]1[NH:18][C:19]([C:22]2[CH:35]=[C:34]3[O:36][CH2:37][C:31]4[C:32]5[C:33]3=[C:24]([CH2:25][O:26][C:27]=5[CH:28]=[C:29]([C:38]3[NH:42][C:41]([C@@H:43]5[CH2:47][C@H:46]([CH2:48][O:49][CH3:50])[CH2:45][N:44]5[C:51]([O:53][C:54]([CH3:56])([CH3:55])[CH3:57])=[O:52])=[N:40][CH:39]=3)[CH:30]=4)[CH:23]=2)=[CH:20][N:21]=1)=[O:65])=[O:61]
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: COC[C@H]1C[C@@H](c2ncc(-c3cc4c5c(c3)OCc3cc(-c6cnc([C@@H]7CC[C@H](C)N7C(=O)OCc7ccccc7)[nH]6)cc(c3-5)OC4)[nH]2)N(C(=O)OC(C)(C)C)C1
Agent: [Pd]
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: COC[C@H]1C[C@@H](c2ncc(-c3cc4c5c(c3)OCc3cc(-c6cnc([C@@H]7CC[C@H](C)N7C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]6)cc(c3-5)OC4)[nH]2)N(C(=O)OC(C)(C)C)C1
Reaction time: 2 h
Yield: 58.5 %

Procedure:
(2S,4S)-tert-butyl 2-(5-(7-(2-((2S,5S)-1-(benzyloxycarbonyl)-5-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromen-2-yl)-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate (300 mg, 0.38 mmol) 10 mL ethanol, and 19 mg 10% Pd/C was stirred under an atmosphere of hydrogen (balloon) overnight. Filtration through celite and concentration afforded the crude amine. The crude amine was dissolved in DMF (4 mL) and then (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (66 mg, 0.38 mmol), HATU (160 mg, 0.42 mmol) and N-methylmorpholine (0.084 mL, 0.76 mmol) were added. After 2 h, the reaction was diluted with EtOAc and washed successively with saturated aqueous NaHCO3, 5% LiCl, and brine. The organic phase was dried over Na2SO4, concentrated, and purified by silica gel chromatography (1% to 20% MeOH/EtOAc) to afford (2S,4S)-tert-butyl 2-(5-(7-(2-((2S,5S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-5-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromen-2-yl)-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate (177 mg, 58%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:16](=[O:24])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[Br:25]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.O>C1C=CC=CC=1>[Br:25][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:17]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:16](=[O:24])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2nc3ccccc3c(=O)n2-c2ccccc2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Solvent: O
Product: O=c1c2ccccc2nc(-c2ccc(CBr)cc2)n1-c1ccccc1

Procedure:
A 0.62 g quantity of 2-(4-methylphenyl)-3-phenyl-4(3H)-quinazolinone, 0.39 g of N-bromosuccinimide (NBS) and 0.05 g of benzoyl peroxide were suspended in 20 ml of benzene and refluxed with heating for 10 hours. After adding 50 ml of water, the reaction mixture was extracted with chloroform. The chloroform layer was washed with water and dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure to give 2-(4-bromomethylphenyl)-3-phenyl-4(3H)-quinazolinone as light yellow crude crystals.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7](Cl)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(C#N)c(Cl)n1
Reactant: C1CCNCC1
Product: CC(C)(C)c1ccc(C#N)c(N2CCCCC2)n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 96.1 %

Procedure:
A mixture of 6-tert-butyl-2-chloronicotinonitrile (Tetrahedron 1965, 21, 2453-2467, 1.5 g, 7.7 mmol) and piperidine (15 ml, 176 mmol) was stirred for 20 hours at room temperature. Then the reaction mixture was evaporated to remove piperidine in vacuo to give the title compound (1.8 g, 98%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH2:10][CH2:11][NH:12][C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][C:14]=1[F:20].C[Al](C)C.[NH:25](/[C:29](/[CH3:35])=[CH:30]\[C:31](OC)=[O:32])[C:26]([CH3:28])=O>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH2:10][CH2:11][NH:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:31](=[O:32])[CH:30]=[C:29]([CH3:35])[N:25]=[C:26]2[CH3:28])=[CH:15][C:14]=1[F:20]
Reactant: Nc1ccc(NCCc2cc3ccccc3[nH]2)c(F)c1
Reactant: COC(=O)/C=C(/C)NC(C)=O
Agent: C[Al](C)C
Solvent: ClCCl
Product: Cc1cc(=O)n(-c2ccc(NCCc3cc4ccccc4[nH]3)c(F)c2)c(C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.5 %

Procedure:
To a solution of N1-(2-(1H-indol-2-yl)ethyl)-2-fluorobenzene-1,4-diamine (2.09 g, 7.76 mmol) in CH2Cl2 (30 mL) was added trimethylaluminium (19.4 mL, 38.8 mmol, 2 M in toluene) slowly. The mixture was stirred at rt for 1 h, followed by the addition of a solution of methyl 3-acetaminocrotonate (2.44 g, 15.52 mmol) in CH2Cl2 (10 mL). The reaction mixture was stirred further at rt for 72 h, then quenched with saturated NH4Cl aqueous solution and extracted with CH2Cl2 (50 mL×2). The combined organic phases were washed with brine (50 mL×3), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=1:1) to give the title compound as a pale yellow solid (0.95 g, 33%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([CH2:18][CH3:19])[S:17][C:13]=2[N:12]2[C:20]([CH2:23][NH:24][C:25]([C:27]3[N:28]([CH2:36][C:37]([O:39]CC)=[O:38])[C:29]4[C:34]([CH:35]=3)=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:26])=[N:21][N:22]=[C:11]2[CH2:10][N:9]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([CH2:18][CH3:19])[S:17][C:13]=2[N:12]2[C:20]([CH2:23][NH:24][C:25]([C:27]3[N:28]([CH2:36][C:37]([OH:39])=[O:38])[C:29]4[C:34]([CH:35]=3)=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:26])=[N:21][N:22]=[C:11]2[CH2:10][N:9]=1
Reactant: CCOC(=O)Cn1c(C(=O)NCc2nnc3n2-c2sc(CC)cc2C(c2ccccc2Cl)=NC3)cc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCc1cc2c(s1)-n1c(nnc1CNC(=O)c1cc3ccccc3n1CC(=O)O)CN=C2c1ccccc1Cl
Reaction time: 4 h
Yield: 79.7 %

Procedure:
Ethyl 2-(4-(2-chlorophenyl)-2-ethyl-6H-thieno[3,2-f] [1,2,4]triazolo[4,3-a] [1,4]diazepin-9-ylmethylcarbamoyl)indole-1-acetate (0.83 g) obtained in Example 61 was dissolved in methanol (20 ml). A 2M aqueous sodium hydroxide solution (1.5 ml) was added, and the mixture was allowed to stand at room temperature for 4 hours. The reaction mixture was concentrated, and the residue was extracted with water. The aqueous layer was washed with ethyl acetate. Citric acid was added to adjust the aqueous layer to about pH 3.0, and the layer was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated, and the residue was crystallized from isopropyl ether to give 0.71 g of crude crystals. The crystals were recrystallized from ethyl acetate to give 0.63 g of 2-(4-(2-chlorophenyl)-2-ethyl-6H-thieno[3,2-f] [1,2,4]triazolo[4,3-a] [1,4]diazepin-9-ylmethylcarbamoyl)indole-1-acetic acid.
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[SH:7].[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([NH:25][CH:26]([CH2:31][CH:32]3[O:34][CH2:33]3)[C:27]([O:29]C)=[O:28])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1>>[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:17]=[CH:18][C:19]([S:22]([NH:25][CH:26]([CH2:31][CH:32]([OH:34])[CH2:33][S:7][C:6]3[CH:5]=[CH:4][O:3][C:2]=3[CH3:1])[C:27]([OH:29])=[O:28])(=[O:23])=[O:24])=[CH:20][CH:21]=2)=[CH:14][CH:15]=1
Reactant: Cc1occc1S
Reactant: COC(=O)C(CC1CO1)NS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1
Product: COc1ccc(-c2ccc(S(=O)(=O)NC(CC(O)CSc3ccoc3C)C(=O)O)cc2)cc1

Procedure:
Example 43 is prepared from 2-methyl-3-furanthiol and 1d using the procedure described for compound 20.
Reaction SMILES: O(P(O[C:18]1[CH2:19][C@@H:20]2[C@@H:30]([C@H:31]([OH:33])[CH3:32])[C:29](=[O:34])[N:21]2[C:22]=1[C:23]([O:25][CH2:26][CH:27]=[CH2:28])=[O:24])(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[CH2:35]([O:38][C:39]([N:41]1[CH2:45][C@@H:44]([SH:46])[CH2:43][C@H:42]1[CH:47]1[N:51]([C:52]([O:54][CH2:55][CH:56]=[CH2:57])=[O:53])[NH:50][C:49](=[O:58])[CH2:48]1)=[O:40])[CH:36]=[CH2:37]>>[CH2:35]([O:38][C:39]([N:41]1[CH2:45][C@@H:44]([S:46][C:18]2[CH2:19][C@@H:20]3[C@@H:30]([C@H:31]([OH:33])[CH3:32])[C:29](=[O:34])[N:21]3[C:22]=2[C:23]([O:25][CH2:26][CH:27]=[CH2:28])=[O:24])[CH2:43][C@H:42]1[CH:47]1[N:51]([C:52]([O:54][CH2:55][CH:56]=[CH2:57])=[O:53])[NH:50][C:49](=[O:58])[CH2:48]1)=[O:40])[CH:36]=[CH2:37]
Reactant: C=CCOC(=O)N1NC(=O)CC1[C@@H]1C[C@H](S)CN1C(=O)OCC=C
Reactant: C=CCOC(=O)C1=C(OP(=O)(Oc2ccccc2)Oc2ccccc2)C[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Product: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](C3CC(=O)NN3C(=O)OCC=C)N(C(=O)OCC=C)C2)C[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Yield: 65.6 %

Procedure:
The same procedure as in Example 8-1 was carried out by using allyl (5R,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-carbapen-2-em-3-carboxylate (195 mg, 0.40 mmol) and (2S,4S)-N-allyloxycarbonyl-2-(1-allyloxycarbonyl-3-pyrazolidinon-5-yl)-4-mercaptopyrrolidine (162 mg, 0.40 mmol) to obtain allyl (5R,6S)-2-[(2S,4S)-N-allyloxycarbonyl-2-(1-allyloxycarbonyl-3-pyrazolidinon-5-yl)pyrrolidin-4-ylthio]-6-[(R)-1-hydroxyethyl]-1-carbapen-2-em-3-carboxylate (155 mg, yield: 65.4%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:18]=[O:19])=[CH:4][C:5]2[C:6]([CH3:17])([CH3:16])[C@@H:7]([CH3:15])[C@H:8]([CH3:14])[C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>CCOCC.O1CCCC1>[CH3:1][C:2]1[C:3]([CH2:18][OH:19])=[CH:4][C:5]2[C:6]([CH3:17])([CH3:16])[C@@H:7]([CH3:15])[C@H:8]([CH3:14])[C:9]([CH3:12])([CH3:13])[C:10]=2[CH:11]=1
Reactant: Cc1cc2c(cc1C=O)C(C)(C)[C@@H](C)[C@H](C)C2(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cc2c(cc1CO)C(C)(C)[C@@H](C)[C@H](C)C2(C)C
Temperature: 25 °C

Procedure:
A solution of 10.00 g (38.7 mmol) of (6S,7S)-3,5,5,6,7,8,8-heptamethyl-5,6,7,8-tetrahydronaphthalene-2-carbaldehyde in ether (50 ml) and tetrahydrofuran (THF, 15 ml) was added dropwise during 45 min to a suspension of LiAlH4 (1.48 g, 39.0 mmol) in ether (55 ml) at 0° C. The reaction mixture was left warming up to room temperature and then heated to reflux for 1.5 h. After cooling to room temperature, the remaining LiAlH4 was quenched with water (2 ml) and NaOH (10%, 2 ml) and water (6 ml) was added. The formation of a white precipitate was observed which was filtered off. Ether was added and the organic phase washed with water, dried (Na2SO4) and concentrated to give 10.11 g (quant.) of the product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12](=[O:19])[O:11][C:10]2=[O:20])[CH:5]=[CH:4][N:3]=1.[C:21]([O:24][CH2:25][C:26](Cl)=[O:27])(=[O:23])[CH3:22]>N1C=CC=CC=1>[O:20]=[C:10]1[N:9]([CH2:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:26]([CH2:25][O:24][C:21](=[O:23])[CH3:22])=[O:27])[CH:7]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:12](=[O:19])[O:11]1
Reactant: Nc1cc(Cn2c(=O)oc(=O)c3ccccc32)ccn1
Reactant: CC(=O)OCC(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)OCC(=O)Nc1cc(Cn2c(=O)oc(=O)c3ccccc32)ccn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 1-(2-amino-pyridin-4-ylmethyl)-1H-benzo[d][1,3]oxazine-2,4-dione (600 mg, see preparation 7b) in pyridine (5 ml) was added acetoxyacetyl chloride (0.29 ml). The reaction mixture was stirred at room temperature for 30 minutes. The solvent was evaporated under reduced pressure. The remaining oil was dissolved in EtOAc and washed with water and brine. The organic layer was concentrated to ca. 10 ml under reduced pressure. The resulting solid material was isolated by filtration and dried in vacuo, affording acetic acid [4-(2,4-dioxo-4H-benzo[d][1,3]oxazin-1-ylmethyl)-pyridin-2-ylcarbamoyl]-methyl ester.
Reaction SMILES: [CH2:1]([N:3]([CH2:16][CH3:17])[C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7](F)[CH:6]=1)[CH3:2].[NH4+:18].[OH-].CCO>>[NH2:18][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][C:8]=1[N+:11]([O-:13])=[O:12])[C:4]([N:3]([CH2:16][CH3:17])[CH2:1][CH3:2])=[O:15]
Reactant: [NH4+]
Reactant: CCN(CC)C(=O)c1ccc([N+](=O)[O-])c(F)c1
Agent: [OH-]
Solvent: CCO
Product: CCN(CC)C(=O)c1ccc([N+](=O)[O-])c(N)c1
Temperature: 25 °C
Yield: 86 %

Procedure:
N,N-Diethyl-3-fluoro-4-nitro-benzamide (5.1 g, 21.2 mmol) was refluxed in a 2:1 mixture of NH4OH/EtOH (150 mL) for 48 h. The solution was cooled to rt and the solvent concentrated. The solution was then extracted (3×) with EtOAc. The combined organic phases were washed with brine and dried over anhydrous MgSO4. The crude product was crystallized from EtOAc/hexanes to give the title compound (4.35 g, 86% yield). 1H NMR (400 MHz, CD3OD) δ 8.12 (d, J=8.8 Hz, 1H), 6.92 (s, 1H), 6.56 (d, J=8.8 Hz, 1H), 3.51 (q, J=7.2 Hz, 2H), 3.28 (m, 2H), 1.23 (t, J=7.2 Hz, 3H), 1.13 (t, J=7.2 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]>C(O)C.[Pd]>[NH2:13][C:10]1[CH:11]=[CH:12][C:2]([F:1])=[C:3]([CH:9]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])ccc1F
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1cc(N)ccc1F
Reaction time: 7 h
Yield: 101.6 %

Procedure:
Ethyl 2-fluoro-5-nitrobenzoate (0.63 g) was dissolved in ethanol (10 ml), and 10% Pd—C (0.064 g) was added to the solution. The mixture was subjected to catalytic reduction at room temperature for 7 hr. The reaction solution was filtered through Celite, and was washed with ethanol. The solvent was then removed by distillation under the reduced pressure to give 0.55 g (100%) of ethyl 5-amino-2-fluorobenzoate.
Reaction SMILES: [C:1]([N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7]1=[O:15])([O:3][CH2:4][CH3:5])=[O:2].[H-].[Na+].Br[CH2:19][C:20]1[CH:41]=[C:40]([Cl:42])[C:23]([O:24][CH:25]([C:31]2[CH:36]=[CH:35][C:34]3[O:37][CH2:38][O:39][C:33]=3[CH:32]=2)[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:22]([Cl:43])[CH:21]=1>CN(C=O)C>[C:26]([CH:25]([C:31]1[CH:36]=[CH:35][C:34]2[O:37][CH2:38][O:39][C:33]=2[CH:32]=1)[O:24][C:23]1[C:40]([Cl:42])=[CH:41][C:20]([CH2:19][N:8]2[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:6]([C:1]([O:3][CH2:4][CH3:5])=[O:2])[C:7]2=[O:15])=[CH:21][C:22]=1[Cl:43])([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOC(=O)n1c(=O)[nH]c2ccccc21
Reactant: CCOC(=O)C(Oc1c(Cl)cc(CBr)cc1Cl)c1ccc2c(c1)OCO2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Oc1c(Cl)cc(Cn2c(=O)n(C(=O)OCC)c3ccccc32)cc1Cl)c1ccc2c(c1)OCO2
Yield: 64 %

Procedure:
To a solution of 0.048 g (0.24 mmol) of 1-carboethoxy-2-benzimidazolinone dissolved in 0.5 mL DMF was added 0.010 g (0.26 mmol) of a 60% oil dispersion of sodium hydride and the resulting mixture was stirred under a nitrogen atmosphere and gently warmed with a heat gun until the solids had dissolved. A solution of the product of step B in 1.0 mL DMF was then added and the reaction mixture was stirred for an additional 1.5 hours. The mixture was then quenched with 5% aqueous ammonium chloride and extracted into ethyl acetate. The organic layer was separated, dried (MgSO4), filtered and evaporated, and the residue was purified on a silica gel flash chromatography column eluted with 30% EtOAc-hexane. Evaporation of the purified fractions and drying in vacuo afforded 0.088 g (64%) of the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][SH:8])=[N:3][CH:2]=1.Cl[CH2:10][CH2:11][OH:12].BrCCO>>[OH:12][CH2:11][CH2:10][S:8][CH2:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][N:3]=1
Reactant: OCCCl
Reactant: SCc1ccncn1
Agent: OCCBr
Product: OCCSCc1ccncn1

Procedure:
According to the methodology of Examples 11 to 15, 4-pyrimidylmethyl mercaptan is reacted with 2-chloroethanol or 2-bromoethanol to yield 4-(2-hydroxyethylthiomethyl)pyrimidine, with chloroacetone to yield 4-pyrimidylmethylthioacetone, with alphabromoacetophenone to yield alpha-(4-pyrimidylmethylthio)acetophenone, with alpha-bromo-p-methoxyacetophenone to yield alpha-(4-pyrimidylmethylthio)-p-methoxyacetophenone, with alpha-bromo-p-nitroacetophenone to yield alpha-(4-pyrimidylmethylthio)-p-nitroacetophenone, with alpha-bromopropiophenone to yield alpha-(4-pyrimidylmethylthio)propiophenone, with ethyl 2-bromoacetate to yield 2-(4-pyrimidylmethylthio)acetate, with ethyl 2-chloropropionate to yield 2-(4-pyrimidylmethylthio)propionate and with ethyl 2-phenyl-2-bromoacetate to yield 2-phenyl-2-(4-pyrimidylmethylthio)acetate (when ethyl esters are prepared, it is preferable to substitute an equivalent of sodium ethoxide for sodium methoxide; when the corresponding methyl esters are prepared, it is preferable to substitute methanol for ethanol).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]2[S:11][C:12]([C:15]([NH:17][C:18]3[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:25])=[O:16])=[CH:13][N:14]=2)[CH:3]=1.[CH2:26]([O:28][C:29]([CH2:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)=[O:30])[CH3:27]>CCO>[Cl:25][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]([CH3:24])[C:18]=1[NH:17][C:15]([C:12]1[S:11][C:10]([NH:9][C:4]2[N:5]=[C:6]([CH3:8])[N:7]=[C:2]([N:35]3[CH2:34][CH2:33][N:32]([CH2:31][C:29]([O:28][CH2:26][CH3:27])=[O:30])[CH2:37][CH2:36]3)[CH:3]=2)=[N:14][CH:13]=1)=[O:16]
Reactant: CCOC(=O)CN1CCNCC1
Reactant: Cc1nc(Cl)cc(Nc2ncc(C(=O)Nc3c(C)cccc3Cl)s2)n1
Solvent: CCO
Product: CCOC(=O)CN1CCN(c2cc(Nc3ncc(C(=O)Nc4c(C)cccc4Cl)s3)nc(C)n2)CC1
Temperature: 150 °C
Reaction time: 1 h
Yield: 88.8 %

Procedure:
A mixture of 2-(6-chloro-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide (1) (0.20 g, 0.51 mmol) and 1-(ethoxycarbonylmethyl)piperazine (3) (0.17 g, 1.01 mmol) in 4 mL of EtOH was heated with a CEM Discover® microwave at 250 W, Pmax 150° C. for 45 min. The resulting mixture was treated with EtOH (6 mL) and then stirred at rt for 1 h. The solid was collected on a filter to give 0.24 g of ethyl 2-(4-(6-(5-((2-chloro-6-methylphenyl)carbamoyl)thiazol-2-ylamino)-2-methylpyrimidin-4-yl)piperazin-1-yl)acetate (4) (89% yield). HPLC>99% pure (Rt 2.517 min); LC/MS (ES+) 530/532 (M+H, 100); 1H NMR (DMSO-d6) δ 11.48 (s, 1H), 9.86 (s, 1H), 8.22 (s, 1H), 7.40 (m, 1H), 7.28 (m, 2H), 6.06 (s, 1H), 4.10 (q, J=7.1 Hz, 2H), 3.53 (s, 4H ??), 3.29 (s, 2H), 2.59 (t, J=4.6 Hz, 4H), 2.41 (s, 3H), 2.24 (s, 3H), 1.20 (t, J=7.1 Hz, 3H); Anal. Calcd for C24H28ClN7O3S: C, 54.38; H, 5.32; Cl, 6.69; N, 18.50; S, 6.05. Found: C, 54.24; H, 5.16; Cl, 6.80; N, 18.59; S, 6.09.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].O=[C:8]1[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:10]([C:20]([O:22][CH3:23])=[O:21])[CH2:9]1.[Cl-].[NH4+]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)C>[CH2:1]=[C:8]1[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:10]([C:20]([O:22][CH3:23])=[O:21])[CH2:9]1
Reactant: CC(C)(C)[O-]
Reactant: COC(=O)[C@@H]1CC(=O)CN1C(=O)OC(C)(C)C
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Cl-]
Solvent: CCOCC
Product: C=C1C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C1
Temperature: 35 °C
Reaction time: 0.5 h
Yield: 69.6 %

Procedure:
Methyltriphenylphosphonium bromide (22 g, 61.6 mmol) was added to a solution of potassium tert-butoxide (6.5 g, 57.6 mmol) in anhydrous diethyl ether (450 ml) at 0° C. under nitrogen and the resulting bright yellow mixture stirred for 30 minutes. A solution of 1-tert-butyl 2-methyl (2S)-4-oxo-1,2-pyrrolidinedicarboxylate (10 g, 41.1 mmol in 150 ml anhydrous diethyl ether) was added slowly to the reaction mixture, which was then warmed at 35° C. for 3 h. Saturated aqueous ammonium chloride solution (0.5 ml) was then added. The organic layer was removed, and the aqueous washed with diethyl ether (3×5 ml). The combined organic layers were dried with brine and magnesium sulfate before filtering and removal of solvent. Silica gel chromatography, eluting with 15% ethyl acetate in hexanes gave the desired product 6.9 g (70% yield) as a off-white wax.