Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[C:16]1([CH3:36])[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[CH2:27][CH2:26][N:25]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=2)[CH2:24][CH2:23]1.Cl>C(O)C>[CH3:36][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[CH2:23][CH2:24][N:25]([CH2:28][C:29]2[CH:30]=[CH:31][C:32]([NH:35][C:2]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=4)[N:5]=[CH:4][CH:3]=3)=[CH:33][CH:34]=2)[CH2:26][CH2:27]1
Reactant: Cc1ccccc1N1CCN(Cc2ccc(N)cc2)CC1
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2c1
Agent: Cl
Solvent: CCO
Product: Cc1ccccc1N1CCN(Cc2ccc(Nc3ccnc4cc(C(F)(F)F)ccc34)cc2)CC1
Yield: 92.3 %

Procedure:
A solution of 4-chloro-7-trifluoromethyl quinoline (1 g, 0.00216 M), 4-(o-tolyl)-1-p-aminobenzylpiperazine (1.3 g, 0.0046 M) and 3 ml of ethanolic hydrogen chloride in 25 ml of ethanol is heated at reflux for 6 hours under nitrogen. The reaction mixture is quenched with ice water, neutralized with aqueous 10% aqueous sodium hydroxide solution and extracted with methylene chloride. The methylene chloride solution is washed with water, dried over anhydrous sodium sulfate and concentrated to a white solid which, after recyrstallization from ethyl acetate/Skellysolve®B, affords 1.9 g (92%) of white crystalline 4-[[4-[[4-(2-methylpenyl)-1-piperazinyl]methyl]phenyl]amino]-7-(trifluoromethyl)quinoline of melting point 208°-210° C.
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([S:14](Cl)(=O)=O)[CH:11]=2)[CH2:6]1)(=[O:3])[CH3:2].O.[CH3:19]I.C[O-].[Na+]>C(O)(=O)C.Cl>[C:1]([NH:4][CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([S:14][CH3:19])[CH:11]=2)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CI
Reactant: CC(=O)NC1Cc2ccc(S(=O)(=O)Cl)cc2C1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CSc1ccc2c(c1)CC(NC(C)=O)C2
Temperature: 75 °C
Reaction time: 1 h

Procedure:
5.6 g. of N-acetyl-5-chlorosulfonyl-2-indanamine (0.02 mole) (as prepared in Example 3) is dissolved in acetic acid (50 ml.), warmed to 75° C., and 19 g. of stannous chloride (0.1 mole) in concentrated hydrochloric acid (20 ml.) is added. An exotherm occurs. When the reduction is complete the mixture is cooled to 25° C. and poured into water. The N-acetyl-5-mercapto-2-indanamine is filtered and suspended in methanol (50 ml.) under a nitrogen atmosphere. 5.7 g. of methyl iodide (0.04 mole) and 1.1 g. of sodium methoxide (0.02 mole) are added and the mixture is stirred for one hour. The mixture is filtered, evaporated and the residue purified by chromatography to give N-acetyl-5-methylthio-2-indanamine which is hydrolyzed following the procedure of Example 3 to give 5-methylthio-2-indanamine.
Reaction SMILES: [C:1]1([C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)=[CH:18][CH:17]=3)[CH2:11][CH2:10]2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:30][CH2:31][O:32][CH3:33].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(=O)CC.C(O)(=O)C>[CH3:33][O:32][CH2:31][CH2:30][N:26]1[CH2:27][CH2:28][CH:23]([O:22][C:19]2[CH:20]=[CH:21][C:16]([CH2:15][N:12]3[CH2:11][CH2:10][N:9]([C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[O:8])[CH2:14][CH2:13]3)=[CH:17][CH:18]=2)[CH2:24][CH2:25]1
Reactant: COCCCl
Reactant: O=C(c1ccccc1)N1CCN(Cc2ccc(OC3CCNCC3)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CC(=O)O
Product: COCCN1CCC(Oc2ccc(CN3CCN(C(=O)c4ccccc4)CC3)cc2)CC1
Temperature: 25 °C
Yield: 43.4 %

Procedure:
1-Phenyl-1-{4-[4-(piperidin-4-yloxy)-benzyl]-piperazin-1-yl}-methanone (E32) (150 mg, 0.40 mmol) was dissolved in 2-butanone and treated with 1-chloro-2-methoxy-ethane (0.08 ml, 0.80 mmol), potassium carbonate (132 mg, 0.96 mmol) and potassium iodide (159 mg, 0.96 mmol). The reaction mixture was heated under reflux for 24 hours. The mixture was allowed to cool to room temperature, acidified by the addition of glacial acetic acid and passed down an SCX ion exchange column (2 g) eluting with methanol followed by ammonia/methanol (1:9). The basic fractions were combined and concentrated in vacuo to afford the title compound (76 mg). MS(ES+) m/e 438 [M+H]+.
Reaction SMILES: COC([C:5]([S:29]([CH3:32])(=[O:31])=[O:30])([CH2:16][CH2:17][CH2:18][CH:19]([O:25]C(=O)C)[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14]C)=[O:13])=O.[Cl-].[Na+].CS(C)=O.Cl>O>[CH3:32][S:29]([CH:5]([CH2:16][CH2:17][CH2:18][CH:19]([OH:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])(=[O:30])=[O:31]
Reactant: CCCCCC(CCCC(CCCCCCC(=O)OC)(C(=O)OC)S(C)(=O)=O)OC(C)=O
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCCCCC(O)CCCC(CCCCCCC(=O)O)S(C)(=O)=O
Temperature: 185 °C
Yield: 110.4 %

Procedure:
A mixture of methyl 8-methoxycarbonyl-8-methylsulfonyl-12-acetoxyheptadecanoate (36.7 g., 0.077 mole), sodium chloride (4.68 g., 0.08 mole), water (1 ml.) and dimethylsulfoxide (60 ml.) is heated in a bath maintained at 185° C. under nitrogen for 5 hours. The resulting reaction mixture is concentrated in vacuo at 100° C. providing an oily residue which is diluted with water. The aqueous mixture is acidified to Congo Red with 6N hydrochloric acid and extracted with ether. The organic extract is washed with water, dried over magnesium sulfate, filtered and evaporated in vacuo leaving the title compound as a viscous oil (31 g., 95%), pmr (CDCl3) δ 2.0 (s, 3H), 2.82 (s, 3H), 3.63 (s, 3H) and 4.9 (b, H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.Br[CH2:14][CH2:15][CH3:16].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:14]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2)[CH2:15][CH3:16]
Reactant: O=C1CCCc2cc(O)ccc21
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CCCOc1ccc2c(c1)CCCC2=O
Temperature: 122 °C
Reaction time: 8 h
Yield: 93.9 %

Procedure:
6-Hydroxy-1-tetralone (2.0 g, 12.3 mmol), bromo-propane (2.24 mL, 24.7 mmol), potassium iodide (2.05 g, 12.3 mmol) and potassium carbonate (3.41 g, 24.7 mmol) were combined in ACN (50 mL) in a sealed vessel, and the reaction was stirred at 122° C. overnight. The reaction was cooled, filtered, and concentrated. Purification by silica gel chromatography (10-50% EtOAc/hexanes) gave 2.36 g (94%) of the title compound as a clear oil. 1H NMR (400 MHz, DMSO-d6): δ 1.04 (3H, t, J=7.4 Hz), 1.79-1.85 (2H, m), 2.09-2.14 (2H, m), 2.60 (2H, t, J=6.3 Hz), 2.88-2.93 (2H, t, J=6.5 Hz), 3.97 (2H, t, J=6.5 Hz), 6.69 (1H, d, J=2.3 Hz), 6.81 (1H, dd, J=8.8, 4.1 Hz), 7.99 (1H, d, J=8.7 Hz). [M+H] calc'd for C13H16O2, 205. found 205.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][N:5]=[C:4]2[NH:10][CH:11]=[CH:12][C:3]=12.[S:13](Cl)([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:15])=[O:14]>CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][N:5]=[C:4]2[N:10]([S:13]([C:16]3[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:11]=[CH:12][C:3]=12
Reactant: O=Cc1cnc2[nH]ccc2c1Cl
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)c(C=O)cnc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
To a solution 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (500 mg, 2.78 mmol) in MC (9 mL) were added TsCl (556 mg, 2.91 mmol) and DMAP (509 mg, 4.17 mmol). The reaction mixture stirred for 8 hours at room temperature. The produced precipitated was filtered, washed with water and dried with nitrogen gas flow. The title product (810 mg, 87% yield) was used without further purification. MS m/z: 335 [M+1].
Reaction SMILES: NC1N=C(N)C2C(=CC=C(N)C=2)N=1.NC1N=C(N)C2C(=CC=C(N)C=2Cl)N=1.[NH2:28][C:29]1[N:38]=[C:37]([NH2:39])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][C:35]=2[Cl:40])[N:30]=1.[N+:41]([O-])([OH:43])=[O:42].S(=O)(=O)(O)O>>[NH2:28][C:29]1[N:38]=[C:37]([NH2:39])[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([N+:41]([O-:43])=[O:42])[C:35]=2[Cl:40])[N:30]=1
Reactant: O=[N+]([O-])O
Reactant: Nc1nc(N)c2c(Cl)cccc2n1
Agent: Nc1ccc2nc(N)nc(N)c2c1
Agent: Nc1nc(N)c2c(Cl)c(N)ccc2n1
Agent: O=S(=O)(O)O
Product: Nc1nc(N)c2c(Cl)c([N+](=O)[O-])ccc2n1

Procedure:
In a similar manner 2,4,6-triaminoquinazoline and 2,4,6-triamino-5-chloroquinazoline can be prepared. This is accomplished by the nitration of, for example, 2,4-diamino-5-chloroquinazoline (above) with 90% nitric acid and sulfuric acid, yielding the corresponding 2,4-diamino-5-chloro-6-nitroquinazoline. The 6-nitroquinazoline is in turn reduced by either hydrogenation in the presence of 10% palladium on carbon or by treatment with stannous chloride dihydrate, affording the corresponding 2,4,6-triaminoquinazoline. Steps A and B of Example 15 describe in detail these two steps in the reaction sequence.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1)[C:6](O)=[O:7].S(Cl)([Cl:16])=O>C1(C)C=CC=CC=1.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1)[C:6]([Cl:16])=[O:7]
Reactant: O=S(Cl)Cl
Reactant: COc1cc(OC)cc(C(=O)O)c1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1cc(OC)cc(C(=O)Cl)c1
Reaction time: 2 h

Procedure:
72.9 g of 3,5-dimethoxybenzoic acid are suspended in 320 ml of toluene, and 2 drops of dimethylformamide are added thereto. The suspension is heated to 50°. 40 ml of thionyl chloride are added dropwise at that temperature within a period of 10 minutes. The whole is then heated to 90° (vigorous evolution of gas) and stirred for 2 hours. The reaction mixture is cooled and concentrated by evaporation in a rotary evaporator. After the addition of toluene, the whole is again concentrated by evaporation. The oily residue is dried for 15 minutes under a high vacuum. 3,5-dimethoxybenzoyl chloride is thus obtained.
Reaction SMILES: [CH3:1][Li].Br[CH2:4][C:5]1[CH:6]=[C:7]([F:12])[CH:8]=[C:9]([CH3:11])[CH:10]=1>C(OCC)C.[Cu]I>[CH2:4]([C:5]1[CH:6]=[C:7]([F:12])[CH:8]=[C:9]([CH3:11])[CH:10]=1)[CH3:1]
Reactant: [Li]C
Reactant: Cc1cc(F)cc(CBr)c1
Agent: [Cu]I
Solvent: CCOCC
Product: CCc1cc(C)cc(F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
Methyllithium (40 ml, 64 mmol) was added dropwise at 0° C. to a slurry of copper(I)iodide (6.42 g, 33.6 mmol) in diethyl ether (20 ml). After being stirred at 0° C. for 30 minutes, the clear colorless homogeneous cuprate solution was cooled to −78° C. where 3-bromomethyl-1-fluoro-5-methylbenzene (5.15 g, 25.4 mmol) in 10 ml diethyl ether was added. The temperature was allowed to rise slowly. The reaction was quenched at −50° C. with NH4Cl/NH3-buffer (50 ml). Extraction with diethyl ether (3×50 ml), brine (1×100 ml). The organic layer was dried over MgSO4, filtered and the solvents were removed to yield 3.3 g (94%) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:44])[CH:5]([CH2:11][C:12]([F:43])([F:42])[CH2:13][C@H:14]([C@@H:16]1[C@:33]2([CH3:34])[C@H:19]([C@H:20]3[C@H:30]([CH2:31][CH2:32]2)[C@:28]2([CH3:29])[C:23]([CH2:24][C@@H:25]([O:35][CH:36]4[CH2:41][CH2:40][CH2:39][CH2:38][O:37]4)[CH2:26][CH2:27]2)=[CH:22][CH2:21]3)[CH2:18][CH2:17]1)[CH3:15])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[H-].[Na+].[Cl:47]N1C(=O)CCC1=O>C(COC)OC>[CH2:1]([O:3][C:4](=[O:44])[C:5]([Cl:47])([CH2:11][C:12]([F:42])([F:43])[CH2:13][C@H:14]([C@@H:16]1[C@:33]2([CH3:34])[C@H:19]([C@H:20]3[C@H:30]([CH2:31][CH2:32]2)[C@:28]2([CH3:29])[C:23]([CH2:24][C@@H:25]([O:35][CH:36]4[CH2:41][CH2:40][CH2:39][CH2:38][O:37]4)[CH2:26][CH2:27]2)=[CH:22][CH2:21]3)[CH2:18][CH2:17]1)[CH3:15])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)C(CC(F)(F)C[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)CC[C@]4(C)[C@H]3CC[C@]12C)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)C(Cl)(CC(F)(F)C[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)CC[C@]4(C)[C@H]3CC[C@]12C)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.7 %

Procedure:
The diester (9) (700 mg, 1.125 mmol) was treated with sodium hydride (39 mg, 1.625 mmol) in dimethoxyethane (20 ml) at room temperature under argon atmosphere for 1 hr. Then, to this solution N-chlorosuccinimide (180 mg, 1.35 mmol) was added and the mixture was stirred at room temperature for 1 hr. The usual work-up (ether for extraction) gave a crude product, which was applied to a column of silica gel (20 g). Elution with n-hexane-ether (10:1) provided tthe chlorodiester (10) (730 mg, 99%), glass. 1H-NMR: 0.72 (3H, s, 18-H3), 1.02 (3H, s, 19-H3), 1.10 (3H, d, J=6 Hz, 21-H3), 1.30 (6H, t, J=7.5 Hz, --CO2CH2CH3), 2.95 (2H, t, J=15 Hz, 24-H2), 3.52 (2H, m, THP), 3.88 (1H, m, 3-H), 4.32 (4H, q, J=7.5 Hz, --CO2CO2CH3), 4.72 (1H, m. THP), 5.38 (1H, m, 6-H). MS m/z: 554, 520.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([OH:11])[CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[S:19](Cl)([C:22]1[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=1)(=[O:21])=[O:20]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([OH:11])[CH2:9][O:10][S:19]([C:22]2[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC[C@@H](O)c1cccc(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@@H](O)c2cccc(Cl)c2)cc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a mixture of (S)-1-(3-Chloro-phenyl)-ethane-1,2-diol (9.83 g, 0.057 mol) and triethylamine (11.8 ml, 0.086 mol) a solution of TsCl (10.87 g, 0.057 mol) in dichloromethane (50 mL) was added at 0° C. over 30 min. The mixture was stirred at 0° C. for 4 h. Precipitate formed was removed by filtration, the filtrate was washed with water (50 mL), dried over Na2SO4 and evaporated. The residue was dissolved in CH2Cl2 (200 mL), filtered through a SiO2 pad and evaporated. Colorless oil, 16.34 g (0.050 mol, 88%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22](O)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][N:26]([CH3:39])[C:27](=[O:38])[O:28][C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=1[CH2:36][NH2:37]>>[CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:20])([CH3:21])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22]([NH:37][CH2:36][C:30]1[CH:31]=[CH:32][C:33]([F:35])=[CH:34][C:29]=1[O:28][C:27](=[O:38])[N:26]([CH3:25])[CH3:39])=[O:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C(=O)Oc1cc(F)ccc1CN
Reactant: CC1(C)OCCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Product: CN(C)C(=O)Oc1cc(F)ccc1CNC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCOC2(C)C

Procedure:
The title compound can be prepared from intermediate 27, 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylic acid and intermediate 133, 2-(aminomethyl)-5-fluorophenyl dimethylcarbamate. 1H NMR (CDCl3, 500 MHz) δ ppm: 1.58 (6H, s, gem-Me), 2.92, 3.05 (2s, NMe), 3.96 (2H, m, NCH2), 4.00 (2H, m, OCH2), 4.48 (2H, d, J=5.5 Hz, NCH2), 5.26 (2H, s, OCH2), 6.84 (1H, dd, J=2.5 Hz, 9 Hz, Ar—H), 6.87 (1H, dt, J=2.5 Hz, 8 Hz, Ar—H), 7.25-7.33 (4H, m, Ar—Hs), 7.53 (2H, d, J=˜7 Hz, Ar—Hs), 7.78 (1H, brt, J=5 Hz, NH); 13C NMR (CDCl3, 125.77 Hz) δ ppm: 27.68, 36.61, 36.89, 37.97, 42.97, 58.06, 74.73, 76.23, 110.58, 110.77, 113.06, 113.23, 126.55, 126.58, 128.31, 128.45, 128.91, 131.23, 131.31, 136.76, 140.70, 142.00, 150.60, 150.69, 154.50, 156.30, 159.79, 161.40, 163.37, 162.43. HRMS (ESI) calcd for C27H30N4O6F (M+H) 525.2149, found 525.2163.
Reaction SMILES: [CH2:1]([N:8]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:9]([C@H:20]([CH2:28][CH:29]([OH:32])[CH2:30][OH:31])[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:40][S:41](Cl)(=[O:43])=[O:42].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>N1C=CC=CC=1>[CH2:1]([N:8]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C@@H:9]([C@H:20]([CH2:28][CH:29]([OH:32])[CH2:30][O:31][S:41]([CH3:40])(=[O:43])=[O:42])[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)[C@@H](CC(O)CO)[C@@H](C(=O)OCc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)[C@@H](CC(O)COS(C)(=O)=O)[C@@H](C(=O)OCc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 80.6 %

Procedure:
1-benzyl 4-tert-butyl (2S,3S)-2-(dibenzylamino)-3-(2,3-dihydroxypropyl)succinate from step 1j (2.917 g, 5.47 mmol) was dissolved in pyridine (10 mL), cooled to 0° C. and MsCl (0.444 mL, 5.74 mmol) was added. The solution was stirred at 0° C. for 4 hours and diluted by 10% citric acid. The reaction mixture was extracted with EtOAc three times. The combined organic solution was washed by 10% citric acid three times, then brine, dried with MgSO4 and concentrated, the residue was purified on silica gel using 50% EtOAc/Hexane as elution to provide of 1-benzyl 4-tert-butyl (2S,3S)-2-(dibenzylamino)-3-{2-hydroxy-3-[(methylsulfonyl)oxy]propyl}succinate (2.696 g, 81%). MS (ESI): 612.1.1 (M+H+).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([C:8]([OH:11])([CH3:10])[CH3:9])[CH2:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[CH3:43][C:44]1[CH:49]=[CH:48][C:47]([C:50]2[O:54][N:53]=[CH:52][C:51]=2[C:55](O)=[O:56])=[CH:46][CH:45]=1>CN(C=O)C>[CH3:43][C:44]1[CH:45]=[CH:46][C:47]([C:50]2[O:54][N:53]=[CH:52][C:51]=2[C:55]([N:2]2[CH2:7][CH2:6][CH2:5][C@@H:4]([C:8]([OH:11])([CH3:10])[CH3:9])[CH2:3]2)=[O:56])=[CH:48][CH:49]=1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Reactant: CC(C)(O)[C@@H]1CCCNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2oncc2C(=O)N2CCC[C@@H](C(C)(C)O)C2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.3 %

Procedure:
A solution of 2-[(3R)-piperidin-3-yl]propan-2-ol hydrochloride (7 mg, 0.039 mmol), TBTU (15 mg, 0.047 mmol, 1.2 equ.) and N-ethyl-N-isopropylpropan-2-amine (14 μL, 0.079 mmol, 2 equ.) in DMF (0.3 mL) was added to 5-(4-methylphenyl)isoxazole-4-carboxylic acid (8 mg, 0.039 mmol) and the reaction mixture was stirred at rt for 2 h. The solvent was evaporated and the crude product was purified by RP-HPLC. After evaporation of the solvents the product was dried in vacuum to yield the title compound (9 mg). MS (ESI, pos. ion) m/z calcd for C19H24N2O3: 328.1787, found 328.1784.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][Cl:7].Cl.[C:9](Cl)([Cl:11])=[O:10]>C1C=CC=CC=1>[Cl:11][C:9]([N:4]([CH2:5][CH2:6][Cl:7])[CH2:3][CH2:2][Cl:1])=[O:10]
Reactant: ClCCNCCCl
Reactant: O=C(Cl)Cl
Agent: Cl
Solvent: c1ccccc1
Product: O=C(Cl)N(CCCl)CCCl
Reaction time: 3 h

Procedure:
A solution in dry benzene of 82 g. of bis-(β-chloroethyl)-amine freshly liberated from its hydrochloride is added gradually to a solution of 36 g. of carbonyl chloride in benzene at a temperature below 10° C. The mixture is mechanically stirred for three hours, the precipitate of bis-(β-chloroethyl)-amine hydrochloride is removed by filtration, and the benzene is distilled off on a water bath. The residue is distilled in vacuo, and the N-chloroformyl-bis-(β-chloroethyl)-amine is obtained as a pale yellow oil with a B.P. of 114-116° C./1 mm. Hg.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](OS(C(F)(F)F)(=O)=O)[C:5]([C:16]#[N:17])=[C:4]([C:18]2[O:19][CH2:20][CH2:21][CH:22]=2)[N:3]=1.Cl.Cl.[CH3:25][C:26]1[CH:31]=[CH:30][N:29]=[C:28]([CH2:32][NH2:33])[CH:27]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([C:18]2[O:19][CH2:20][CH2:21][CH:22]=2)[C:5]([C:16]#[N:17])=[C:6]([NH:33][CH2:32][C:28]2[CH:27]=[C:26]([CH3:25])[CH:31]=[CH:30][N:29]=2)[N:7]=1
Reactant: Cc1ccnc(CN)c1
Reactant: N#Cc1c(OS(=O)(=O)C(F)(F)F)nc(N)nc1C1=CCCO1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: Cc1ccnc(CNc2nc(N)nc(C3=CCCO3)c2C#N)c1

Procedure:
From trifluoromethanesulfonic acid 2-amino-5-cyano-6-(4,5-dihydro-furan-2-yl)-pyrimidin-4-yl ester, C-(4-methyl-pyridin-2-yl)-methylamine dihydrochioride and DBU in DME. ES-MS m/e (%): 309 (M+H+, 100).
Reaction SMILES: C[C:2]([O-])([CH3:4])[CH3:3].[K+].[CH:7]1([CH:13]=[CH:14][CH2:15][N:16]=C)CCCCC1.O1C[CH2:21][CH2:20][CH2:19]1>>[CH:14](=[CH:15][N:16]=[C:3]1[CH2:2][CH2:4][CH2:21][CH2:20][CH2:19]1)[CH2:13][CH3:7]
Reactant: CC(C)(C)[O-]
Reactant: C1CCOC1
Reactant: C=NCC=CC1CCCCC1
Agent: [K+]
Product: CCC=CN=C1CCCCC1
Yield: 83 %

Procedure:
The procedure is carried out as described in Example 1, with the use however in this case of 5 g of potassium tert-butylate, 240 g (1.59 mols) of cyclohexyl-methylidene-allylamine and 250 ml of tetrahydrofuran. After a reaction time of 1 hour at 30° C., there is obtained 199 g (1.32 mols) of propylidene(cyclohexylidene-methylamine), corresponding to a yield of 83% of theory; b.p. 51°-53° C./0.3 Torr; nD20 =1.5072.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:17][CH:18]([CH3:20])[CH3:19])[CH:8]1[O:16][CH2:15][C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].C(=O)([O-])[O-].[Na+].[Na+].[N+:27]([O-])([N+]([O-])=O)=[O:28]>O1CCCC1.C(Cl)Cl>[Cl:1][CH2:2][CH2:3][N:4]([N:27]=[O:28])[C:5]([N:7]([CH2:17][CH:18]([CH3:20])[CH3:19])[CH:8]1[O:16][CH2:15][C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: CC(C)CN(C(=O)NCCCl)C1OC[C@H](O)[C@H](O)[C@H]1O
Reactant: O=[N+]([O-])[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)CN(C(=O)N(CCCl)N=O)C1OC[C@H](O)[C@H](O)[C@H]1O
Yield: 67.9 %

Procedure:
3.1 g of 1-(2-chloroethyl)-3-isobutyl-3-L-arabinopyranosylurea are dissolved in a mixture of 60 ml of tetrahydrofuran and 60 ml of methylene chloride, and 15 g of sodium carbonate anhydrate are added thereto. 5 g of nitrogen tetroxide gas are introduced into the mixture for 10 minutes under ice-cooling. The mixture is treated in the same manner as described in Example 2. 2.3 g of 1-(2-chloroethyl)-1-nitroso-3-isobutyl-3-L-arabinopyranosylurea are thereby obtained as pale yellow caramel.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([C:8]#[N:9])[CH2:4][CH2:3]1.[C:16]1([N:22]2[C:26]3([CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[C:25](=[O:32])[NH:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CC1C=CC(S(O)(=O)=O)=CC=1.CC1C=CC=CC=1>O>[O:32]=[C:25]1[C:26]2([CH2:27][CH2:28][N:29]([C:2]3[CH2:7][CH2:6][C:5]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)([C:8]#[N:9])[CH2:4][CH:3]=3)[CH2:30][CH2:31]2)[N:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:23][NH:24]1
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Reactant: N#CC1(c2ccccc2)CCC(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: N#CC1(c2ccccc2)CC=C(N2CCC3(CC2)C(=O)NCN3c2ccccc2)CC1

Procedure:
A mixture of 5 parts of 4-oxo-1-phenyl-1-cyclohexanecarbonitrile, 5.8 parts of 1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one, 0.1 parts of 4-methylbenzenesulfonic acid and 225 parts of methylbenzene is stirred and refluxed overnight with water-separator. The reaction mixture is cooled and evaporated, yielding 10.35 parts of 4-(4-oxo-1-phenyl-1,3,8-triazaspiro[4,5]dec-8-yl)-1-phenyl-3-cyclohexene-1-carbonitrile as a residue.