Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][C:7]([CH2:8][O:9][C:10]([NH:12][CH:13]([CH2:16][OH:17])[CH2:14][OH:15])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:20]([S:23][C@@H:24]1[CH2:28][N:27]([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=2)=[O:30])[C@H:26]([CH:42]=O)[CH2:25]1)(=[O:22])[CH3:21].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:20]([S:23][C@@H:24]1[CH2:28][N:27]([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=2)=[O:30])[C@H:26]([CH:42]2[O:17][CH2:16][CH:13]([NH:12][C:10]([O:9][CH2:8][C:7]3[CH:18]=[CH:19][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)=[O:11])[CH2:14][O:15]2)[CH2:25]1)(=[O:22])[CH3:21]
Reactant: O=C(NC(CO)CO)OCc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)S[C@H]1C[C@@H](C=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)S[C@H]1C[C@@H](C2OCC(NC(=O)OCc3ccc([N+](=O)[O-])cc3)CO2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Yield: 85.7 %

Procedure:
A solution of 2-(4-nitrobenzyloxycarbonyl)amino-1,3-propanediol (1.42 g), (2S,4S)-4-acetylthio-2-formyl-1-(4-nitrobenzyloxycarbonyl) pyrrolidine (1.00 g) and 4-toluene-sulfonic acid (0.30 g) in toluene was refluxed for 2 hours with removing water under azeotropic condition. The reaction mixture was poured into a mixture of water and ethyl acetate. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel (80 ml) and eluted with a mixture of acetone and dichloromethane (1:9, V/V) to give (2S, 4S)-4-acetylthio-1- (4-nitrobenzyloxycarbonyl)-2-[5-(4-nitrobenzyloxycarbonylamino) -1,3-dioxan-2-yl]pyrrolidine (1.47 g).
Reaction SMILES: [OH:1][C@H:2]([CH3:25])[C@H:3]([NH:8][C:9]([C:11]1[CH:16]=[CH:15][C:14](C(C2C=CC=CC=2)=O)=[CH:13][CH:12]=1)=[O:10])[C:4]([O:6][CH3:7])=[O:5].C(OC(NCC(N[C:38]1[CH:43]=[CH:42]C(I)=[CH:40][CH:39]=1)=O)=O)(C)(C)C.CCN(CC)CC.N#N.[CH2:54]1[CH2:58][O:57][CH2:56][CH2:55]1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:7][O:6][C:4](=[O:5])[C@@H:3]([NH:8][C:9](=[O:10])[C:11]1[CH:16]=[CH:15][C:14]([C:42]#[C:43][C:38]2[CH:56]=[CH:55][C:54]([CH:58]=[O:57])=[CH:40][CH:39]=2)=[CH:13][CH:12]=1)[C@H:2]([OH:1])[CH3:25]
Reactant: COC(=O)[C@@H](NC(=O)c1ccc(C(=O)c2ccccc2)cc1)[C@@H](C)O
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)NCC(=O)Nc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: N#N
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](NC(=O)c1ccc(C#Cc2ccc(C=O)cc2)cc1)[C@@H](C)O
Reaction time: 40 h
Yield: 80 %

Procedure:
A solution of alkyne 1 (745 mg, 2.85 mmol), 4-iodobenzaldehyde 2 (902 mg, 3.89 mmol), and Et3N (900 μL, 6.5 mmol) in THF (50 mL) was purged with a stream of N2 for two minutes and then treated with PdCl2(PPh3)2 (70 mg, 0.10 mmol) and CuI (34 mg, 0.18 mmol). The reaction mixture was stirred 40 h, concentrated by rotary evaporation and purified by silica gel chromatography (40:1 DCM/MeOH) to give 0.833 g (80% yield) of (2S,3R)-2-[4-(4-formyl-phenylethynyl)-benzoylamino]-3-hydroxy-butyric acid methyl ester 3 as a pale yellow powder, mp=143-144° C. Rf=0.3 (25:1 DCM/MeOH); LRMS (ES+) m/z 366.1 (C21H19NO5+H requires 366.13); HPLC (300 nm, 47 min) 15.3 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.C([Li])CCC.CN(C)[C:16](=[O:18])[CH3:17].Cl>C(OCC)C>[Br:1][C:2]1[N:3]=[C:4]([C:16](=[O:18])[CH3:17])[C:5]([F:8])=[CH:6][CH:7]=1
Reactant: CC(=O)N(C)C
Reactant: Fc1ccc(Br)nc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(=O)c1nc(Br)ccc1F
Temperature: -65 °C
Reaction time: 1 h
Yield: 33.8 %

Procedure:
2-Bromo-5-fluoro-pyridine (11 g, 62.5 mmol) was dissolved in diethyl ether at room temperature under a nitrogen atmosphere. The reaction mixture was cooled until the internal temperature was −66° C. Butyl lithium (2.5 M in hexanes, 26 mL, 65 mmol) was added dropwise over 0.5 h. The resulting reaction mixture was left at −65° C. for 1 h. N,N-Dimethylacetamide (6.5 mL, 70 mmol) was added over 10 min. and the reaction mixture was stirred at −65° C. for 2 h. 1M hydrochloric acid aq. (50 mL) was added and the mixture was warmed to room temperature. The pH was adjusted to 7 with additional hydrochloric acid. The aqueous phase was extracted with diethyl ether three times. The combined organic phases were washed with Brine, dried over sodium sulphate, and concentrated in vacuo. Purification by flash column chromatography (eluent heptane:diethyl ether gradient) yielded 4.6 g (34% yield) of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N+:12]([O-])=[C:11]([CH3:20])[C:10]=1[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-:23].[K+].[K+].[C:28]1([CH3:38])[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>C(#N)C>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([CH2:20][O:35][S:34]([C:31]2[CH:32]=[CH:33][C:28]([CH3:38])=[CH:29][CH:30]=2)(=[O:23])=[O:36])[C:10]=1[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1c(OCc2ccccc2)c2ccccc2[n+]([O-])c1C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [K+]
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)OCc2nc3ccccc3c(OCc3ccccc3)c2C)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 40.7 %

Procedure:
To a mixture of 4-benzyloxy-2,3-dimethylquinoline-1-oxide (21.2 g), potassium carbonate (20.9 g), and acetonitrile (400 mL) was added p-toluenesulfonyl chloride (18.8 g), followed by stirring at room temperature for 12 hours. Insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure. Water (500 mL) was added to the residue, followed by twice extractions with ethyl acetate (500 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=5/1) to obtain p-toluenesulfonic acid [4-(benzyloxy)-3-methylquinolin-2-yl]methyl ester (13.4 g).
Reaction SMILES: Cl.[O:2]1[C:6]2[CH2:7][NH:8][CH2:9][CH2:10][C:5]=2[CH:4]=[CH:3]1.[C:11]1([C:17]2([C:22]3[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=3)[S:21][CH2:20][CH2:19][S:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>CN(C)C=O.O>[C:11]1([C:17]2([C:22]3[CH:23]=[CH:24][C:25]([C:26]([N:8]4[CH2:9][CH2:10][C:5]5[CH:4]=[CH:3][O:2][C:6]=5[CH2:7]4)=[O:27])=[CH:29][CH:30]=3)[S:21][CH2:20][CH2:19][S:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: c1cc2c(o1)CNCC2
Reactant: O=C(O)c1ccc(C2(c3ccccc3)SCCS2)cc1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1ccc(C2(c3ccccc3)SCCS2)cc1)N1CCc2ccoc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1.582 g (9.912 mmol) of 4,5,6,7-tetrahydrofuro[2,3-c]pyridine hydrochloride, 3.00 g (9.91 mmol) of 4-(2-phenyl-1,3-dithiolan-2-yl)benzoic acid and 5.53 ml (39.6 mmol) of triethylamine in 50 ml of N,N-dimethylformamide, 1.80 ml (11.9 mmol) of diethyl cyanophosphonate was added dropwise, followed by overnight stirring at room temperature. This mixture was poured into water and extracted with diethyl ether 3 times. The combined organic layer was dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=6/1 to 2/1) to yield the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1.[Br:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[C:28](I)[CH:27]=1>CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:25][C:26]1[CH:27]=[CH:28][C:29]([F:32])=[C:30]([C:3]2[C:4]([OH:8])=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH:31]=1
Reactant: OB(O)c1c(O)cccc1Cl
Reactant: Fc1ccc(Br)cc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: Oc1cccc(Cl)c1-c1cc(Br)ccc1F
Temperature: 105 °C
Yield: 91.5 %

Procedure:
(2-Chloro-6-hydroxyphenyl)boronic acid (250 mg, 1.450 mmol, 1.0 equiv), Pd(PPh3)4 (168 mg, 0.145 mmol, 0.1 equiv) and aqueous Na2CO3 (2 M, 1.8 mL, 3.63 mmol, 2.5 equiv) were mixed with toluene (3 mL) in a sealed microwave tube. 4-Bromo-1-fluoro-2-iodobenzene (436 mg, 1.450 mmol) in MeOH (1.50 mL) was added to the above mixture. The mixture was heated at 105° C. overnight. Then, the reaction mixture was loaded on 12 g column and purified using 30% EtOAc/Hex to afford 5′-bromo-6-chloro-2′-fluoro-[1,1′-biphenyl]-2-ol (400 mg, 91% yield). 1H NMR (400 MHz, CDCl3) δ 7.57 (ddd, J=8.8, 4.5, 2.5 Hz, 1H), 7.47 (dd, J=6.3, 2.5 Hz, 1H), 7.24 (t, J=8.2 Hz, 1H), 7.17-7.06 (m, 2H), 6.90 (d, J=8.0 Hz, 1H). LCMS (M+1)=302.9.
Reaction SMILES: [NH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][N:4]=1)[NH2:2].[C:12]([C:14]1[CH:19]=[CH:18][C:17]([C:20](=[CH:25]N(C)C)[C:21](OC)=[O:22])=[C:16]([CH3:29])[C:15]=1[F:30])#[N:13].Cl.C(N(C(C)C)C(C)C)C>O.CC(O)C>[C:12]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[N:2][N:1]([C:3]3[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][N:4]=3)[C:21]=2[OH:22])=[C:16]([CH3:29])[C:15]=1[F:30])#[N:13]
Reactant: COC(=O)C(=CN(C)C)c1ccc(C#N)c(F)c1C
Reactant: NNc1ccc(C(=O)O)cn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Solvent: O
Product: Cc1c(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccc(C#N)c1F
Reaction time: 2 h
Yield: 65.9 %

Procedure:
Combined 6-hydrazinylnicotinic acid (1.10 g, 7.18 mmol), methyl 2-(4-cyano-3-fluoro-2-methylphenyl)-3-(dimethylamino)acrylate (2.072 g, 7.90 mmol), 2-propanol (18 mL), and 0.5M aqueous hydrochloric acid (17.24 mL, 8.62 mmol). After 2 hours, N-ethyl-N-isopropylpropan-2-amine (6.26 mL, 35.9 mmol) was added. After another hour the reaction mixture was diluted with water and washed twice with IPAc. The aqueous phase was acidified to ˜pH=3.5 and stirred for 30 minutes to give a solid which was collected by filtration, washed with water, ethanol, and heptanes, and dried overnight under vacuum to give the title compound (1.60 g, 66%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.34 (d, J=2.27 Hz, 3H) 7.64 (d, J=8.08 Hz, 1H) 7.69-7.80 (m, 1H) 8.26 (br. s., 1H) 8.48 (br. s., 2H) 8.98 (t, J=1.52 Hz, 1H) 13.45 (br. s., 2H). ESI-MS m/z [M+H]+ 339.2.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:4]=[C:5]([NH:13][C:14](=[O:26])[C:15]2[CH:20]=[C:19](I)[CH:18]=[CH:17][C:16]=2[O:22][CH2:23][O:24][CH3:25])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C([Sn](CCCC)(CCCC)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1)CCC.O>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]([F:28])([F:27])[C:3]1[CH:4]=[C:5]([NH:13][C:14](=[O:26])[C:15]2[CH:20]=[C:19]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=3)[CH:18]=[CH:17][C:16]=2[O:22][CH2:23][O:24][CH3:25])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: COCOc1ccc(I)cc1C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1ccc(-c2ccccn2)cc1C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 20.7 %

Procedure:
N-[3,5-Bis(trifluoromethyl)phenyl]-5-iodo-2-methoxymethoxybenzamide (0.20 g, 0.39 mmol) was dissolved in N,N-dimethylformamide (8 ml). Tri-n-butyl(2-pyridyl)tin (0.13 ml, 0.41 mmol) and dichlorobis(triphenylphosphine)palladium (32.1 mg, 0.05 mmol) were added, and the mixture was stirred at 100° C. for 1.5 hours. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel (n-hexane:ethyl acetate=2:1→1:1) to give the title compound (37.9 mg, 20.8%) as a white powder.
Reaction SMILES: [CH2:1](OCCl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:11]1[CH:15]=[CH:14][N:13]=[CH:12]1.[O-:16][CH2:17]C.[Na+]>>[C:2]1([CH2:1][CH2:17][O:16][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1c[nH]cn1
Reactant: CC[O-]
Reactant: ClCOCc1ccccc1
Agent: [Na+]
Product: c1ccc(CCOn2ccnc2)cc1

Procedure:
Chloromethyl benzyl ether (32.3 g, 0.2 mol) was added dropwise to a stirred, boiling solution of imidazole (13.6 g, 0.2 ml) and ethanolic sodium ethoxide (prepared from sodium (4.6 g, 0.2 mol) in dry ethanol (150 ml)). Following the addition, the reaction mixture was stirred and heated under reflux for 8 h.
Reaction SMILES: [N+]([NH:4][C:5]([NH2:7])=[O:6])([O-])=O.[N:8]1([CH2:14][CH2:15][O:16][CH:17]2[CH2:21][CH2:20]N[CH2:18]2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[OH-].[Na+]>C(O)C>[N:8]1([CH2:14][CH2:15][O:16][CH:17]2[CH2:21][CH2:20][N:4]([C:5]([NH2:7])=[O:6])[CH2:18]2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: C1CCN(CCOC2CCNC2)CC1
Reactant: NC(=O)N[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NC(=O)N1CCC(OCCN2CCCCC2)C1

Procedure:
Nitrourea (7.3 g., 0.055 mole of 80% wet reagent) and 3-(2-piperidinoethoxy)pyrrolidine were stirred together in 100 ml. ethanol at reflux for 2 hr. After cooling, the reaction mixture was filtered and the filtrate concentrated to give 12.5 g. solid material which was determined by nuclear magnetic resonance spectrum analysis to be a salt. The crude product was treated with dilute sodium hydroxide solution and the free base extracted into chloroform twice. The chloroform extracts were combined, washed with water, dried over magnesium sulfate, filtered, and concentrated to give 6.8 g. of off-white solid product. Recrystallization from isopropyl ether-isopropanol gave 3.7 g. (30.7%) white solid, m.p. 133.5°-135.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:13][CH:12]=[CH:11][CH2:10]2)=[C:4]([N+:14]([O-:16])=[O:15])[CH:3]=1.B1C2CCCC1CCC2.[OH-:26].[Na+].OO>C1COCC1.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:10][CH2:11][CH:12]([OH:26])[CH2:13]2)=[C:4]([N+:14]([O-:16])=[O:15])[CH:3]=1
Reactant: [OH-]
Reactant: O=[N+]([O-])c1cc(Cl)ccc1OC1CC=CC1
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: O=[N+]([O-])c1cc(Cl)ccc1OC1CCC(O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.7 %

Procedure:
A solution of Example 25A (1.18 g, 5 mmol) in THF (20 mL) was treated with a solution of 9-BBN (0.5M in THF, 10 mL, 5.0 mmol) via syringe. After stirring at room temperature overnight, the solution was cooled with an ice bath, treated with a solution of NaOH (0.2 g) in water (2 mL), treated dropwise with hydrogen peroxide (30% wt, 0.56 g, 5.0 mmol), and stirred for 3 hours. The mixture was treated with water (50 mL) and ethyl acetate (150 mL) and the organic phase was extracted with ethyl acetate. The combined organic extracts were dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 60% ethyl acetate/hexanes to provide 0.55 g (42.8%) of the desired product. MS (DCI/NH3) m/z 275 (M+NH4)+; 1H NMR indicated two isomers in ˜4:1 ratio. The spectrum of the major isomer (300 MHz, CDCl3) δ 7.79 (d, J=2.4 Hz, 1H), 7.46 (dd, J=8.8, 2.7 Hz, 1H), 7.01 (d, J=8.8 Hz, 1H), 4.95–5.05 (m, 1H), 4.55–4.60 (m, 1H), 1.4–2.30 (m, 7H).
Reaction SMILES: [C:1]1(/[CH:18]=[CH:19]\[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:14][CH2:13][C:12]3[O:15][CH:16]=[CH:17][C:11]=3[CH2:10]2)=[O:8])=[CH:3][CH:2]=1.[CH3:26][NH:27][CH3:28].[CH2:29]=O>C(O)(=O)C>[CH3:26][N:27]([CH2:29][C:16]1[O:15][C:12]2[CH2:13][CH2:14][N:9]([C:7]([C:4]3[CH:3]=[CH:2][C:1](/[CH:18]=[CH:19]\[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:6][CH:5]=3)=[O:8])[CH2:10][C:11]=2[CH:17]=1)[CH3:28]
Reactant: CNC
Reactant: O=C(c1ccc(/C=C\c2ccccc2)cc1)N1CCc2occc2C1
Reactant: C=O
Solvent: CC(=O)O
Product: CN(C)Cc1cc2c(o1)CCN(C(=O)c1ccc(/C=C\c3ccccc3)cc1)C2
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of 0.295 g (0.895 mmol) of (Z)-5-(4-stilbenecarbonyl)-4,5,6,7-tetrahydrofuro[3,2-c]pyridine in 20 ml of acetic acid, 0.12 ml (1.3 mmol) of 50% aqueous dimethylamine and 0.11 ml (1.3 mmol) of 37% aqueous formaldehyde were added, followed by stirring at 100° C. for 60 minutes. After the solvent was distilled off under reduced pressure, the residual solution was alkalified with 5% aqueous sodium hydrogen carbonate, and extracted with dichloromethane 2 times. The combined organic layer was washed with water and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (chloroform/methanol=50/1) to yield the desired product.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[C:6](Cl)[N:5]=[C:4]([CH3:10])[N:3]=1.Cl.Cl.[CH3:13][C:14]1([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:17][NH:16][CH2:15]1.CCN(C(C)C)C(C)C.O.[NH2:33][NH2:34]>CS(C)=O>[F:8][C:7]1[C:2]([NH:33][NH2:34])=[N:3][C:4]([CH3:10])=[N:5][C:6]=1[N:16]1[CH2:17][C:14]([CH3:13])([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:15]1
Reactant: NN
Reactant: CC1(N2CCCC2)CNC1
Reactant: Cc1nc(Cl)c(F)c(Cl)n1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1nc(NN)c(F)c(N2CC(C)(N3CCCC3)C2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
To a mixture of 4,6-dichloro-5-fluoro-2-methylpyrimidine (90 mg, 0.50 mmol), 1-(3-methyl-3-azetidinyl)pyrrolidine dihydrochloride (Example 176) (131 mg, assumed 86% pure, 0.53 mmol) in 5 mL of DMSO was added DIPEA (0.345 mL, 1.98 mmol). The resulting reaction mixture was stirred at rt overnight, and then hydrazine monohydrate was added (0.5 mL) and the contents were heated to 80° C. for 4 h. The reaction mixture was then cooled to room temperature and purified by RP-HPLC to provide 5-fluoro-4-hydrazino-2-methyl-6-[3-methyl-3-(1-pyrrolidinyl)-1-azetidinyl]pyrimidine (100 mg, 71%). LCMS: (M+H)+: 281.0.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].CN(C)C=O.Br[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=1>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: Cc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1nc(C)n(Cc2ccc(C)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61.2 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), sodium hydride (0.17 g) and N,N-dimethylformamide (15 mL) was stirred at room temperature for 10 min, 1-(bromomethyl)-4-methylbenzene (0.62 g) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.79 g, 61%).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)[CH3:3].[H-].[Na+].[CH:20]([N:23]1[CH2:28][CH2:27][CH:26](OS(C)(=O)=O)[CH2:25][CH2:24]1)([CH3:22])[CH3:21]>CN(C=O)C.CC(OC)(C)C.O.[OH-].[Na+]>[CH:20]([N:23]1[CH2:28][CH2:27][CH:26]([O:17][C:14]2[CH:15]=[CH:16][C:11]([C:5]3([CH2:4][N:2]([CH3:1])[CH3:3])[CH2:6][CH2:7][O:8][CH2:9][CH2:10]3)=[CH:12][CH:13]=2)[CH2:25][CH2:24]1)([CH3:22])[CH3:21]
Reactant: CN(C)CC1(c2ccc(O)cc2)CCOCC1
Reactant: CC(C)N1CCC(OS(C)(=O)=O)CC1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)N1CCC(Oc2ccc(C3(CN(C)C)CCOCC3)cc2)CC1
Temperature: 75 °C
Reaction time: 1 h
Yield: 17.3 %

Procedure:
4-(4-Dimethylaminomethyl-tetrahydro-pyran-4-yl)-phenol (532 mg, 2.26 mmol) in DMF (2 ml) was added to a solution of NaH (100 mg, 2.5 mmol) in DMF (2 ml) at room temperature under N2. The reaction was stirred for 1 hr and a solution of methanesulfonic acid 1-isopropyl-piperidin-4-yl ester (400 mg, 1.81 mmol) in DMF (1.3 ml) was slowly added. The reaction was heated to 75° C. and stirred for 6 hrs. The reaction was allowed to cool to room temperature and diluted with TBME (20 ml), water (10 ml) and 5M NaOH solution (10 ml). The organic layer was washed with 2.5M NaOH (2×20 ml), brine (2×20 ml), dried over MgSO4, filtered and concentrated in vacuo. The crude reaction was purified by column chromatography, eluting with DCM:MeOH:NH3 (98:1:1) to give the title compound as a white crystalline solid (113 mg, 17%). 1H NMR (400 MHz, CDCl3) δ7.20 (d, 2H), 6.87 (d, 2H), 4.27 (m, 1H), 3.75 (dt, 2H), 3.55 (td, 2H), 2.85-2.68 (m, 3H), 2.45-2.32 (m, 2H), 2.40 (s, 2H), 2.14-1.94 (m, 4H), 1.96 (s, 6H), 1.93-1.75 (m, 4H), 1.06 (d, 6H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.CN[C:19]1[NH:20][C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=1.[CH2:28]([N:30](CC)CC)C>>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:30][CH2:28][C:19]2[NH:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[N:20]=2)[N:3]=1
Reactant: CNc1nc2ccccc2[nH]1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Reactant: CCN(CC)CC
Product: Clc1nc(NCc2nc3ccccc3[nH]2)c2ncn(C3CCCC3)c2n1

Procedure:
2-Chloro-6-[(2-benzimidazolyl)methylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 2-(methylamino)benzimidazole, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [C:1]([O:4][CH2:5][CH3:6])(=[O:3])[CH3:2].[O-:7]CC.[Na+].[F:11][C:12](N(C)C)([F:16])[CH:13](F)F.O>C(O)C>[F:11][CH:12]([F:16])[C:13](=[O:7])[CH2:2][C:1]([O:4][CH2:5][CH3:6])=[O:3]
Reactant: CC[O-]
Reactant: CCOC(C)=O
Reactant: CN(C)C(F)(F)C(F)F
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CC(=O)C(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.5 %

Procedure:
An initial charge of 48 g of ethyl acetate was admixed at RT with a 10% solution of 32.4 g of sodium ethoxide in ethanol. The mixture was stirred at RT for 1 h and then admixed with 36 g of 1,1,2,2-tetrafluoroethyldimethylamine. Subsequently, the solution was stirred at 30° C. for 2 h, admixed with H2O and adjusted to pH 5. After extraction with ethyl acetate and subsequent distillation, 27 g (65%) of ethyl difluoroacetoacetate (boiling point 90-94° C./100 mbar) were obtained.