Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]([C:9]1[C:17]([O:18][CH3:19])=[CH:16][C:15]([CH3:20])=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])([CH3:8])[C:4]([O:6]C)=[O:5])#[N:2].[OH-].[K+].Cl>CCO.O.C(OCC)(=O)C>[C:24]([O:23][C:21]([N:13]1[C:14]2[C:10](=[C:9]([C:3]([C:1]#[N:2])([CH3:8])[C:4]([OH:6])=[O:5])[C:17]([O:18][CH3:19])=[CH:16][C:15]=2[CH3:20])[CH:11]=[CH:12]1)=[O:22])([CH3:27])([CH3:25])[CH3:26]
Reactant: COC(=O)C(C)(C#N)c1c(OC)cc(C)c2c1ccn2C(=O)OC(C)(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(C)(C#N)C(=O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(±)-tert-Butyl 4-(2-cyano-1-methoxy-1-oxopropan-2-yl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (Example 155-D) (0.35 g, 0.940 mmol) was dissolved in EtOH (4.70 ml), cooled to 0° C. and added 10% KOH (2.64 ml, 4.70 mmol) and stirred for 1 hour. At this point, the reaction was placed in an ice bath and quenched with 1 N HCl (4.70 ml, 4.70 mmol). The reaction was diluted with water and ethyl acetate. The layers were separated and the ethyl acetate layer was removed, dried over Na2SO4 and concentrated to obtain the title compound which was used directly in the next reaction without purification. MS (ESI+) m/z 359.4 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:12]=[C:11]([N:13]2[CH2:17][CH2:16][CH2:15][C:14]2=[O:18])[CH:10]=[C:6]([C:7]([OH:9])=O)[CH:5]=1.C(Cl)(C(Cl)=O)=O.[CH2:26]([NH2:29])[CH2:27][CH3:28]>C(Cl)Cl.CN(C=O)C>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:12]=[C:11]([N:13]2[CH2:17][CH2:16][CH2:15][C:14]2=[O:18])[CH:10]=[C:6]([C:7]([NH:29][CH2:26][CH2:27][CH3:28])=[O:9])[CH:5]=1
Reactant: CCCN
Reactant: COC(=O)c1cc(C(=O)O)cc(N2CCCC2=O)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCNC(=O)c1cc(C(=O)OC)cc(N2CCCC2=O)c1
Reaction time: 1 h
Yield: 17.4 %

Procedure:
A suspension of 5-(2-oxo-pyrrolidin-1-yl)-isophthalic acid monomethyl ester (A75) (200 mg, 76 mmol, 1 equiv) in CH2Cl2 (20 ml) at room temperature was treated with a few drops of DMF followed by (COCl)2 (100 mg, 0.8 mmol, 1.1 equiv). The resulting mixture was stirred for 1 h and then propylamine (140 mg, 2.4 mmol, 3.3 equiv) was added and the resulting solution was stirred for 30 min. The solution was then washed with 2N aqueous HCl solution (30 ml), saturated aqueous NaHCO3 solution (30 ml), dried over MgSO4 and concentrated in vacuo to give 5-(2-oxo-pyrrolidin-1-yl)-N-propyl-isophthalamic acid methyl ester (B77) (127 mg, 55%) as a cream waxy solid.
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[NH:13][N:12]=[N:11][C:10]=2[N:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:27]I>CN(C=O)C>[CH3:27][N:12]1[NH:11][C:10]([N:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]2)=[C:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:13]1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCN(c2nn[nH]c2-c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1NC(c2ccccc2)=C(N2CCN(C(=O)OC(C)(C)C)CC2)N1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (0.02 g) was taken in dry DMF (5 ml) and a solution of tert-butyl 4-(5-phenyl-1H-1,2,3-triazol-4-yl)piperazine-1-carboxylate (0.015 g in 5 ml of DMF) was added slowly at 0° C. The reaction mixture was stirred for 30 min at 0° C. and methyl iodide (0.13 g) was added very slowly. The reaction mixture was allowed to stir over night at room temperature. The reaction mixture was quenched with cold water (5 ml) and extracted with ethyl acetate (3×40 ml). Evaporation of solvent under reduced pressure gave crude product, which, was purified by column chromatography using 60-120 silica gel methanol\dichloromethane (1:9) as eluent to afford tert-butyl 4-(2-methyl-5-phenyl-1H-1,2,3-triazol-4-yl)piperazine-1-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6](Cl)=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1.[OH-].[K+]>>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6]([O:21][C:18]3[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=3)=[CH:7][CH:8]=2)[N:3]=1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Reactant: COc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Product: COc1ccc(Oc2ccc3ccc(N)nc3n2)cc1
Yield: 99.3 %

Procedure:
The procedure is similar to that described in Example 4, but starting with 2-amino-7-chloro-1,8-napthyridine (35.8 g), 4-methoxyphenol (99.2 g) and potassium hydroxide pellets (22.4 g; 85% purity). After treatment with caustic soda and washing, 2-amino-7-(4-methoxyphenoxy)-1,8-naphthyridine (52.9 g) is produced, m.p. 200° C. EXAMPLE 13
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:45]1[N:49]=[C:48]([NH2:50])[S:47][N:46]=1)[C:5]([NH:7][CH:8]1[C:43](=[O:44])[N:10]2[C:11]([C:27]([O:29][CH:30]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[O:28])=[C:12]([CH2:16][O:17][C:18]([N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)=[O:19])[CH2:13][S:14](=O)[C@H:9]12)=[O:6].CC(C)=O.[I-].[Na+].FC(F)(F)C(OC(=O)C(F)(F)F)=O>O1CCCC1>[CH3:1][O:2][N:3]=[C:4]([C:45]1[N:49]=[C:48]([NH2:50])[S:47][N:46]=1)[C:5]([NH:7][CH:8]1[C:43](=[O:44])[N:10]2[C:11]([C:27]([O:29][CH:30]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[O:28])=[C:12]([CH2:16][O:17][C:18]([N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)=[O:19])[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(COC(=O)N3CCN(C)CC3)CS(=O)[C@H]12)c1nsc(N)n1
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: C1CCOC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(COC(=O)N3CCN(C)CC3)CS[C@H]12)c1nsc(N)n1

Procedure:
A mixture of benzhydryl 7-[2-methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-methyl-1-piperazinyl)carbonyloxymethyl-3-cephem-4-carboxylate-1-oxide (syn isomer)(1.25 g) in a mixture of dry acetone (150 ml) and tetrahydrofuran (50 ml) was stirred under ice-water cooling and thereto were added sodium iodide (620 mg) and trifluoroacetic anhydride (0.59 ml) followed by stirring for 4 hours at the same temperature. The reaction mixture was evaporated under reduced pressure and to the residue were added ethyl acetate (60 ml) and water (20 ml). The ethyl acetate layer was separated therefrom, washed with 5% aqueous solution of sodium thiosulfate (20 ml×3), and a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, treated with activated charcoal and then evaporated under reduced pressure. The residue was washed with diethyl ether and dried to give benzhydryl 7-[2-methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-methyl-1-piperazinyl)carbonyloxymethyl-3-cephem-4-carboxylate.ditrifluoroacetate (syn isomer)(0.9 g).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([B:8]([OH:10])[OH:9])[CH:7]=1.BrC1C=[C:18]([O:20]C)C=CC=1OC.[Li]CCCC.COB(OC)OC>>[CH3:12][O:11][C:5]1[CH:4]=[CH:3][C:2]([O:20][CH3:18])=[CH:7][C:6]=1[B:8]([OH:10])[OH:9]
Reactant: COc1ccc(F)cc1B(O)O
Reactant: COc1ccc(OC)c(Br)c1
Agent: COB(OC)OC
Agent: [Li]CCCC
Product: COc1ccc(OC)c(B(O)O)c1
Yield: 99 %

Procedure:
This compound was prepared in a manner similar to that of 5-fluoro-2-methoxyphenylboronic acid (EXAMPLE 107) from 1-bromo-2,5-dimethoxybenzene (2.00 mL, 13.3 mmol), n-BuLi (2.5M in hexanes; 5.34 mL, 13.3 mmol), and trimethylborate (4.5 mL, 40 mmol) to afford 2.43 g (99%) of 2,5-dimethoxyphenylboronic acid which was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH:13]=[C:14]([Br:16])Br)[CH2:11][O:10][C:9]1([CH3:18])[CH3:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:1]([O:5][C:6]([N:8]1[C@@H:12](/[CH:13]=[C:14](\[Br:16])/[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:11][O:10][C:9]1([CH3:18])[CH3:17])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1[C@@H](C=C(Br)Br)COC1(C)C
Product: CC(C)(C)OC(=O)N1[C@@H](/C=C(\Br)c2ccccc2)COC1(C)C

Procedure:
In analogy to example 162b (S)-4-(2,2-dibromo-vinyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester was reacted with phenylboronic acid to give (S)-4-((Z)-2-bromo-2-phenyl-vinyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester. Light yellow crystalline solid.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:8]([C:9]([NH:11][C:12]2[C:13]3[C:17]([CH:18]=[C:19](B4OC(C)(C)CC(C)(C)O4)[CH:20]=2)=[N:16][N:15](C2CCCCO2)[CH:14]=3)=[O:10])=[CH:7][CH:6]=[N:5]1)[CH3:3].P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:46]1[CH:54]=[CH:53][CH:52]=[C:51]2[C:47]=1[CH2:48][C:49](=[O:55])[NH:50]2.O1CCOCC1>O>[CH3:3][CH:2]([N:4]1[C:8]([C:9]([NH:11][C:12]2[CH:20]=[C:19]([C:46]3[CH:54]=[CH:53][CH:52]=[C:51]4[C:47]=3[CH2:48][C:49](=[O:55])[NH:50]4)[CH:18]=[C:17]3[C:13]=2[CH:14]=[N:15][NH:16]3)=[O:10])=[CH:7][CH:6]=[N:5]1)[CH3:1]
Reactant: CC(C)n1nccc1C(=O)Nc1cc(B2OC(C)(C)CC(C)(C)O2)cc2nn(C3CCCCO3)cc12
Reactant: O=C1Cc2c(Br)cccc2N1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)n1nccc1C(=O)Nc1cc(-c2cccc3c2CC(=O)N3)cc2[nH]ncc12
Temperature: 120 °C

Procedure:
A microwave vial was charged with 1-(1-methylethyl)-N-[2-(tetrahydro-2H-pyran-2-yl)-6-(4,4,6,6-tetramethyl-1,3,2-dioxaborinan-2-yl)-2H-indazol-4-yl]-1H-pyrazole-5-carboxamide (70 mg), Solvias catalyst (8 mg), tripotassium phosphate (90 mg) and 4-bromo-1,3-dihydro-2H-indol-2-one (available from Apollo, 33 mg), 1,4-dioxane (0.5 ml) and water (0.1 ml). The reaction was heated under microwave irradiation for a total of 30 min at 120° C.). Further tripotassium phosphate (60 mg) and Solvias catalyst (8 mg) were added and the reaction was heated under microwave irradiation for 10 min at 120° C. The reaction was passed through a silica cartridge, dried, then extracted with DCM and water before drying the DCM under a stream of nitrogen. The residue was purified as follows:
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][C:4]([C:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)=[CH:8][CH2:9][OH:10])=[CH:3][CH:2]=1.C(P(CCCC)CCCC)CCC.[CH2:42]([O:44][C:45](=[O:58])[C@@H:46]([O:55][CH2:56][CH3:57])[CH2:47][C:48]1[CH:53]=[CH:52][C:51](O)=[CH:50][CH:49]=1)[CH3:43]>>[CH2:42]([O:44][C:45](=[O:58])[C@@H:46]([O:55][CH2:56][CH3:57])[CH2:47][C:48]1[CH:53]=[CH:52][C:51]([O:10][CH2:9][CH:8]=[C:7]([C:4]2[CH:3]=[CH:2][C:1]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:6][CH:5]=2)[C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)=[CH:50][CH:49]=1)[CH3:43]
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Reactant: OCC=C(c1ccc(-c2ccccc2)cc1)c1ccc(-c2ccccc2)cc1
Agent: CCCCP(CCCC)CCCC
Product: CCOC(=O)[C@H](Cc1ccc(OCC=C(c2ccc(-c3ccccc3)cc2)c2ccc(-c3ccccc3)cc2)cc1)OCC
Yield: 76.4 %

Procedure:
Reaction of 3,3-bis-biphenyl-4-yl-prop-2-en-1-ol (363 mg, 1.0 mmol), tributylphosphine (303 mg, 1.5 mmol), (2S)-2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (262 mg, 1.1 mmol) and azodicarboxylic dipiperidide (378 mg, 1.5 mmol) in an identical manner to example 3 gave the title compound (445 mg, 76%) containing 0.8 equivalents of ethyl acetate.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:19][CH2:20][CH:21]([CH2:39][OH:40])[O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:41]([C:43]1[CH:44]=[C:45]([CH:48]=[CH:49][CH:50]=1)[CH2:46]Br)#[N:42].O>O1CCCC1>[CH2:3]([O:19][CH2:20][CH:21]([CH2:39][O:40][CH2:46][C:45]1[CH:48]=[CH:49][CH:50]=[C:43]([C:41]#[N:42])[CH:44]=1)[O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCOCC(CO)OCCCCCCCCCCCCCCCC
Reactant: N#Cc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCCCCCCCCOCC(COCc1cccc(C#N)c1)OCCCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 68 %

Procedure:
Sodium hydride (1.056 g. of 50 wt. % mineral oil dispersion, 22 mmoles) was added to a solution of 1,2-di-O-(n-hexadecyl)-glycerol (9.73 g., 18 mmoles) in tetrahydrofuran (150 ml.) and the resulting solution stirred for 20 minutes at room temperature under nitrogen. m-Cyanobenzyl bromide (4.0 g., 20 mmoles) was added and the reaction mixture stirred overnight at room temperature under nitrogen. Water (200 ml.) was then added cautiously and the resulting mixture extracted with ethyl acetate (3×150 ml.). The combined ethyl acetate extract was dried (MgSO4), filtered and evaporated in vacuo to an oil (12 g.), which was purified by silica gel chromatography (elution with benzene:hexane) [8.0 g., 68% yield, oil, ir (CHCl3) 2230 cm-1 ].
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:28])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[S:13][C:14]([C:23]([O:25]CC)=[O:24])=[C:15]([C:17](=[O:22])[NH:18][CH2:19][CH2:20][CH3:21])[N:16]=2)=[CH:8][CH:7]=1)[CH3:2].[OH-].[Li+]>CO>[CH2:1]([NH:3][C:4](=[O:28])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[S:13][C:14]([C:23]([OH:25])=[O:24])=[C:15]([C:17](=[O:22])[NH:18][CH2:19][CH2:20][CH3:21])[N:16]=2)=[CH:8][CH:7]=1)[CH3:2]
Reactant: CCCNC(=O)c1nc(-c2ccc(NC(=O)NCC)nc2)sc1C(=O)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CCCNC(=O)c1nc(-c2ccc(NC(=O)NCC)nc2)sc1C(=O)O
Temperature: 50 °C
Yield: 84.3 %

Procedure:
To a stirred solution of ethyl 2-[6-(3-ethyl-ureido)-pyridin-3-yl]-4-propylcarbamoyl-thiazole-5-carboxylate (Example 62, 0.33 g, 0.8 mM) in methanol (15 mL) was added 2 N lithium hydroxide (4 mL). The mixture was heated to 50° C. overnight, then concentrated to dryness. 2N hydrochloric acid was added to the concentrate, and the precipitated solid was filtered and dried under vacuum to afford 0.259 g (72%) of the title compound as solid. NMR: 0.92 (t, 3H), 1.10 (t, 3H), 1.63 (m, 2H), 3.20 (q, 2H), 3.36 (q, 2H), 7.67 (d, 1H), 7.68 (br s, 1H), 8.39 (dd, 1H), 9.02 (s, 1H), 9.62 (br s, 1H), 9.78 (br s, 1H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[C:13]([NH2:15])[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1.[C:16]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:21]=[CH:20][C:19]([C:22](Cl)=[O:23])=[CH:18][CH:17]=1>>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[C:13]([NH:15][C:22]([C:19]4[CH:20]=[CH:21][C:16]([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)=[CH:17][CH:18]=4)=[O:23])[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: Nc1nc2cccc(-c3ccoc3)n2n1
Product: O=C(Nc1nc2cccc(-c3ccoc3)n2n1)c1ccc(-c2ccccc2)cc1

Procedure:
The title compound was prepared following procedure described for intermediate B1, but starting from 5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A2), 50 mg; 0.25 mmol; 1.0 eq.) and 4-biphenylcarbonyl chloride (87 mg; 0.37 mmol; 1.5 eq.) as a white powder (53.7 mg, 56%). HPLC, Rt: 4.25 min. (purity 95.2%). LC/MS, M+(ESI): 381.4, M−(ESI): 379.4.
Reaction SMILES: [N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:23][CH:22]=[C:21]([CH3:24])[N:9]2[C:10](=[O:20])[C:11]=1[C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[F:19])[CH3:5])=[N+]=[N-].CP(C)C>O1CCCC1>[NH2:1][CH:4]([C:6]1[N:7]=[C:8]2[S:23][CH:22]=[C:21]([CH3:24])[N:9]2[C:10](=[O:20])[C:11]=1[C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[F:19])[CH3:5]
Reactant: Cc1csc2nc(C(C)N=[N+]=[N-])c(-c3cc(F)ccc3F)c(=O)n12
Agent: CP(C)C
Solvent: C1CCOC1
Product: Cc1csc2nc(C(C)N)c(-c3cc(F)ccc3F)c(=O)n12
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.5 %

Procedure:
To a solution of 7-(1-azidoethyl)-6-(2,5-difluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.054 g, 0.16 mmol) in tetrahydrofuran (2 mL) was added 1.00 M of trimethylphosphine in tetrahydrofuran (0.23 mL, 0.23 mmol), and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated to give the crude product (45 mg), which was used directly in the next step. LCMS calculated for C15H14F2N3OS (M+H)+: m/z=322.1. Found: 322.0.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9](O)=[O:10].[BH4-].[Na+].B(F)(F)F.CCOCC>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][OH:10]
Reactant: O=C(O)Cc1ccccc1Br
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OCCc1ccccc1Br
Temperature: 0 °C
Reaction time: 16 h

Procedure:
A solution of (2-bromophenyl)acetic acid (100 g, 0.46 mmol) in dry THF (2 L) was added NaBH4 (29 g, 0.77 mol) in portions. The contents were cooled to 0° C., and BF3. Et2O (123 mL, 0.770 mol) was added drop-wise over 1 h. The mixture was allowed to warm to 25° C. and stirred for 16 h. The reaction was cooled to 0° C. and cautiously quenched with aqueous sodium hydroxide. The contents were stirred for 3 h, and then extracted with EtOAc. The organic layer was dried and concentrated to give 2-(2-bromophenyl)ethanol. 1H-NMR (400 MHz, CDCl3) δ 7.54˜7.56 (m, 1H), 7.23˜7.28 (m, 2 H), 7.07˜7.11 (m, 1H), 3.88 (s, J=6.6 Hz, 2H), 3.03 (t, J=6.8 Hz, 2H).
Reaction SMILES: [O:1]=[C:2]1[NH:11][CH:10]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=2C)[C:9]2[C:8](=[O:21])[CH2:7][CH2:6][CH2:5][C:4]=2[N:3]1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=1.Cl.NC(C1C(=O)CCCC=1NC1C=CC=C(C(F)(F)F)C=1)C1C=CC(C#N)=CC=1[Cl:43]>>[Cl:43][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:12]=1[CH:10]1[C:9]2[C:8](=[O:21])[CH2:7][CH2:6][CH2:5][C:4]=2[N:3]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[C:2](=[O:1])[NH:11]1)[C:16]#[N:17]
Reactant: N#Cc1ccc(C(N)C2=C(Nc3cccc(C(F)(F)F)c3)CCCC2=O)c(Cl)c1
Reactant: Cc1cc(C#N)ccc1C1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)CCC2
Agent: Cl
Product: N#Cc1ccc(C2NC(=O)N(c3cccc(C(F)(F)F)c3)C3=C2C(=O)CCC3)c(Cl)c1

Procedure:
The title compound is prepared in analogy to 4-(2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4,5,6,7,8-octahydroquinazolin-4-yl)-3-methylbenzonitrile (example 55), using 4-(amino(6-oxo-2-(3-(trifluoromethyl)phenylamino)cyclohex-1-enyl)methyl)-3-chloro-benzonitrile hydrochloride (intermediate 54, 620 mg, 1.36 mmol) as starting material. Yield: 191 mg; ESI mass spectrum [M+H]+=446; Retention time HPLC: 0.65 min (X012_S01).
Reaction SMILES: Cl.O[NH:3][C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1>[Zn]>[NH2:3][C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: O=C1c2ccccc2C(=O)c2c(NO)cccc21
Agent: Cl
Agent: [Zn]
Product: Nc1cccc2c1C(=O)c1ccccc1C2=O
Temperature: 70 °C

Procedure:
To 700 parts of a 3 % aqueous hydrochloric acid there was added 50 parts of 1-hydroxylaminoanthraquinone and the mixture was heated with stirring to 70°C, then added thereto little by little 16 parts of zinc dust over 1 hour. The reaction mixture was maintained at 70°C for additional 4 hours. Zinc dust was completely consumed during the reaction course but a fairly large amount of 1-hydroxylaminoanthraquinone remained unreacted. The reaction mixture was cooled to 25°C and filtered. The residue was washed with water and then with 200 parts of a 3 % solution of sodium hydroxide in a 20 % aqueous acetone to extract therefrom unreacted 1-hydroxylaminoanthraquinone and washed with water again and dried to obtain 15.5 parts of 1-aminoanthraquinone of a purity of 90 %.
Reaction SMILES: O=C[C@@H:3]([C@H:5]([C@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[OH-:13].[K+:14]>>[O:13]=[C:3]([O-:4])[C@H:5]([C@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6].[K+:14]
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Reactant: [OH-]
Agent: [K+]
Product: O=C([O-])[C@@H](O)[C@@H](O)[C@H](O)CO

Procedure:
The multi-step synthesis from D-galactose comprises oxidizing the D-galactose in KOH solution to open the pyranose ring and form potassium D-lyxonate, subjecting the latter compound to alcoholic solution under acid conditions to provide furanose ring closure and form the D-lyxono-1,4-lactone, and then introducing a protecting group at C-2 and C-3 by reaction with ketone in the presence of a dehydrating agent. Use of acetone as the ketone in the latter step gives the compound 2,3-0-isopropylidene-D-lyxono-1,4-lactone. From that point on the multi-step system includes the general reaction steps of the above short synthesis.
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]1=[S:3].[OH-].[Na+].[Cl-].Cl[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH+:20]([CH3:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[CH3:21][N:20]([CH3:22])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][S:3][C:2]1[NH:4][C:5](=[O:6])[CH:7]=[CH:8][N:1]=1
Reactant: C[NH+](C)c1ccccc1CCl
Reactant: O=c1cc[nH]c(=S)[nH]1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CN(C)c1ccccc1CSc1nccc(=O)[nH]1
Reaction time: 0.5 h
Yield: 84.2 %

Procedure:
The solution of 0.38 g (3.0 mmol) of 2-thiouracil [Am. Chem. J. 40, 550 (1908)] in 6 ml of aqueous 1N sodium hydroxide solution is added to the solution of 0.62 g (3.0 mmol) of (2-chloromethylphenyl)dimethylammonium chloride in 6 ml of chloroform at room temperature under vigorous stirring within about 30 minutes. After termination of the addition the pH value of the aqueous solution is controlled and, when necessary, it is adjusted to 9 by adding 20% potassium carbonate solution. Thereafter, the reaction mixture is stirred for 2 hours, the phases are separated, the aqoeous layer is extracted twice with 5 ml of chloroform each, the combined organic phase is washed with 5 ml of 1N sodium hydroxide solution and then twice with 5 ml of water each, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue is thoroughly triturated with petroleum ether, filtered and recrystallized from ethanol to give 0.66 g (84%) of the title compound as a white crystalline product, m.p.: 156°-158° C.
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:9]=[C:8]([F:10])[C:7]([F:11])=[CH:6][C:5]=1[OH:12].Br[CH2:14][CH2:15][C:16]([OH:18])=[O:17].Cl>O>[Br:3][C:4]1[CH:9]=[C:8]([F:10])[C:7]([F:11])=[CH:6][C:5]=1[O:12][CH2:14][CH2:15][C:16]([OH:18])=[O:17]
Reactant: O=C(O)CCBr
Reactant: Oc1cc(F)c(F)cc1Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CCOc1cc(F)c(F)cc1Br
Temperature: 100 °C
Yield: 65.8 %

Procedure:
A solution of 1.68 g of NaOH (42 mmol) in 5 mL of water was added slowly to the suspension of 2.29 mL (20 mmol) 2-bromo-4,5-difluorophenol and 3.07 g (20 mmol) 3-bromopropionic acid. The mixture was heated at 100° C. in an oil bath for 5 hours, and then allowed to cool to room temperature. Water was added to completely dissolve any solid material and the reaction mixture was made acidic with concentrated HCl. The product was extracted into ether (3 times), and the combined organic layers was dried over Na2SO4 and evaporated to give 3.7 g (66%) of the title compound as a light brown solid. 1H NMR (300 MHz, CDCl3): δ 7.4 (t, 1H), 6.8 (q, 1H), 4.3 (t, 2H), 2.9 (t, 2H).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[NH:10][C:9]=2[C:8](=[O:15])[N:7]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22]CC)=[O:21])[C:6]1=[O:25])[CH2:2][CH2:3][CH3:4].[Li+].[OH-].O.CO>CCOC(C)=O>[CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[NH:10][C:9]=2[C:8](=[O:15])[N:7]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[C:6]1=[O:25])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)n(CCCCC(=O)OCC)c(=O)c2[nH]c(Cl)nc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCCn1c(=O)n(CCCCC(=O)O)c(=O)c2[nH]c(Cl)nc21
Temperature: 25 °C
Reaction time: 60 h
Yield: 84.2 %

Procedure:
A mixture of ethyl 5-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoate (2.8 g, 7.55 mmol), LiOH (542 mg, 22.7 mmol), water (2.5 ml) and methanol (50 ml) was stirred at rt for 60 h. The mixture was portioned between water and EtOAc and the pH of the aqueous phase adjusted to pH 4-5. The organic layer was separated, washed with brine, dried (MgSO4) and evaporated to give the title compound as a white solid (2.18 g).