Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[C:2]#[C:3][CH3:4].C(N(CC)CC)C.[OH:16]/[N:17]=[C:18](\Cl)/[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[F:25]>C(O)C>[CH2:7]([O:6][C:1]([C:2]1[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])=[N:17][O:16][C:3]=1[CH3:4])=[O:5])[CH3:8]
Reactant: O/N=C(\Cl)c1ccccc1F
Reactant: CC#CC(=O)OCC
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1c(-c2ccccc2F)noc1C
Temperature: 25 °C
Reaction time: 48 h
Yield: 61.5 %

Procedure:
To a solution of ethyl 2-butynoate (65.5 mL, 562 mmol) and triethylamine (80.7 mL, 576 mmol) in ethanol (600 mL) was added, at 0-4° C. over 2 h, 500 mL of a solution of (E)- and/or (Z)—N-hydroxy-2-fluoro-benzenecarboximidoyl chloride (83.3 g 480 mmol) in ethanol (900 mL). Ethyl 2-butynoate (44.6 ml, 383 mmol) in ethanol (125 mL) was added at 0° C., then the remaining 400 ml of the (E)- and/or (Z)—N-hydroxy-2-fluoro-benzenecarboximidoyl chloride solution were added over a 1 h period. The resulting mixture was then stirred for 48 h at room temperature and evaporated. The mixture was then poured onto HCl (1.2 L), and extracted with tert-butyl methyl ether. The combined organic layers were then washed with water and brine, dried over sodium sulfate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 9:1) afforded the title product (73.6 g, 62%) which was obtained as a yellow oil, MS: m/e=250.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[N:11][NH:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=1)=[O:14])[C:6]([C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)([OH:26])[CH2:5]2.C=O.O.[C:37]1(C)C=CC(S(O)(=O)=O)=CC=1>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7]1=[N:11][N:12]([C:13]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:21]=3)=[O:14])[CH2:37][O:26][C:6]1([C:27]1[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=1)[CH2:5]2
Reactant: O=C(NN=C1c2ccc(Cl)cc2CC1(O)c1ccc(Cl)cc1)Nc1ccc(C(F)(F)F)cc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: C=O
Solvent: O
Solvent: CC#N
Product: O=C(Nc1ccc(C(F)(F)F)cc1)N1COC2(c3ccc(Cl)cc3)Cc3cc(Cl)ccc3C2=N1
Yield: 172.8 %

Procedure:
A mixture of 0.30 g (0.0006 moles) of the product obtained in Step D, 0.36 g (0.012 moles) of paraformaldehyde, 50 mg of p-toluene sulfonic acid monohydrate and 30 mL of acetonitrile was refluxed for 1 hour. The resulting mixture was partitioned between CH2Cl2 and saturated aqueous sodium bicarbonate and the aqueous layer was extracted twice with CH2Cl2. The combined organic layers were dried over MgSO4 and concentrated to give an oil that was chromatographed on silica gel using 4:1 hexanes-ethyl acetate to give 0.23 g of an oil that solidified on standing, melting point, 213°-214° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].[Cl:16][CH2:17][C:18](Cl)=[O:19].O>CC(C)CC(=O)C>[Cl:16][CH2:17][C:18]([NH:1][C:2]1[CH:3]=[C:4]([CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8])=[O:19]
Reactant: CCOC(=O)C(C)c1ccc(O)c(N)c1
Reactant: O=C(Cl)CCl
Solvent: CC(=O)CC(C)C
Solvent: O
Product: CCOC(=O)C(C)c1ccc(O)c(NC(=O)CCl)c1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
Ethyl 2-(3-amino-4-hydroxyphenyl)propanoate (104 mg, 0.497 mmol) in 4-methyl-2-pentanone (4 mL) was added chloroacetylchloride (56 mg, 0.496 mmol) at room temperature and stirred for 20 hours at 80° C. The reaction mixture was cooled to room temperature and added water (30 mL). The mixture was extracted with EtOAc. The organic layer was dried with MgSO4 and filtered. EtOAc was removed by evaporation. The residue was purified by column chromatography eluting with n-Hexane/EtOAc=2/1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11]CC)=[O:10])=[CH:4][C:3]=1[OH:14].[C:15]1([CH3:24])[C:16]([N:21]=[C:22]=S)=[CH:17][CH:18]=[CH:19][CH:20]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(O)C>[C:15]1([CH3:24])[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][C:22]1[O:14][C:3]2[CH:4]=[C:5]([CH2:8][C:9]([OH:11])=[O:10])[CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: Cc1ccccc1N=C=S
Reactant: CCOC(=O)Cc1ccc(N)c(O)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCO
Product: Cc1ccccc1Nc1nc2ccc(CC(=O)O)cc2o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of ethyl 4-amino-3-hydroxy-phenylacetate (3.3 g, Reference Example 5) and o-tolylisothiocyanate (2.5 mL) in ethanol (150 mL) was stirred at room temperature for about 2 hours. After standing at room temperature overnight the mixture was evaporated and the residue was subjected to flash chromatography (on silica eluting with a mixture of pentane and ethyl acetate, 7:3 v/v) to give a yellow foam. A solution of this material in ethanol (150 mL) was treated with dicyclohexylcarbodiimide (3.0 g) and the mixture was heated at reflux temperature for 2 hours. The mixture was evaporated and the residue subjected to short column chromatography (on silica eluting with a mixture of tert-butyl methyl ether and dichloromethane, 1:19 to 1:9 v/v). The resulting light yellow oil was dissolved in ethanol (100 mL) and the solution was treated with sodium hydroxide solution (15 mL, 1M) then heated at reflux temperature for 2 hours. The reaction mixture was evaporated and the residue was dissolved in water. The solution was washed with ethyl acetate and the aqueous layer was acidified to pH 1 by addition of concentrated hydrochloric acid. The resulting white precipitate was collected by filtration, then washed thoroughly with water, and then dried to give the title compound (1.8 g) as a white solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:37])[CH:10]([O:20][C:21]2[CH:26]=[CH:25][C:24]([S:27]([C:30]3[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=3)(=[O:29])=[O:28])=[CH:23][CH:22]=2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:4][C:3]=1[N+:38]([O-:40])=[O:39].O.[NH2:42][NH2:43]>CS(C)=O>[NH:42]([C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:37])[CH:10]([O:20][C:21]2[CH:26]=[CH:25][C:24]([S:27]([C:30]3[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=3)(=[O:29])=[O:28])=[CH:23][CH:22]=2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:4][C:3]=1[N+:38]([O-:40])=[O:39])[NH2:43]
Reactant: CCCCCCCCCC(Oc1ccc(S(=O)(=O)c2ccc(O)cc2)cc1)C(=O)Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: NN
Solvent: CS(C)=O
Solvent: O
Product: CCCCCCCCCC(Oc1ccc(S(=O)(=O)c2ccc(O)cc2)cc1)C(=O)Nc1ccc(NN)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
N-(4-Fluoro-3-nitrophenyl)-2-[4-(4-hydroxyphenylsulphonyl)-phenoxy]undecylamide (86.0 g, 147.0 mmole) was dissolved in dimethyl sulphoxide (500 ml), and hydrazine monohydrate (17.8 g, 355 mmole) was added in a dropwise fashion whilst keeping the temperature below 40° C. The reaction mixture was stirred for 1.5 hr at room temperature, and was then drowned in an ice/brine mixture (61). The red solid obtained was filtered off and dried at room temperature. The product was used in this crude form without any further purification.
Reaction SMILES: [CH2:1]1[C@H:6]([NH2:7])[C@@H:5]([O:8][C@H:9]2[O:14][C@H:13]([CH2:15][NH2:16])[C@@H:12](O)[C@H:11](O)[C@H:10]2O)[C@H:4]([OH:20])[C@@H:3]([O:21][C@H:22]2[O:27][C@H:26]([CH2:28][OH:29])[C@@H:25]([OH:30])[C@H:24]([NH2:31])[C@H:23]2[OH:32])[C@@H:2]1[NH2:33].O.C([N:37](CC)CC)C.C(OC(N=[N+]=[N-])=O)(C)(C)C>N1C=CC=CC=1>[CH2:12]1[C@@H:13]([CH2:15][NH2:16])[O:14][C@H:9]([O:8][C@H:5]2[C@H:4]([OH:20])[C@@H:3]([O:21][C@H:22]3[O:27][C@H:26]([CH2:28][OH:29])[C@@H:25]([OH:30])[C@H:24]([NH2:31])[C@H:23]3[OH:32])[C@H:2]([NH2:33])[CH2:1][C@@H:6]2[NH2:7])[C@H:10]([NH2:37])[CH2:11]1
Reactant: NC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O[C@H]3O[C@H](CO)[C@@H](O)[C@H](N)[C@H]3O)[C@H](N)C[C@@H]2N)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: CCN(CC)CC
Agent: CC(C)(C)OC(=O)N=[N+]=[N-]
Solvent: c1ccncc1
Solvent: O
Product: NC[C@@H]1CC[C@@H](N)[C@@H](O[C@H]2[C@H](O)[C@@H](O[C@H]3O[C@H](CO)[C@@H](O)[C@H](N)[C@H]3O)[C@H](N)C[C@@H]2N)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
For instance, 6'-N-t-butoxycarbonylkanamycin may be prepared in a high yield by reacting kanamycin in solution in a mixture of pyridine, water and triethylamine with a 1 to 3 molar proportion of t-butoxycarbonyl azide added dropwise thereto under agitation, stirring the admixture at ambient temperature overnight, concentrating the reaction mixture to dryness in vacuo and then purifying the solid residue in a column chromatography with a cation-exchange resin such as Amberlite CG 50 (NH4 form), while recovering the unreacted kanamycin. Moreover, 2',6'-di-N-t-butoxycarbonylkanamycin B or 3',4'-dideoxykanamycin B may be prepared in a high yield, for example, by reacting kanamycin B or 3',4'-dideoxykanamycin B in solution in a mixture of pyridine, water and triethylamine with a 2-3 molar proportion of t-butoxycarbonyl azide added dropwise thereto under agitation, stirring the admixture at ambient temperature overnight, concentrating the reaction mixture to dryness in vacuo, and then purifying the solid residue in column chromatography with a cation-exchange resin such as Amberlite CG 50 (NH4 form). When this preparation procedure is repeated with 2 molar proportions or less of t-butoxycarbonyl azide, there may be obtained 6'-N-t-butoxycarbonyl-kanamycin B or 3',4'-dideoxykanamycin B in a high yield. 6'-N-t-butoxycarbonyl-kanamycin B or 3',4'-dideoxykanamycin B once isolated may also be converted into the 2',6'-di-N-t-butoxycarbonyl derivative by further reacting with 1 to 2 molar proportions of t-butoxycarbonyl azide in a similar manner. The compounds of the formula (IV) prepared in the above procedures may be employed as a starting compound in the process of this invention without purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([O:9][CH3:10])=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:17]([OH:20])[CH:18]=[CH2:19]>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([O:20][CH2:17][CH:18]=[CH2:19])[C:5]([O:9][CH3:10])=[CH:4][N:3]=1
Reactant: COc1cnc(Cl)nc1Cl
Reactant: C=CCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: C=CCOc1nc(Cl)ncc1OC
Temperature: 70 °C
Yield: 99.7 %

Procedure:
A mixture of 2,4-dichloro-5-methoxypyrimidine (85 g, 475 mmol), and K2CO3 (78.8 g, 570 mmol) in allyl alcohol (320 mL, 4.75 mol) was heated to 70° C. for 5 h before being cooled to r.t. and diluted with DCM, filtered through Celite (DCM wash) and concentrated to give 95.0 g (99.7%) of 2-chloro-5-methoxy-4-(prop-2-en-1-yloxy)pyrimidine. 1H-NMR (CDCl3, 300 MHz) δ 7.85 (s, 1H), 6.09-5.99 (m, 1H), 5.43-5.38 (m, 1H), 5.31-5.27 (m, 1H), 4.91 (m, 2H), 3.87 (s, 3H). MS (ESI) m/z (M+H)+ 201.0.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([F:10])[CH:3]=1.[OH-].[Na+].ClCCl.[CH3:16][C:17]([CH3:19])=[O:18]>O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[CH:16]/[C:17](=[O:18])[CH3:19])=[C:4]([F:10])[CH:3]=1
Reactant: CC(C)=O
Reactant: O=Cc1ccc(Cl)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC(=O)/C=C/c1ccc(Cl)cc1F
Yield: 76 %

Procedure:
To a mechanically stirred solution of 4-chloro-2-fluorobenzaldehyde (23.8 grams (g), 0.15 mole (mol)) in acetone (100 milliliters (mL)) at room temperature was added over 20 minutes (min) a solution of sodium hydroxide (NaOH, 6.6 g, 0.165 mol) in water (H2O, 400 mL). After stirring the reaction mixture overnight, dichloromethane (CH2Cl2, 100 mL) was added. The aqueous layer was separated and extracted with CH2Cl2 (100 mL), and the combined organic extracts were washed with brine and dried over magnesium sulfate (MgSO4). Solvent removal followed by Kugelrohr distillation gave 4-(4-chloro-2-fluorophenyl)-3-buten-2-one (1; 22.5 g, 76%) as a colorless liquid, which solidified upon standing: by 70-80° C., 0.1 mmHg (13.33 pascals (Pa)); 1H NMR (400 MHz, CDCl3) δ 7.59 (d, J=16.5 Hz, 1H), 7.50 (t, J=8.1 Hz, 1H), 7.22-7.12 (m, 2H), 6.76 (d, J=16.5 Hz, 1H), 2.39 (s, 3H); HRMS-ESI (m/z): calcd for C10H8ClFO, 198.024. found 198.025.
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14]C)=[O:13])=[CH:7][CH:6]=2.[N:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1>>[C:16]1([C:3]2[C:2]([C:25]3[CH:26]=[CH:27][N:22]=[CH:23][CH:24]=3)=[N:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:12]([OH:14])=[O:13])[CH:9]=3)[N:4]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Reactant: OB(O)c1ccncc1
Product: O=C(O)c1ccc2nc(-c3ccccc3)c(-c3ccncc3)nc2c1
Yield: 31.6 %

Procedure:
The product was obtained via a Suzuki coupling reaction using the method previously shown in Example 20, Step 3, with methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (100 mg, 0.29 mmol, 1.00 equiv) and pyridin-4-yl boronic acid (54 mg, 0.44 mmol, 1.50 equiv) as reactants. Purification by Prep-TLC (silica gel) yielded 30 mg (30%) of 2-phenyl-3-(pyridin-4-yl)quinoxaline-6-carboxylic acid as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]([OH:18])[CH2:15][CH2:16][CH2:17][C:12]=3[N:11]=[C:10]2[CH:19]([CH3:21])[CH3:20])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:13]3[CH:14]([O:18][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:15][CH2:16][CH2:17][C:12]=3[N:11]=[C:10]2[CH:19]([CH3:21])[CH3:20])=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)c1nc2c(n1Cc1ccc(Cl)cc1)C(O)CCC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)c1nc2c(n1Cc1ccc(Cl)cc1)C(OCC(=O)OC(C)(C)C)CCC2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of Intermediate 58 (352 mg) in anhydrous N,N-dimethylformamide (15 mL) at 0° C. under an atmosphere of nitrogen was added sodium hydride (55 mg) as a 60% by weight suspension on mineral oil in one charge. The reaction was stirred at 0° C. for 30 min. To the reaction was added neat tert-butyl bromoacetate (0.18 mL) in one charge the reaction was stirred at 0° C. for a further 30 min before allowing to warm to ambient temperature over 1 hr. The reaction was stirred at ambient temperature for 3 hr. Sodium hydride (55 mg) as a 60% wt suspension on oil was added and the reaction stirred for 30 min. To the reaction was added tert-butyl bromoacetate (0.18 mL) in one charge. The reaction was quenched with water (75 mL) and extracted with ethyl acetate (75 mL). The extract was dried (hydrophobic frit) and concentrated in vacuo. The sample was loaded in dichloromethane and purified on silica using a 0-25% methanol-dichloromethane gradient. Separation poor all product containing fractions were combined and concentrated in vacuo. The sample was loaded in dichloromethane and purified on silica using a 0-100% ethyl acetate-cyclohexane gradient. The appropriate fractions were combined and concentrated in vacuo to give the title compound (130 mg). LC/MS MH+ 419, 421, Rt 1.00 min (2 min run). Chiral separation of this material using a chiralpak AD column eluting with 5% ethanol in heptane to provide the two enantiomers in order of elution:
Reaction SMILES: C([O:8][C:9]1[CH:31]=[CH:30][C:12]2[N:13]=[C:14]([C:16]3[CH:29]=[CH:28][C:19]([O:20][CH2:21][C@@H:22]([NH:24][C:25](=[O:27])[CH3:26])[CH3:23])=[CH:18][CH:17]=3)[S:15][C:11]=2[CH:10]=1)C1C=CC=CC=1.FC(F)(F)C(O)=O.C1(SC)C=CC=CC=1>>[OH:8][C:9]1[CH:31]=[CH:30][C:12]2[N:13]=[C:14]([C:16]3[CH:17]=[CH:18][C:19]([O:20][CH2:21][C@@H:22]([NH:24][C:25](=[O:27])[CH3:26])[CH3:23])=[CH:28][CH:29]=3)[S:15][C:11]=2[CH:10]=1
Reactant: CC(=O)N[C@@H](C)COc1ccc(-c2nc3ccc(OCc4ccccc4)cc3s2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CSc1ccccc1
Product: CC(=O)N[C@@H](C)COc1ccc(-c2nc3ccc(O)cc3s2)cc1
Temperature: 55 °C
Reaction time: 16 h
Yield: 106 %

Procedure:
A mixture of N-[(1S)-2-{4-[6-(benzyloxy)-1,3-benzothiazol-2-yl]phenoxy}-1-methylethyl]acetamide (46 mg), trifluoroacetic acid (1 mL) and thioanisole (0.1 mL) was stirred at 55° C. for 16 hr. The reaction mixture was concentrated under reduced pressure, and the residue was washed with diisopropyl ether to give N-{(1S)-2-[4-(6-hydroxy-1,3-benzothiazol-2-yl)phenoxy]-1-methylethyl}acetamide (38.6 mg) as a powder. Using the obtained powder, and in the same manner as in Example 1, step A, the title compound was obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.Cl.[NH:13]1[CH2:18][CH2:17][O:16][C@@H:15]([C:19]([N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:20])[CH2:14]1.C(N(CC)CC)C>C(#N)C>[NH2:8][C:6]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=[C:2]([N:13]2[CH2:18][CH2:17][O:16][C@@H:15]([C:19]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[O:20])[CH2:14]2)[N:7]=1
Reactant: O=C([C@H]1CNCCO1)N1CCCC1
Reactant: Nc1nc(Cl)ncc1[N+](=O)[O-]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Nc1nc(N2CCO[C@@H](C(=O)N3CCCC3)C2)ncc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 12 h
Yield: 55.8 %

Procedure:
2-Chloro-5-nitropyrimidin-4-amine (106 mg, 0.612 mmol) was added to a solution of (R)-morpholin-2-yl(pyrrolidin-1-yl)methanone hydrochloride (0.15 g, 0.68 mmol) and triethylamine (0.28 mL, 2.04 mmol) in acetonitrile (10 mL) at room temperature. The reaction mixture was heated at 80° C. for 1 h, then was cooled to room temperature and stirred for 12 h. The solvent was removed under reduced pressure and the resulting crude material was triturated with diethyl ether to afford (R)-(4-(4-amino-5-nitropyrimidin-2-yl)morpholin-2-yl)(pyrrolidin-1-yl)methanone (0.11 g). MS (ES+APCI) (M+H) 323.1; LCMS retention time: 3.518 min (Method S1).
Reaction SMILES: [Cl-].[C:2]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][CH:10]=[C:9]([CH2:12][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:8]=2[CH:32]=1)#[N:3].[CH3:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41][CH:42]=O)=[CH:37][CH:36]=1>O1CCCC1.C(O)C>[CH3:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([CH:41]=[CH:42][CH2:12][C:9]2[C:8]3[CH:32]=[C:4]([C:2]#[N:3])[CH:5]=[CH:6][C:7]=3[O:11][CH:10]=2)=[CH:37][CH:36]=1
Reactant: N#Cc1ccc2occ(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)c2c1
Reactant: COc1ccc(CC=O)cc1
Agent: [Cl-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(C=CCc2coc3ccc(C#N)cc23)cc1
Reaction time: 24 h

Procedure:
2.14 g of (5-cyano-3-benzofuranyl)methyltriphenylphosphonium chloride and 0.7 g of 4-methoxyphenylacetaldehyde were dissolved in a solvent mixture of 100 ml of tetrahydrofuran and 100 ml of ethanol. The thus prepared solution was mixed with 0.71 g of 1,8-diaza-bicyclo[5.4.0]-7-undecene and stirred for 24 hours. After distilling off the solvent, the resulting residue was purified by subjecting it to silica gel column chromatography using toluene as an elution solvent, thereby obtaining 0.86 g of yellow and oily 3-[3-(4-methoxyphenyl)allyl]-5-benzofurancarbonitrile as a mixture of E and Z forms. The thus obtained E/Z mixture was dissolved in 100 ml of ethanol, and the solution was subjected to catalytic hydrogenation under normal pressure in the presence of 370 mg of 5% palladium carbon catalyst. Thereafter, the catalyst was removed by filtration, and the solvent was distilled off to obtain 0.6 g of 3-[3-(4-methoxyphenyl)propyl]-5-benzofurancarbonitrile. The thus obtained methoxy compound was dissolved in 20 ml of dichloromethane. With stirring at -40° C., to the resulting solution was added dropwise 10 ml of a dichloromethane solution containing 0.4 ml of boron tribromide. The resulting mixture was warmed up to room temperature and stirred for 2 hours. The resulting reaction solution was poured into cold dilute hydrochloric acid and extracted with chloroform. After drying the resulting organic layer and distilling off the solvent, the thus obtained residue was purified by subjecting it to silica gel column chromatography using toluene as an elution solvent. In this way, 280 mg of 3-[3-(4-hydroxyphenyl)propyl]-5-benzofurancarbonitrile.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[N:14]=[CH:15][N:16]([C:18]4[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][N:19]=4)[CH:17]=3)=[C:11]([CH3:27])[N:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:28][C:29]([CH3:33])([CH3:32])[CH2:30][OH:31]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[N:14]=[CH:15][N:16]([C:18]4[CH:26]=[CH:25][C:21]([C:22]([NH:28][C:29]([CH3:33])([CH3:32])[CH2:30][OH:31])=[O:23])=[CH:20][N:19]=4)[CH:17]=3)=[C:11]([CH3:27])[N:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(N)CO
Reactant: Cc1nnn(-c2ccc(F)cc2)c1-c1cn(-c2ccc(C(=O)O)cn2)cn1
Product: Cc1nnn(-c2ccc(F)cc2)c1-c1cn(-c2ccc(C(=O)NC(C)(C)CO)cn2)cn1
Yield: 79 %

Procedure:
As described for example 36b, 6-(4-(1-(4-fluorophenyl)-4-methyl-1H-1,2,3-triazol-5-yl)-1H-imidazol-1-yl)nicotinic acid (65 mg, 0.178 mmol) was converted, using 2-amino-2-methyl-1-propanol instead of isopropylamine, to the title compound (61 mg, 79%) which was obtained as a white solid. MS: m/e=436.2 [M+H]+.
Reaction SMILES: C([Li])CCC.CCCCCC.[CH3:12][C:13]1[N:20]2[C:16]([S:17][CH:18]=[CH:19]2)=[C:15]([CH3:21])[N:14]=1.[CH2:22]([Sn:26](Cl)([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH3:25]>C1COCC1>[CH3:12][C:13]1[N:20]2[C:16]([S:17][C:18]([Sn:26]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:22][CH2:23][CH2:24][CH3:25])=[CH:19]2)=[C:15]([CH3:21])[N:14]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Cc1nc(C)n2ccsc12
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cn2c(C)nc(C)c2s1
Temperature: -30 °C
Reaction time: 1.33 h

Procedure:
To 50 ml of anhydrous THF cooled to −65° C. under the atmosphere of argon was added 10.9 ml of a 1.63 N n-butyl lithium/n-hexane solution, and a solution of 2.564 g of 5,7-dimethylimidazo[5,1-b]thiazole in 17 ml of anhydrous THF was further added dropwise at −64-−60° C. over a period of 15 minutes. The reaction mixture was then stirred at the same temperature for 80 minutes. After 5.0 ml of tri-n-butylstannyl chloride was added dropwise to the mixture at a temperature of −63-−58° C. over a period of 10 minutes, it was warmed to −30° C., and further stirred for 110 minutes. The reaction mixture was diluted with 100 ml of semi-saturated aqueous saline, extracted with 150 ml of ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The oil thus obtained was purified by column chromatography on silica gel (n-hexane:ethyl acetate=1:1-−1:2) to give the title compound as a light orange oil in a yield of 6.164 g.
Reaction SMILES: C1CO[C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[N:17]=[C:16]([NH:18][C:19]4[CH:24]=[CH:23][C:22]5OCC[O:28][C:21]=5[CH:20]=4)[C:15]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:14][N:13]=3)=[CH:4][C:3]=2[O:2]1.OC1C=C(NC2N=C(NC3C=CC=C(O)C=3)C(Br)=CN=2)C=CC=1.C1(B(O)O)C=CC=CC=1>>[OH:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[N:17]=[C:16]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([OH:28])[CH:20]=3)[C:15]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[CH:14][N:13]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: c1ccc(-c2cnc(Nc3ccc4c(c3)OCCO4)nc2Nc2ccc3c(c2)OCCO3)cc1
Agent: OB(O)c1ccccc1
Agent: Oc1cccc(Nc2ncc(Br)c(Nc3cccc(O)c3)n2)c1
Product: Oc1cccc(Nc2ncc(-c3ccccc3)c(Nc3cccc(O)c3)n2)c1

Procedure:
In a manner similar to the preparation of N2,N4-bis(3,4-ethylenedioxyphenyl)-5-phenyl-2,4-pyrimidinediamine, N2,N4-bis(3-hydroxyphenyl)-5-bromo-2,4-pyrimidinediamine and phenylboronic acid were reacted to yield N2,N4-bis(3-hydroxyphenyl)-5-phenyl-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 7.85 (bs, 1H), 7.54-7.38 (m, 5H), 7.13-7.11 (m, 2H), 7.10-7.04 (m, 3H), 6.97 (dt, 1H, J=1.8 and 8.1 Hz), 6.54 (ddd, 1H, J=1.9, 2.4, and 7.2 Hz), 6.44 (dt, 1H, J=1.8 and 6.0 Hz); LCMS: ret. time: 20.66 min.; purity: 96%; MS (m/e): 371 (MH+).