Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(Cl)(Cl)Cl.C[O:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[C:9]([CH3:15])[CH:8]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[OH:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[C:9]([CH3:15])[CH:8]=1
Reactant: COc1ccc(C#N)c(C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: ClB(Cl)Cl
Agent: [I-]
Solvent: ClCCl
Product: Cc1cc(O)ccc1C#N
Temperature: 25 °C
Reaction time: 16 h
Yield: 27.3 %

Procedure:
Boron trichloride (1M in dichloromethane, 747 ml, 747 mmol) was added dropwise, at −78° C., to a suspension of commercially available 4-methoxy-2-methyl-benzonitrile (44 g, 298 mmol) and tetrabutylammonium iodide (121 g, 327 mmol) in dichloromethane (750 ml), under nitrogen, over 40 minutes. Once the addition was complete, the yellow solution was warmed to room temperature and stirred for 16 hours at room temperature. The reaction mixture was then quenched by dropwise addition of water maintaining the internal at temperature below 10° C. The mixture was then filtered through Arbocel™, and the layers were separated. The aqueous layers were extracted with dichloromethane (250 ml). The organic layers were combined, washed with a sodium thiosulphate solution, dried over magnesium sulphate, filtered and concentrated under reduced pressure to give a thick yellow oil. Trituration of the oil in dichloromethane, followed by filtration, provided a first crop of the title compound (10.85 g, 27.4%) as a white solid. The filtrate was evaporated and purified by flash chromatography on silica gel, eluting with pentane:ethyl acetate (70:30, by volume) to provide more of the title compound as a white solid (14.44 g, 36.4%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16].Cl.[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH2:26][CH2:27][NH:28][CH2:29][CH:30]=2)=[CH:21][CH:20]=1.C(N(CC)CC)C>C(#N)C>[CH3:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH2:30][CH2:29][N:28]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:10](=[O:11])[C:9]4=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]4[C:7]3=[O:16])[CH2:27][CH:26]=2)=[CH:23][CH:24]=1
Reactant: Cc1ccc(C2=CCNCC2)cc1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ccc(C2=CCN(CCCCN3C(=O)c4ccccc4C3=O)CC2)cc1
Yield: 88 %

Procedure:
A solution N-(4-bromobutyl)phthalimide (0.85 g), 4-(4-methylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride (0.63 g) and triethylamine (0.91 g) in dry acetonitrile (10 ml) was refluxed for 3 hours. After evaporation of the solvent, crude residue was dissolved in ethyl acetate, washed with water, sat. ammonium chloride solution and brine successively, dried over magnesium sulfate and evaporated to give a yellow solid of N-[4-{4-(4-methylphenyl)-1,2,3,6-tetrahydropyridin-1-yl}butyl]phthalimide (0.99 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[NH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][C:12]([C:16]#[N:17])=[CH:11][CH:10]=3)[CH:2]=1.CC(C)([O-])C.[K+].[CH3:24][C:25]([CH3:31])([CH3:30])[C:26](=[O:29])[CH:27]=[CH2:28].C(OCC)(=O)C>CS(C)=O.Cl.C(OCC)C>[CH3:24][C:25]([CH3:31])([CH3:30])[C:26](=[O:29])[CH2:27][CH2:28][N:8]1[C:9]2[C:14](=[CH:13][C:12]([C:16]#[N:17])=[CH:11][CH:10]=2)[CH:15]=[C:7]1[C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: N#Cc1ccc2[nH]c(-c3cccnc3)cc2c1
Reactant: C=CC(=O)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: CS(C)=O
Product: CC(C)(C)C(=O)CCn1c(-c2cccnc2)cc2cc(C#N)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-pyridin-3-yl-1H-indole-5-carbonitrile (Example 8, 0.225 g, 1.026 mmol) in DMSO (5 mL) is added potassium tert-butoxide (0.182 g, 1.53 mmol) and the mixture is stirred at room temperature for 0.5 h. 4,4-Dimethyl-pent-1-en-3-one (0.345 g, 3.078 mmol) is added and the mixture is stirred at 50° C. overnight. Dilution with ethyl acetate gives a solution which is washed with water twice, dried over sodium sulfate and concentrated in vacuo. The residue is purified by Xbridge Shield RP18 with a gradient of acetonitrile in 0.1% NH4OH to give an oil. Addition of diethyl ether and a few drops of concentrated HCl, followed by lyophilization affords 1-(4,4-dimethyl-3-oxo-pentyl)-2-pyridin-3-yl-1H-indole-5-carbonitrile as a light yellow color solid. 1H NMR (400 MHz, MeOD) δ ppm (HCl salt) 0.90 (s, 9H), 2.94 (t, J=6.4 Hz, 2H), 4.61 (t, J=6.6 Hz, 2H), 6.88 (s, 1H), 7.59 (dd, J=8.7, 1.6 Hz, 1H), 7.77 (d, J=8.6 Hz, 1H), 7.93 (dd, J=8.0, 5.4 Hz, 1H), 8.10 (d, J=1.0 Hz, 1H), 8.44 (dt, J=7.9, 1.7 Hz, 1H), 8.82 (dd, J=5.3, 1.3 Hz, 1H), 8.96 (d, J=1.8 Hz, 1H). HRMS (ESI) m/z 332.1762 [(M+H)+ Calcd for C21H22N3O: 332.1763].
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=[CH:9][C:10](OCC)=[O:11])=[C:6]([CH3:15])[C:5]([NH:16]C(=O)C)=[C:4]([CH3:20])[N:3]=1>Cl>[NH2:16][C:5]1[C:6]([CH3:15])=[C:7]2[C:2](=[N:3][C:4]=1[CH3:20])[NH:1][C:10](=[O:11])[CH:9]=[CH:8]2
Reactant: CCOC(=O)C=Cc1c(N)nc(C)c(NC(C)=O)c1C
Agent: Cl
Product: Cc1nc2[nH]c(=O)ccc2c(C)c1N

Procedure:
Ethyl 3-(2-amino-5-acetamido-4,6-dimethylpyrid-3-yl)-acrylate (2.48 g., 8.95 mmole) is heated under reflux in solution in 6N hydrochloric acid (24.8 ml.) for 6 days. The reaction mixture is filtered through a glass-fiber filter disc, the filtrate diluted slowly over a period of 15 minutes with ethanol (75 ml.) whereupon 1.043 g. (51.7%) of product in the form of the hydrochloride crystallizes from solution, m.p. 325° C. (dec.). A second crop raises the yield to 79%. Following recrystallization of the crude product from a mixture of dilute hydrochloric acid and isopropanol the purified product melts at 325° C. (dec.).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:22]=[CH:23][C:24]=1[N+:25]([O-])=O)[NH:7][C:8]([C:10]1[CH:11]=[CH:12][C:13]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[N:14][CH:15]=1)=[O:9])([O-])=O.[N:28]1([C:34]2[CH:39]=[CH:38][C:37]([NH:40][C:41]([C:43]3[CH:50]=[CH:49][C:46]([CH:47]=O)=[CH:45][CH:44]=3)=[O:42])=[CH:36][CH:35]=2)[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[O:19]1[CH2:20][CH2:21][N:16]([C:13]2[CH:12]=[CH:11][C:10]([C:8]([NH:7][C:6]3[CH:22]=[CH:23][C:24]4[NH:25][C:47]([C:46]5[CH:49]=[CH:50][C:43]([C:41](=[O:42])[NH:40][C:37]6[CH:38]=[CH:39][C:34]([N:28]7[CH2:29][CH2:30][O:31][CH2:32][CH2:33]7)=[CH:35][CH:36]=6)=[CH:44][CH:45]=5)=[N:1][C:4]=4[CH:5]=3)=[O:9])=[CH:15][N:14]=2)[CH2:17][CH2:18]1
Reactant: O=Cc1ccc(C(=O)Nc2ccc(N3CCOCC3)cc2)cc1
Reactant: O=C(Nc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)c1ccc(N2CCOCC2)nc1
Product: O=C(Nc1ccc(N2CCOCC2)cc1)c1ccc(-c2nc3cc(NC(=O)c4ccc(N5CCOCC5)nc4)ccc3[nH]2)cc1

Procedure:
Compound 253 was prepared according to the procedure similar to that described in Scheme III from 3,4-dinitro-N-(2-morpholinyl-5-pyridinecarbonyl)aniline and 4-(4-morpholinylphenyl)aminocarbonylbenzaldehyde. [M+H]+ calcd for C34H33N7O4: 604.26; found: 604.10.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][CH:11]([CH2:14][OH:15])[CH2:12][OH:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:16](I)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>CN(C)C=O>[CH2:31]([O:15][CH2:14][CH:11]([O:10][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH2:12][OH:13])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH3:16]
Reactant: OCC(CO)OCc1ccccc1
Reactant: CCCCCCCCCCCCCCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCOCC(CO)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 26.2 %

Procedure:
To a suspension of about 14.26 g of washed about 50% sodium hydride in about 500 ml of dimethylformamide was added about 49.2 g of 2-(benzyloxy)-1,3-propanediol over about 20 minutes. The mixture was stirred for about 40 minutes, then cooled to about 0° C. and about 95.13 g of hexadecyl iodide were added. After standing about 10 minutes, the mixture was stirred at room temperature for about 3 hours, then filtered through celite and diluted with about 1000 ml of water. This mixture was extracted with petroleum ether. The ether extract was dried and the solvent removed giving an oil. This oil was chromatographed on a column of florisil, eluting first with petroleum ether and then successively with about 5% and about 10% ether in petroleum ether to elute the product, giving about 28.8 g of the desired title compound as a light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[NH2:12][C:13]1[CH:28]=[CH:27][C:16]([C:17]([O:19][CH2:20][CH2:21][N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[O:18])=[CH:15][CH:14]=1>C(O)CCC>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([NH:12][C:13]2[CH:28]=[CH:27][C:16]([C:17]([O:19][CH2:20][CH2:21][N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[O:18])=[CH:15][CH:14]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: CCN(CC)CCOC(=O)c1ccc(N)cc1
Solvent: CCCCO
Product: CCN(CC)CCOC(=O)c1ccc(Nc2nc(Cl)nc3[nH]cnc23)cc1
Yield: 100 %

Procedure:
The procedure is carried out as in Example 1, starting with 472.5 mg of 2,6-dichloropurine, 5 ml of butanol and 737.3 mg of 2-(N,N-diethylamino)ethyl 4-amino-benzoate. 972.2 mg of the expected product are thus obtained.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:12]([O:14]C)=[O:13])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.Cl>[OH-].[Na+].CO.CS(C)=O>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:12]([OH:14])=[O:13])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: COC(=O)C(c1ccccc1)C(c1ccccc1)c1ccc2[nH]ncc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CS(C)=O
Product: O=C(O)C(c1ccccc1)C(c1ccccc1)c1ccc2[nH]ncc2c1
Yield: 82 %

Procedure:
Methyl 3-(1H-indazol-5-yl)-2,3-diphenylpropanoate was heated to 100° C. overnight in a mixture of 2 M NaOH/MeOH/DMSO (1:1:1). The next day, the reaction was cooled, acidified to pH 5 with HCl and extracted 2×EtOAc. The organic layers were washed with water×2, dried over MgSO4, filtered, concentrated in vacuo, and purified by HPLC to give 10 mg (82% yield) and 30 mg of the diastereomers of acid 3-(1H-indazol-5-yl)-2,3-diphenylpropanoic acid. MS found: (M+H)+=343.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12](OC)=[C:11](Cl)[CH:10]=2)[N:5]=[C:4]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([Cl:27])[CH:20]=2)[N:3]=1.Cl[C:29]1C=C(NC2N=C(Cl)N=C(Cl)N=2)C=CC=1OC.[OH-].[Na+]>>[Cl:1][C:2]1[N:3]=[C:4]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([Cl:27])[CH:20]=2)[N:5]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:29][CH2:11][CH2:10]2)[N:7]=1
Reactant: COc1ccc(Nc2nc(Cl)nc(Nc3ccc(OC)c(Cl)c3)n2)cc1Cl
Reactant: COc1ccc(Nc2nc(Cl)nc(Cl)n2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(Nc2nc(Cl)nc(NC3CCCCCC3)n2)cc1Cl

Procedure:
Attempts to minimize the impurity involved scanning several bases and solvents, but the production 6-chloro-N-(3-chloro-4-methoxyphenyl)-N′-(3-chloro-4-methoxyphenyl)[1,3,5]triazine-2,4-diamine remained. The preparation of compound 101 was then carried out without addition of base, resulting in the levels of the impurity being negligible. Compound 133 was prepared from compound 101 using aqueous NaOH as base.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([N:10]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[N:11]2)[CH:7]=[CH:6][C:3]=1[CH:4]=O.C([O-])(=O)C.[NH4+].[N+:24]([CH3:27])([O-:26])=[O:25]>C(O)(=O)C>[Cl:1][C:2]1[CH:9]=[C:8]([N:10]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[N:11]2)[CH:7]=[CH:6][C:3]=1[CH:4]=[CH:27][N+:24]([O-:26])=[O:25]
Reactant: O=Cc1ccc(-n2ccc(C(F)(F)F)n2)cc1Cl
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=[N+]([O-])C=Cc1ccc(-n2ccc(C(F)(F)F)n2)cc1Cl
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-chloro-4-[3-(trifluoromethyl)-1H-pyrazol-1-yl]benzaldehyde (i.e. the product of Step A; 6.0 g, 0.025 mol) in acetic acid (24 mL) was added ammonium acetate (5.6 g, 73 mmol), and the resulting mixture was stirred for 15 min at 0° C. Nitromethane (12.5 g, 204 mmol) was then added, and the mixture was stirred at 80° C. for 2 h. The reaction mixture was poured into ice water and extracted with ethyl acetate (100 mL). The aqueous layer was extracted with ethyl acetate (2×250 mL), and the combined organic layers were washed with brine (200 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluted with 30% ethyl acetate in hexanes to afford the title compound (7.1 g).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][N:8]2[C:16]([C:19]([OH:21])=O)=[CH:17][CH:18]=[C:7]2[CH2:6]1)=[O:4].[NH2:22][CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1>>[CH3:1][O:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][N:8]2[C:16]([C:19]([NH:22][CH2:23][C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)=[O:21])=[CH:17][CH:18]=[C:7]2[CH2:6]1)=[O:4]
Reactant: NCc1cccnc1
Reactant: COC(=O)N1Cc2ccc(C(=O)O)n2Cc2ccccc21
Product: COC(=O)N1Cc2ccc(C(=O)NCc3cccnc3)n2Cc2ccccc21

Procedure:
The title compound was prepared by coupling the 10-(methoxycarbonyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid of Step A with 3-(aminomethyl)pyridine (1.2 equiv.), in the manner of Example 1, Step G.
Reaction SMILES: [C:1]([C:6]1[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=1[C:8]([O:10]C)=[O:9])#[C:2][CH2:3][CH2:4][CH3:5].[I:16]I.C(=O)(O)[O-].[Na+]>C(#N)C.CCOCC>[I:16][C:1]1[C:6]2[C:7](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:8](=[O:10])[O:9][C:2]=1[CH2:3][CH2:4][CH3:5]
Reactant: CCCC#Cc1ccccc1C(=O)OC
Reactant: II
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCOCC
Product: CCCc1oc(=O)c2ccccc2c1I
Yield: 76 %

Procedure:
Methyl 2-(pent-1-ynyl)benzoate (intermediate C20.1, 3 g, 14.83 mmol), iodine (11.29 g, 44.5 mmol) and sodium bicarbonate (3.74 g, 44.5 mmol) were reacted in Acetonitrile (50 mL) for 20 min. at RT. The reaction mixture was diluted with Et2O and washed with 20% Na2S2O3aqueous and brine. The organic phase was then dried over Na2SO4 and concentrated under reduced pressure. The crude was dissolved in Et2O and purified over a silica pad to give the title compound (3.54 g, 76%) as a brown oil.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:30]2[C:31]([CH2:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([O:42][CH2:43][CH2:44]O)=[CH:38][CH:37]=3)=[CH:32][O:33][C:29]=2[CH:28]=[CH:27][CH:26]=1)(=O)C.[NH2:46][CH2:47][CH2:48][CH2:49][OH:50].NCCO>>[C@@H:6]1([O:24][C:25]2[C:30]3[C:31]([CH2:34][CH2:35][C:36]4[CH:41]=[CH:40][C:39]([O:42][CH2:43][CH2:44][NH:46][CH2:47][CH2:48][CH2:49][OH:50])=[CH:38][CH:37]=4)=[CH:32][O:33][C:29]=3[CH:28]=[CH:27][CH:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: NCCCO
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2cccc3occ(CCc4ccc(OCCO)cc4)c23)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: NCCO
Product: OCCCNCCOc1ccc(CCc2coc3cccc(O[C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)c23)cc1

Procedure:
The title compound was prepared in a similar manner to that described in Example 21 using 4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-3-(2-[4-(2-hydroxyethoxy)phenyl]ethyl)benzofuran and 3-amino-1-propanol instead of 4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-3-(2-[4-(3-hydroxypropoxy)phenyl]ethyl)benzofuran and 2-aminoethanol, respectively.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7]Cl)([O-:3])=[O:2].[OH:12][CH2:13][C:14]1[S:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:7][O:12][CH2:13][C:14]2[S:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)[CH:9]=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: OCc1nc2ccccc2s1
Reactant: O=[N+]([O-])c1cccc(CCl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1cccc(COCc2nc3ccccc3s2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 71.9 %

Procedure:
A mixture of 1.60 g of 3-nitrobenzyl chloride, 1.3 g of 2-hydroxymethylbenzothiazole and 0.54 of potassium carbonate in 20 ml of acetone was stirred at room temperature for 1.5 hours and then refluxed for 30 minutes. After evaporation of acetone under reduced pressure, the residue was dissolved in ethyl acetate, washed with water and dried over magnesium sulfate, followed by evaporation of the solvent under reduced pressure. The residue was purified through a silica gel column chromatography by use of ethyl ether-n-hexane to obtain 1.7 g (yield 73%) of the title compound.
Reaction SMILES: C(=O)([O-])OC(C)(C)C[C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([N:12](C(=O)C)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:6]=1[CH3:23].[OH2:28].NN.Cl>CC(O)(C)C>[OH:28][C:5]1[C:6]([CH3:23])=[C:7]([NH:12][C:13](=[O:14])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:8]([CH3:11])=[CH:9][CH:10]=1
Reactant: O
Reactant: CC(=O)N(C(=O)OC(C)(C)C)c1c(C)ccc(CC(C)(C)OC(=O)[O-])c1C
Agent: Cl
Agent: NN
Solvent: CC(C)(C)O
Product: Cc1ccc(O)c(C)c1NC(=O)OC(C)(C)C

Procedure:
A solution of [3-(acetyl(tert-butoxycarbonyl)amino)-2,4-dimethyl-phenyl]tert-butyl carbonate (800 mg, 2.11 mmol, 1.0 eq) and hydrazine hydrate (5 mL) in t-BuOH (5 mL) was stirred under N2 at 110° C. overnight. The solution was adjusted to pH 6 by addition of diluted HCl and the aqueous layer extracted with EtOAc. The organic extract was dried (Na2SO4), filtered and evaporated in vacuo. The crude solid was used in the next step without further purification (657 mg, 100%).
Reaction SMILES: [C:1]1([C:7]2[S:8][C:9]([CH:12]=[O:13])=[CH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F-].[Cs+].[C:16]([Si](C)(C)C)([F:19])([F:18])[F:17]>COCCOC>[F:17][C:16]([F:19])([F:18])[C:12]([C:9]1[S:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:11][CH:10]=1)=[O:13]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=Cc1cnc(-c2ccccc2)s1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Product: O=C(c1cnc(-c2ccccc2)s1)C(F)(F)F
Reaction time: 3 h

Procedure:
A solution (0.15 M) of 2-phenyl-1,3-thiazole-5-carbaldehyde (1.0 eq.) and CsF (0.2 eq.) in DME was treated with CF3SiMe3 (1.5 eq.) and then stiffed for 3 h at RT. The reaction mixture was quenched by adding 1N HCl and stirred for 30 min. The mixture was diluted with EtOAc, the organic phase was separated, washed with sat. aq. NaHCO3 solution and dried (Na2SO4). Evaporation of the solvent under reduced pressure afforded the product as an yellow oil. MS (ES+) C11H8F3NOS requires: 259, found: 260
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:10][CH:11]([CH2:14][OH:15])[CH2:12][OH:13])=[N:4][CH:5]=[N:6][C:7]=1[CH2:8][CH3:9].[CH3:16][C:17](=O)[CH2:18][CH2:19][CH2:20][CH3:21].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH2:18]([C:17]1([CH3:16])[O:15][CH2:14][CH:11]([NH:10][C:3]2[C:2]([Cl:1])=[C:7]([CH2:8][CH3:9])[N:6]=[CH:5][N:4]=2)[CH2:12][O:13]1)[CH2:19][CH2:20][CH3:21]
Reactant: CCc1ncnc(NC(CO)CO)c1Cl
Reactant: CCCCC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCC1(C)OCC(Nc2ncnc(CC)c2Cl)CO1

Procedure:
2.16 g (9 mmol) of 5-chloro-6-ethyl-4-(1,3-dihydroxy-2-propylamino)-pyrimidine (Example 1), 1.80 g (18 mmol) of 2-hexanone and 500 mg of p-toluenesulfonic acid were heated in 100 ml of toluene for 8 hours, using a water separator. After the mixture had been extracted by stirring with dilute sodium hydroxide solution, the organic phase was dried and concentrated. The cis/trans isomers were separated by chromatography over silica gel (mobile phase: ethyl acetate/petroleum ether 4:1). 0.29 g of trans isomer (10.3% of theory, colorless oil) was first eluted, followed by 0.49 g of the cis isomer (17.3% of theory, colorless oil).
Reaction SMILES: C1([NH:7][C:8]([C:10]2[C:11](=[O:29])[N:12]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:13]3[C:18]([C:19]=2O)=[CH:17][C:16]([F:21])=[CH:15][CH:14]=3)=O)CCCCC1.P(Cl)(Cl)([Cl:32])=O>>[CH2:22]([N:12]1[C:13]2[C:18](=[CH:17][C:16]([F:21])=[CH:15][CH:14]=2)[C:19]([Cl:32])=[C:10]([C:8]#[N:7])[C:11]1=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C(NC1CCCCC1)c1c(O)c2cc(F)ccc2n(Cc2ccccc2)c1=O
Product: N#Cc1c(Cl)c2cc(F)ccc2n(Cc2ccccc2)c1=O
Yield: 47 %

Procedure:
A solution of Compound 42 (3.5 g, 8.86 mmol) in 30 mL neat phosphorus oxychloride was heated at 90° C. for 5 h. The solvent was evaporated under reduced pressure. The residue was suspended in ice water and neutralized by solid sodium bicarbonate. The solids formed were filtered, washed by water, and purified by flash chromatography eluting with 1% methanol in dichloromethane to yield 1.29 g (47%) of yellow solids. M.P. 228° C. 1H NMR (DMSO-d6): δ 5.29 (s, 2H), 7.27 (m, 4H), 7.32 (m, 2H), 7.58 (dd, J=4.3, 9.3 Hz, 1H), 7.71 (td, J=2.4, 8.0 Hz, 1H), 7.91 (dd, J=2.9, 8.9 Hz, 1H). EIMS m/z 335 (M+23).
Reaction SMILES: [C:1]([CH2:4][NH:5][CH2:6][CH2:7][OH:8])([OH:3])=[O:2].[C:9](#[N:12])[CH2:10]O>>[C:1]([CH2:4][N:5]([CH2:6][CH2:7][OH:8])[CH2:10][C:9]#[N:12])([OH:3])=[O:2]
Reactant: N#CCO
Reactant: O=C(O)CNCCO
Product: N#CCN(CCO)CC(=O)O

Procedure:
The hydrolysis of (I) with base gives N-carboxymethylamino-2-ethanol (II). Compound (II) is then reacted with additional glycolonitrile to form N-carboxymethyl-N-cyanomethylamino-2-ethanol (III). The molar ratio of (II) to glycolonitrile is generally about 1:1. In the above reactions, hydrogen cyanide and formaldehyde can be substituted for glycolonitrile.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([Br:9])[C:3]=1[OH:10].[C:11](OC(=O)C)(=[O:13])[CH3:12]>>[C:11]([NH:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([Br:9])[C:3]=1[OH:10])(=[O:13])[CH3:12]
Reactant: Nc1cc(Br)cc(Br)c1O
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1cc(Br)cc(Br)c1O

Procedure:
44.2 g. of 2-amino-4,6-dibromo-phenol were processed with 85.5 ml. of acetic anhydride keeping the temperature under 50° C. By cooling, the 2-acetylamino-4,6-dibromo-phenol separated; it was collected on a filter and crystallized from ethyl alcohol. 30 g. of pure product were obtained. M.P. = 175°-176° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1B(O)O.Br[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=1[Cl:21].CC1C=CN=CC=1C1C=CC=C2C=1C=NN2>>[Cl:21][C:13]1[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:12]=1[C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1ccncc1B(O)O
Reactant: O=[N+]([O-])c1ccc(Br)c(Cl)c1
Agent: Cc1ccncc1-c1cccc2[nH]ncc12
Product: Cc1ccncc1-c1ccc([N+](=O)[O-])cc1Cl

Procedure:
Intermediate 27A was prepared from Intermediate 1A and 1-bromo-2-chloro-4-nitrobenzene by the procedure described for the preparation of Intermediate 1C. HPLC Ret timej:1.30 min. MS (ES): m/z=249.0 [M+H]+.
Reaction SMILES: [F:1][CH2:2][C:3]1([CH3:9])[CH2:7][O:6][C:5](=[O:8])[NH:4]1.C(O[Cl:15])(C)(C)C>CO>[Cl:15][N:4]1[C:3]([CH2:2][F:1])([CH3:9])[CH2:7][O:6][C:5]1=[O:8]
Reactant: CC(C)(C)OCl
Reactant: CC1(CF)COC(=O)N1
Solvent: CO
Product: CC1(CF)COC(=O)N1Cl
Reaction time: 2 h
Yield: 99.4 %

Procedure:
A solution of 4-(fluoromethyl)-4-methyloxazolidin-2-one (245 mg, 1.82 mmol) in MeOH (5 ml) was cooled to 0° C. and tert-butylhypochlorite (251 mg, 2.3 mmol) was added dropwise. The solution was stirred for 2 h, concentrated in vacuo, and the residue purified by flash chromatography (0% to 10% MeOH in DCM) to afford the title compound as a white solid (303 mg, 100%). 1H NMR (CDCl3, 400 MHz) δ 1.38 (d, J=2.4 Hz, 3H), 4.22 (dd, J=1.2, 8.8 Hz), 1H), 4.24 (d, J=11.2 Hz, 0.5H), 4.35 (d, J=10.4 Hz, 0.5H), 4.53 (d, J=10.4 Hz, 0.5H), 4.54 (dd, J=0.8, 8.8 Hz, 1H), 4.64 (d, J=10.4 Hz, 0.5H). 19F NMR (CDCl3, 376 MHz) δ −228.4 (t, J=84 Hz). 13C NMR (CDCl3, 100 MHz) δ 17.7 (d, J=3.7 Hz), 63.5 (d, J=18 Hz), 70.7 (d, J=4 Hz), 82 (d, J=179 Hz), 155.8 (s). LRMS (ESI/APCI): 168 [M+H]+, 209 [M+H+CH3CN]+.