Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7](/[CH:11]=[C:12]3/[C:13](=[O:18])[NH:14][C:15](=[S:17])[S:16]/3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.IC.[CH:21](N(CC)C(C)C)(C)C.O.[CH2:31]([OH:33])[CH3:32]>>[CH2:31]([O:33][C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([CH:11]=[C:12]3[S:16][C:15]([S:17][CH3:21])=[N:14][C:13]3=[O:18])[CH:6]=2)[N:1]=[CH:2][CH:3]=1)[CH3:32]
Reactant: CCO
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C1NC(=S)S/C1=C\c1ccc2ncccc2c1
Solvent: CI
Solvent: O
Product: CCOc1ccnc2ccc(C=C3SC(SC)=NC3=O)cc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 84 %

Procedure:
To the suspension of 5-[1-quinolin-6-yl-meth-(Z)-ylidene]-2-thioxo-thiazolidin-4-one (example 40a) (2.4 g, 20 mmol), iodomethane (2.54 mL, 40 mmol) and DIEA (N,N-diisopropylethylamine) (6.4 mL, 30 mmol) in anhydrous ethanol (70 mL) was stirred at room temperature for 24 h. After adding water (50 mL), the solid was collected by filtration, washed with water and dried to give 5-(4-ethoxy-quinolin-6-ylmethylene)-2-methylsulfanyl-thiazol-4-one (5.67 g, 84%) as a yellow solid. LC-MS m/e 331 (MH+)
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C@@H:9]([C:10]#[C:11][CH3:12])[CH2:8][CH2:7][C@H:6]1[C:13]#[N:14])=[O:4].[NH2:15][C:16]1([CH2:21][OH:22])[CH2:20][CH2:19][CH2:18][CH2:17]1>C(#N)C>[OH:22][CH2:21][C:16]1([NH:15][CH2:2][C:3]([N:5]2[C@@H:9]([C:10]#[C:11][CH3:12])[CH2:8][CH2:7][C@H:6]2[C:13]#[N:14])=[O:4])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: NC1(CO)CCCC1
Reactant: CC#C[C@H]1CC[C@@H](C#N)N1C(=O)CCl
Solvent: CC#N
Product: CC#C[C@H]1CC[C@@H](C#N)N1C(=O)CNC1(CO)CCCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of (2S,5R)-1-(chloroacetyl)-5-propynylpyrrolidine-2-carbonitrile (0.03 g, 0.14 mmol, Example 88D) in acetonitrile (1 mL) at room temperature was added 1-amino-1-cyclopentanemethanol (35 mg, 0.28 mmol). The reaction mixture was stirred at room temperature for 18 hours, concentrated under reduced pressure and purified by flash chromatography with 3% methanol/97% dichloromethane to provide the titled compound. MS (ESI) m/z 290 (M+H)+; 1H NMR (DMSO) δ ppm 4.86 (m, 1H), 4.16 (m, 1H), 3.52 (m, 2H), 3.44 (m, 2H), 2.06-2.39 (m, 4H), 1.96 (m, 2H), 1.86 (d, 3H), 1.75 (m, 6H), 1.56 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH2:9])[CH:3]=1.C1(C)C=C(C)C=C(C)C=1S(O[NH2:22])(=O)=O.[OH:24][CH2:25][C:26]1[O:32][C:29]([CH:30]=O)=[CH:28][CH:27]=1>>[NH2:8][C:6]1[N:5]2[N:22]=[C:30]([C:29]3[O:32][C:26]([CH2:25][OH:24])=[CH:27][CH:28]=3)[N:9]=[C:4]2[CH:3]=[C:2]([Br:1])[CH:7]=1
Reactant: Nc1cc(Br)cc(N)n1
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Reactant: O=Cc1ccc(CO)o1
Product: Nc1cc(Br)cc2nc(-c3ccc(CO)o3)nn12

Procedure:
The title compound, MS m/e (%): 311 (M30 +2, 100), was prepared in accordance with the general method of example 63 from 4-bromo-pyridine-2,6-diamine, O-mesitylene-sulfonylhydroxylamine, and 5-hydroxymethyl-furfural. The purification was performed with reversed phase HPLC eluting with an acetonitrile/water gradient.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:11][NH:12][C:13]1[NH:23][C:22]2[C:15](=[C:16]([CH2:24][C:25]3[CH:30]=[C:29]([Br:31])[C:28]([O:32][CH3:33])=[C:27]([Br:34])[CH:26]=3)[C:17]([N:19]=[CH:20][CH:21]=2)=[O:18])[N:14]=1.I[CH3:36]>CN(C=O)C.C1COCC1>[CH3:11][NH:12][C:13]1[N:23]=[C:22]2[C:15](=[C:16]([CH2:24][C:25]3[CH:26]=[C:27]([Br:34])[C:28]([O:32][CH3:33])=[C:29]([Br:31])[CH:30]=3)[C:17]([N:19]([CH3:36])[CH:20]=[CH:21]2)=[O:18])[N:14]=1
Reactant: CNc1nc2c(Cc3cc(Br)c(OC)c(Br)c3)c(=O)nccc2[nH]1
Reactant: CI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CNc1nc2ccn(C)c(=O)c(Cc3cc(Br)c(OC)c(Br)c3)c-2n1
Temperature: -78 °C
Yield: 43.6 %

Procedure:
Sodium bis(trimethylsilyl)amide (1 M in THF, 24 μL, 0.0240 mmol) was added dropwise to a solution of ceratamine B from Example 12 (formula (IIIB); R1=methyl) (12.1 mg, 0.0266 mmol) in DMF:THF (1:1, 0.27 mL) at 0° C. The reaction mixture was cooled to −78° C. and iodomethane (2.1 μL, 0.0346 mmol) was added dropwise followed by warming to −10° C. The reaction was quenched by the addition H2O (2 mL), and was extracted with EtOAc (6×5 mL). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo to afford crude ceratamine A (formula (IIIA); R1=methyl). Purification by flash chromatography (C-18 reverse-phase silica, 70% MeOH:H2O) yielded pure ceratamine A (formula (IIIA); R1=methyl) (5.4 mg, 0.0116 mmol, 43%) as a yellow solid. The major tautomer was characterized: 1H NMR (400 MHz, DMSO) δ 8.68 (m, NH), 7.74 (d, J=9.9 Hz, 1H), 7.66 (s, 2H), 6.42 (d, J=9.9 Hz, 1H), 4.23 (s, 2H), 3.72 (s, 3H), 3.55 (s, 3H), 3.07 (d, J=4.9 Hz, 3H); 13C NMR (100 MHz, DMSO) δ 175.6, 169.7, 164.1, 160.5, 151.4, 142.9, 140.2, 133.1, 121.3, 116.6, 100.4, 60.3, 43.7, 35.0, 29.2; HRMS (ESI) m/z calcd for C17H17Br2N4O2: 466.9713. found: 466.9701. These data from synthetic ceratamine A are consistent with data reported for natural products.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:16]3=[N:17][S:18](=[O:22])(=[O:21])[CH2:19][CH2:20][N:15]3[CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)[CH3:3]>C1COCC1.C(O)C.[C].[Rh]>[CH3:3][CH:2]([O:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[C:16]3=[N:17][S:18](=[O:21])(=[O:22])[CH2:19][CH2:20][N:15]3[CH2:14][CH2:13][CH2:12]2)=[CH:9][CH:10]=1)[CH3:1]
Reactant: CC(C)Oc1ccc(C2=CC=CN3CCS(=O)(=O)N=C23)cc1
Agent: [Rh]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)Oc1ccc(C2CCCN3CCS(=O)(=O)N=C23)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 108.6 %

Procedure:
A mixture of 5% rhodium-carbon (50% wet, 10 mg) and 9-[4-(1-methylethoxy)phenyl]-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (110 mg) in THF (30 mL) and ethanol (30 ml) was stirred under a hydrogen atmosphere (3 atm) at room temperature for 7 hr. The reaction mixture was filtered, the filtrate was concentrated to give the title compound (121 mg) as a white solid. The obtained solid was crystallized from THF and diisopropyl ether to give a white solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:21]=[C:20]([N:22]([CH3:24])[CH3:23])[CH:19]=[CH:18][C:6]=1[C:7]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12])=O)(=[O:3])[CH3:2].[CH3:25][N:26]([CH3:36])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N:33]([CH3:35])[CH3:34])[CH:28]=1>>[CH3:34][N:33]([CH3:35])[C:29]1[CH:28]=[C:27]([N:26]([CH3:36])[CH3:25])[CH:32]=[CH:31][C:30]=1[C:7]1([C:6]2[CH:18]=[CH:19][C:20]([N:22]([CH3:24])[CH3:23])=[CH:21][C:5]=2[NH:4][C:1](=[O:3])[CH3:2])[C:9]2[C:10](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:11](=[O:13])[O:12]1
Reactant: CC(=O)Nc1cc(N(C)C)ccc1C(=O)c1ccccc1C(=O)O
Reactant: CN(C)c1cccc(N(C)C)c1
Product: CC(=O)Nc1cc(N(C)C)ccc1C1(c2ccc(N(C)C)cc2N(C)C)OC(=O)c2ccccc21

Procedure:
Condensation of 2-(2-acetamido-4-(dimethylamino)benzoyl)benzoic acid and N,N,N',N'-tetramethyl-m-phenylenediamine by the method of part B of Example 1 affords 3-(2,4-bis(dimethylamino)phenyl)-3-(2-acetamido-4-(dimethylamino)phenyl)phthalide, the compound of part A of this example.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([S@@](C)=O)=[CH:3][CH:2]=1.C([Si](Cl)(Cl)Cl)C=C.[CH3:18][C:19](=[N:28][NH:29][C:30](=[O:39])[C:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH3:38])=[CH:33][CH:32]=1)[CH2:20][CH2:21][C:22]1C=CC=CC=1>CC(=CC)C.C(Cl)Cl>[CH2:18]([C@@H:19]([NH:28][NH:29][C:30](=[O:39])[C:31]1[CH:32]=[CH:33][C:34]([CH2:37][CH3:38])=[CH:35][CH:36]=1)[CH2:20][CH:21]=[CH2:22])[CH2:10][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc([S@@](C)=O)cc1
Reactant: CCc1ccc(C(=O)NN=C(C)CCc2ccccc2)cc1
Agent: C=CC[Si](Cl)(Cl)Cl
Agent: CC=C(C)C
Solvent: ClCCl
Product: C=CC[C@@H](CCc1ccccc1)NNC(=O)c1ccc(CC)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 41.4 %

Procedure:
(R)-(+)-methyl p-tolyl sulfoxide (0.5 g, 3.21 mmoles) and tetrabutylammonium triphenyl-difluorosilicate (TBAT) (0.12 g, 0.214 mmoles) were dissolved in 0.038 mL of 2-methyl-2-butene and 2.4 mL of anhydrous methylene chloride under nitrogen and with magnetic stirring. Allyltrichlorosilane (0.23 mL, 1.61 mmoles) was added at −78° C. and the reaction was stirred for 15 minutes. 4-ethyl-benzoic acid (1-methyl-3-phenyl-propylidene)hydrazide (0.3 g, 1.07 mmoles) was dissolved in 11.6 mL of anhydrous methylene chloride and added to the reaction over a period of 30 minutes. The reaction mixture was stirred for 5 hours under nitrogen and maintained at −78° C. to −70° C., with TLC monitoring. The reaction was quenched with 1.5 mL triethylamine and 3 mL anhydrous methanol at −78° C. Brine was then added and the mixture was allowed to warm to room temperature. The organic layer was removed, combined with three methylene chloride extractions, and dried over sodium sulfate. The solvent was evaporated, and the crude mixture was purified by flash chromatography using a step gradient of 2:1 and 1:1 pentane:ethyl acetate. Purified (R)-4-ethyl-benzoic acid N′-(1-phenethyl-but-3-enyl)-hydrazide was obtained as a clear oil (0.145 g, 41.4% yield, 57.6% ee by chiral HPLC on Chiralcel ADH). Rf=0.50 (1:1 EtOAc:n-hexane); 1H NMR (400 MHz, CDCl3) δ 7.64-7.13 (m, 9H), 5.91 (m, 1H), 5.15 (t, J=28.0 Hz, 2H), 3.12 (m, 1H), 2.76-2.63 (m, 4H), 2.38-2.24 (m, 2H), 1.88-1.74 (m, 2H), 1.23 (t, J=8.0 Hz, 3H).
Reaction SMILES: N[C@H:2](C(OCC)=O)[CH2:3]CC(OCC)=O.CO.C([C:19]1[CH:40]=[CH:39][CH:38]=[CH:37][C:20]=1[C:21]([NH:23][C@H:24]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:22])#C.[K+].[Br-]>C(Cl)Cl>[C:2]([C:39]1[CH:40]=[CH:19][C:20]([C:21]([NH:23][C@H:24]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:22])=[CH:37][CH:38]=1)#[CH:3]
Reactant: CCOC(=O)CC[C@H](N)C(=O)OCC
Reactant: C#Cc1ccccc1C(=O)N[C@@H](CCC(=O)OCC)C(=O)OCC
Agent: [Br-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: C#Cc1ccc(C(=O)N[C@@H](CCC(=O)OCC)C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.55 g of 4-ethynylbenzoic acid (obtained from tert.-butyl 4-ethynylbenzoate in 84% yield by hydrolysis with trifluoroacetic acid) in 50 ml of anhydrous ether and 25 ml of anhydrous tetrahydrofuran is added 1.58 ml of triethylamine. This is followed by 1.00 g of phenyl N-phenylphosphoraminochloridate. After stirring the reaction mixture at room temperature under nitrogen for 0.5 hour, 0.90 g of diethyl L-glutamate is added in one portion. The mixture is allowed to stir for another 8 hrs. After a workup, the residue is subjected to column chromatography using a 1% methanol:methylene chloride mixture as the eluent. The major fraction isolated from the column contained 0.68 g (54%) of diethyl N-(ethynylbenzoyl)-L-glutamate as an oil which slowly solidified: NMR (CDCl3, 300 MHz) delta 1.25 (t, 3H, J=6.9 Hz), 1.33 (t, 3H, J=6.9 Hz), 2.11-2.60 (m, 4H), 3.23 (s, 1H), 4.09 (q, 2H, J=6.9 Hz), 4.27 (l, 2H, J=6.9 Hz), 4.80 (m, 1H), 7.12 (d, 1H, J=7.2 Hz), 7.59 (d, 2H, J=8.4 Hz), 7.81 (d, 2H, J=8.4 Hz); IR (KBr) 3330, 3280, 2990, 1735, 1640, 1520, 1380, 1200, 1105, 1020, 855, and 770 cm- 1.
Reaction SMILES: C[C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[CH3:39])[C:5]([N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]([N:17]2[C:26]3[C:21](=[CH:22][C:23]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32](O)=[O:33])=[CH:24][CH:25]=3)[CH2:20][CH2:19][CH2:18]2)[CH2:9][CH:8]1[CH3:35])=[O:6].O[N:41]1[C:45]2C=CC=[CH:49][C:44]=2N=N1.Cl.[CH2:51](N=C=NCCCN(C)C)C.C(N)CC.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:35][CH:8]1[CH2:9][CH:10]([N:17]2[C:26]3[C:21](=[CH:22][C:23]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([NH:41][CH2:45][CH2:44][CH3:49])=[O:33])=[CH:24][CH:25]=3)[CH2:20][CH2:19][CH2:18]2)[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:7]1[C:5](=[O:6])[C:4]1[CH:36]=[CH:37][C:38]([CH3:39])=[C:2]([CH3:51])[CH:3]=1
Reactant: Cc1ccc(C(=O)N2c3ccccc3C(N3CCCc4cc(OCCCCC(=O)O)ccc43)CC2C)cc1C
Reactant: On1nnc2ccccc21
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCN
Solvent: CN(C)C=O
Product: CCCNC(=O)CCCCOc1ccc2c(c1)CCCN2C1CC(C)N(C(=O)c2ccc(C)c(C)c2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 66.6 %

Procedure:
5-[[1-[1-(3,4-Dimethylbenzoyl)-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]-1,2,3,4-tetrahydro-6-quinolinyl]oxy]pentanoic acid (0.20 g, 0.37 mmol) prepared in Example 164 and 1-hydroxybenzotriazole (50 mg, 0.37 mmol) were dissolved in N,N-dimethylformamide (3 ml). To this solution, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC) (92 mg, 0.48 mmol) was added and the resulting mixture was stirred at room temperature for 10 minutes. After addition of propylamine (91 μl), the mixture was stirred at room temperature for an additional 15 hours. Aqueous sodium bicarbonate was added to the reaction mixture, which was then extracted with ethyl acetate. The extracted solution was washed with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1 to 4:1) to give the titled compound (0.14 g, yield: 68%) as an amorphous powder. (cis:trans=3:2)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.C(N(CC)CC)C.FC(F)(F)S(O[Si:23]([CH3:26])([CH3:25])[CH3:24])(=O)=O>C1(C)C=CC=CC=1>[CH3:24][Si:23]([N:1]([Si:23]([CH3:26])([CH3:25])[CH3:24])[C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1)([CH3:26])[CH3:25]
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: N#Cc1ccc(N)cn1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)N(c1ccc(C#N)nc1)[Si](C)(C)C
Yield: 63.5 %

Procedure:
About 6.17 g of 5-amino-2-pyridinecarbonitrile, 11.54 g of triethylamine, and 10 ml of toluene were mixed in a round-bottom reaction flask cooled with an ice bath. To this mixture was added, in a dropwise fashion, a solution of 25.34 g of trimethylsilyl trifluoromethanesulfonate in 70 ml of toluene. The resulting mixture was heated to reflux for 2.5 hours and then evaporated under vacuum. The residue was extracted with 100 ml of hexane. The hexane layer was washed twice with saturated aqueous sodium bicarbonate solution (80 ml each time), dried with anhydrous sodium sulfate, and evaporated under vacuum, yielding 5-[bis(trimethylsilyl)amino]-2-pyridinecarbonitrile (BTMSAPyCN) as a green oil (8.67 g, 64% yield). The 1H NMR data (C6D6, 25° C., referenced to tetramethylsilane) of the product are listed as follows: δ 8.07 (doublet of doubets, 1H, aromatic proton), 6.70 (doublet of doublets, 1H, aromatic proton), 6.45 (doublet of doublets, 1H, aromatic proton), −0.16 (singlet, 18H, Si—CH3 protons). From the 1H NMR data, the structure of the product was determined to be as follows:
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([NH:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=2)[N:12]=[N:11][C:10]=1[C:25]([NH:27][CH:28]1[CH2:30][CH2:29]1)=[O:26])(=O)=O.[O:31]=[C:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34](=[O:41])[N-:33]1.[K+]>CN(C=O)C.O>[CH:28]1([NH:27][C:25]([C:10]2[N:11]=[N:12][N:13]([C:14]3[CH:15]=[CH:16][C:17]([C:20]([NH:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:19]=3)[C:9]=2[CH2:8][CH2:7][CH2:6][N:33]2[C:34](=[O:41])[C:35]3[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:32]2=[O:31])=[O:26])[CH2:29][CH2:30]1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCCOS(C)(=O)=O)cc1
Reactant: O=C1[N-]C(=O)c2ccccc21
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCCN2C(=O)c3ccccc3C2=O)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 90.4 %

Procedure:
(4-[(Cyclopropylamino)carbonyl]-1-{4-[(ethylamino)carbonyl]phenyl}-1H-1,2,3-triazol-5-yl)propyl methanesulfonate (1.31 g, 3 mmol) obtained in Example 1201a) and potassium 1,3-dioxo-1,3-dihydroisoindol-2-ide (556 mg, 3 mmol, 1.0 eq.) were dissolved in DMF (20 ml) and the mixture was stirred at 60° C. for 3 hr. The reaction mixture was diluted with water (20 ml), and the precipitate was collected by filtration, washed with water and dried to give the title compound as a white powder (1.32 g, 90.4%).
Reaction SMILES: [CH2:1]([O:3][C:4](Cl)=[O:5])[CH3:2].[CH:7]12[CH2:15][CH:11]([CH2:12][NH:13][CH2:14]1)[CH2:10][N:9]([CH2:16][CH:17]([OH:28])[CH2:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1)[CH2:8]2.[OH-].[Na+]>C(Cl)Cl>[C:24]([C:23]1[CH:22]=[CH:21][C:20]([O:19][CH2:18][CH:17]([OH:28])[CH2:16][N:9]2[CH2:8][CH:7]3[CH2:15][CH:11]([CH2:12][N:13]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:14]3)[CH2:10]2)=[CH:27][CH:26]=1)#[N:25]
Reactant: CCOC(=O)Cl
Reactant: N#Cc1ccc(OCC(O)CN2CC3CNCC(C3)C2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCOC(=O)N1CC2CC(CN(CC(O)COc3ccc(C#N)cc3)C2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.3 %

Procedure:
Ethylchloroformate (930 mg; 8.4 mmol) was added to a stirred solution of 4-[3-(3,7-diazabicyclo[3.3.1]non-3-yl)-2-hydroxypropoxy]benzonitrile (2.3 g; 7.6 mmol; see Example G above) and NaOH (1.5 mL; 10 M) in DCM (60 mL). The solution was stirred at rt. for 1 h, washed with water and the organic layer was separated, dried (Na2SO4) and concentrated. Purification using column chromatography (DCM:MeOH; 19:1) gave the title compound (1.4 g).
Reaction SMILES: [CH:1]([N:4]([CH:7]([CH3:9])[CH3:8])[CH2:5][CH3:6])(C)C.[CH2:10]([NH:12][C:13]1[N:18]=[C:17]([NH:19][CH2:20][CH3:21])[N:16]=C(Cl)[N:14]=1)C.[CH3:23][C:24](N(C)C)=O>>[CH2:10]([NH2:12])[CH2:9][CH2:7][CH3:8].[CH2:7]([N:4]([CH2:5][CH3:6])[C:1]1[N:14]=[C:13]([NH2:12])[N:18]=[C:17]([NH:19][CH2:20][CH2:21][CH2:23][CH3:24])[N:16]=1)[CH3:9]
Reactant: CC(=O)N(C)C
Reactant: CCN(C(C)C)C(C)C
Reactant: CCNc1nc(Cl)nc(NCC)n1
Product: CCCCN
Product: CCCCNc1nc(N)nc(N(CC)CC)n1
Temperature: 0 °C

Procedure:
A solution of 150 millimoles of n-butylamine in 50 ml of dimethylacetamide was prepared and cooled to 0° C. To this solution was added at 0° C. a solution of 250 millimoles of diisopropylethylamine and 50 millimoles of N,N′-diethyl-6-chloro-[1,3,5]triazine-2,4-diamine in 50 ml of dimethylacetamide, the resulting solution was heated under reflux for 4 hours, then cooled to room temperature, and the solvent was distilled off by an evaporator. The reaction mixture was then isolated and purified by silica gel column chromatography to give N,N-diethyl-N″-n-butyl-[1,3,5]triazine-2,4,6-triamine as an oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([OH:17])([CH3:16])[CH3:15])[N:11]3[N:18]=[CH:19][C:20]([C:21]#[CH:22])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.Br[C:24]1[CH:31]=[CH:30][C:27]([CH2:28][OH:29])=[CH:26][CH:25]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([OH:17])([CH3:16])[CH3:15])[N:11]3[N:18]=[CH:19][C:20]([C:21]#[C:22][C:24]4[CH:31]=[CH:30][C:27]([CH2:28][OH:29])=[CH:26][CH:25]=4)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: C#Cc1cnn2c(C(C)(C)O)cc(-c3ccc(Cl)cc3)nc12
Reactant: OCc1ccc(Br)cc1
Product: CC(C)(O)c1cc(-c2ccc(Cl)cc2)nc2c(C#Cc3ccc(CO)cc3)cnn12

Procedure:
The title compound was prepared from 2-[5-(4-chloro-phenyl)-3-ethynyl-pyrazolo[1,5-a]pyrimidin-7-yl]-propan-2-ol (example C.13) (78 mg, 0.25 mmol) and 4-bromobenzyl alcohol (47 mg, 0.25 mmol) according to general procedure II. Obtained as a yellow solid (16 mg, 15%). MS (ISP) 418.1 [(M+H)+].
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1[CH:12]=[C:11]([OH:13])[C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([CH3:14])[N:4]=1.[C:16](=O)([O-])[O-].[Na+].[Na+].CI.O>CN(C=O)C>[CH3:15][N:2]([CH3:1])[C:3]1[CH:12]=[C:11]([O:13][CH3:16])[C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([CH3:14])[N:4]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1c(O)cc(N(C)C)nc1C
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1c(OC)cc(N(C)C)nc1C
Temperature: 23 °C
Reaction time: 16 h

Procedure:
To a stirred solution containing 689 mg (3.27 mmol) of methyl 6-(Dimethylamino)-4-hydroxy-2-methylnicotinate in 10 mL of anhydrous DMF were added 1.91 g (18.0 mmol) of anhydrous sodium carbonate followed by 611 μL (9.81 mmol) of methyl iodide. The reaction mixture was stirred at 23° C. for 16 h. Then, the reaction mixture was poured into 80 mL of water and extracted with two 80-mL portions of ethyl acetate. The combined organic solution was washed with one 80-mL portion of brine, dried (MgSO4) and concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column (3×10 cm). Elution with 1:1 hexanes-diethyl ether afforded the expected product as a white solid: yield 340 mg (47%); mp: 65-66° C.; silica gel TLC Rf 0.15 (1:1 hexanes-diethyl ether); 1H NMR (CDCl3) δ 2.37 (s, 3H), 3.07 (s, 6H), 3.80 (s, 3H) and 5.72 (s, 1H), 3.82 (s, 3H); 13C NMR (CDCl3) δ 168.4, 165.2, 160.3, 156.7, 107.6, 84.5, 55.2, 51.7, 37.8, 37.8 and 23.5; mass spectrum (APCI), m/z 225.1246 (M+H)+ (C11H17N2O3 requires 225.1239).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH2:5]([OH:17])[CH2:6][C:7]1[CH:16]=[CH:15][C:12]([O:13][CH3:14])=[C:9]([O:10][CH3:11])[CH:8]=1.C([O-])(O)=O.[Na+]>C(O)(=O)C.O>[CH3:14][O:13][C:12]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([CH2:6][CH2:5][OH:17])=[C:16]([N+:1]([O-:4])=[O:2])[CH:15]=1
Reactant: O=[N+]([O-])O
Reactant: COc1ccc(CCO)cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(CCO)c([N+](=O)[O-])cc1OC
Temperature: -10 °C
Reaction time: 0.1 h
Yield: 56 %

Procedure:
For 6 min, conc. HNO3 (4.8 ml, 65%, d=1.4) was added dropwise to a mixture of homoveratryl alcohol (3.02 g, 16.6 mmol) in glacial acetic acid (30 ml) under stirring, this mixture having been cooled to -10° C. (common salt/ice) It was then allowed to warm up to 23° C. in 30 min. After being stirred for 1 h at this temperature, the mixture was diluted with H2O, neutralized with NaHCO3 and extracted with EtOAc (3×30 ml). The combined organic phases were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue (3.25 g) was purified by column chromatography (90 g SiO2 toluene/EtOAc 4:1 500 ml, toluene/EtOAc 3:1 400 ml, toluene/EtOAc 2:1 300 ml). 2-(4,5-dimethoxy-2-nitrophenyl)ethanol (2.13 g, 56%) was obtained as a yellow solid.
Reaction SMILES: [NH2:1][CH:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.[CH3:10][C:11]1[CH:21]=[CH:20][CH:19]=[CH:18][C:12]=1[C:13]([N:15]=[C:16]=[O:17])=[O:14].C([O-])(=O)/C=C/C([O-])=O>>[N:4]12[CH2:9][CH2:8][CH:7]([CH2:6][CH2:5]1)[CH:2]([NH:1][C:16]([NH:15][C:13](=[O:14])[C:12]1[CH:18]=[CH:19][CH:20]=[CH:21][C:11]=1[CH3:10])=[O:17])[CH2:3]2
Reactant: Cc1ccccc1C(=O)N=C=O
Reactant: NC1CN2CCC1CC2
Agent: O=C([O-])/C=C/C(=O)[O-]
Product: Cc1ccccc1C(=O)NC(=O)NC1CN2CCC1CC2

Procedure:
The above compound was prepared, following the procedure of Example 1, from 3-aminoquinuclidine (0.63 g, 5 mmol) and crude 2-methylbenzoyl isocyanate (1.35 g, ca 7 mmol). The product (1.23 g) was converted to the 1:1 fumarate, mp 216°-217° C.
Reaction SMILES: [OH:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[O:4][CH:5]([CH:12]1[O:17][CH2:16][C:15](=[O:18])[N:14]([CH3:19])[CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][CH3:32].O>CN(C=O)C>[CH2:31]([O:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[O:4][CH:5]([CH:12]1[O:17][CH2:16][C:15](=[O:18])[N:14]([CH3:19])[CH2:13]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[CH3:32]
Reactant: CN1CC(C(Oc2ccccc2O)c2ccccc2)OCC1=O
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccccc1OC(c1ccccc1)C1CN(C)C(=O)CO1
Temperature: 60 °C
Yield: 78 %

Procedure:
To a solution of 10 g of 2-[α-(2-hydroxy-phenoxy)-benzyl]-4-methylmorpholin -5-one in 150 ml of anhydrous DMF addition was made of 4.8 g of potassium carbonate, and then dropwise addition was made under stirring of 2.6 ml of bromoethane in 20 ml of DMF. The mixture was heated for 4 hours at 60° C. under stirring. The mixture was poured into 1.5 liters of water and extracted with ethyl acetate. The organic extracts were washed with H2O, dehydrated over Na2SO4 and concentrated under reduced pressure. There was obtained 8.49 g (Yield 78%) of 2-[α-(2-ethoxy-phenoxy)-benzyl]-4-methyl-morpholin -5-one.