Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:7]2[C:11]3[CH:12]=[C:13]([CH3:19])[C:14]([C:16](O)=[O:17])=[CH:15][C:10]=3[N:9]=[C:8]2[C:20]2[CH:24]=[CH:23][O:22][CH:21]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.C[O:27][C:28](=[O:42])[C@H:29]([CH2:31][C:32]1[C:40]2[C:35](=[CH:36][CH:37]=[C:38]([OH:41])[CH:39]=2)[NH:34][CH:33]=1)[NH2:30].Br[CH2:44][C:45]([O:47]C)=[O:46]>>[C:45]([CH2:44][O:41][C:38]1[CH:39]=[C:40]2[C:35](=[CH:36][CH:37]=1)[NH:34][CH:33]=[C:32]2[CH2:31][C@H:29]([NH:30][C:16]([C:14]1[C:13]([CH3:19])=[CH:12][C:11]2[N:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[C:8]([C:20]3[CH:24]=[CH:23][O:22][CH:21]=3)=[N:9][C:10]=2[CH:15]=1)=[O:17])[C:28]([OH:27])=[O:42])([OH:47])=[O:46]
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccc(O)cc12
Reactant: COC(=O)CBr
Reactant: Cc1cc2c(cc1C(=O)O)nc(-c1ccoc1)n2C1CCCCC1
Agent: Cl
Product: Cc1cc2c(cc1C(=O)N[C@@H](Cc1c[nH]c3ccc(OCC(=O)O)cc13)C(=O)O)nc(-c1ccoc1)n2C1CCCCC1

Procedure:
1-Cyclohexyl-2-furan-3-yl-6-methyl-1H-benzimidazole-5-carboxylic acid was coupled to 5-hydroxy-(S)-tryptophan methyl ester hydrochloride in the usual manner (Example 154). The material was then alkylated with methyl bromoacetate as described previously to give after deprotection by saponification and preparative C18 reversed-phase HPLC, the title compound of example 155.
Reaction SMILES: Cl[S:2]([N:5]=C=O)(=[O:4])=[O:3].O.[S:9]([O:13][CH2:14][CH:15]([OH:26])[CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[O:24][CH3:25])(=[O:12])(=[O:11])[NH2:10].[CH2:27](N(CC)CC)C>C(#N)C.C(OCC)(=O)C>[NH2:5][S:2]([O:26][CH:15]([CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[O:24][CH3:25])[CH2:14][O:13][S:9](=[O:12])(=[O:11])[NH:10][CH3:27])(=[O:4])=[O:3]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CCN(CC)CC
Reactant: COc1ccccc1OCC(O)COS(N)(=O)=O
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: CNS(=O)(=O)OCC(COc1ccccc1OC)OS(N)(=O)=O
Reaction time: 0.17 h
Yield: 27 %

Procedure:
To a cold solution (ice-acetone bath) of 14.7 ml (0.166 mole) of chlorosulfonyl isocyanate (98%; Aldrich) in 100 ml of acetonitrile was added dropwise a solution of 2.7 g (0.15 mole) of water in 5 ml of acetonitrile such that the reaction mixture temperature was maintained at ≤7° C. The mixture was stirred vigorously for 10 min, and to it was added a solution of 12.3 g (0.042 mole) of 3-(2-methoxyphenoxy)-1,2-propanediol methyl sulfamate ester (Example 68) and 17.0 g (0.168 mol) of triethylamine in 100 ml of acetonitrile at such a rate that the temperature of the reaction mixture was maintained at ≤12° C. The reaction mixture was stirred vigorously for 3 hr at ambient temperature and treated with 100 ml of water and 200 ml of ethyl acetate. The layers were separated, and the organic layer was washed with 200 ml of water and evaporated under reduced pressure to yield a viscous residue. The residue was partitioned between 200 ml of water and 300 ml of ethyl ether. The organic layer was washed with three 200 ml portions of water (pH neutral to pH paper), dried over magnesium sulfate and the solvent evaporated under reduced pressure to give 8.5 g (55%) of a viscous, oily residue which solidified upon standing. The solid was triturated with 75 ml of methylene chloride, and the precipitate was collected by filtration to yield 4.2 g (27%) of the title compound as a white solid, mp 110°-113° C.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:7][C:8]1[C:12]([NH:13][C:14](=[O:24])[CH2:15][CH2:16][S:17][CH2:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[CH:11][N:10]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[N:9]=1.CN(C)C=O.I[CH2:37][CH3:38]>O.C(OCC)(=O)C>[Cl:7][C:8]1[C:12]([N:13]([CH2:37][CH3:38])[C:14](=[O:24])[CH2:15][CH2:16][S:17][CH2:18][CH2:19][C:20]([F:22])([F:21])[F:23])=[CH:11][N:10]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[N:9]=1
Reactant: CCI
Reactant: O=C(CCSCCC(F)(F)F)Nc1cn(-c2cccnc2)nc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCN(C(=O)CCSCCC(F)(F)F)c1cn(-c2cccnc2)nc1Cl
Temperature: 40 °C
Reaction time: 2 h
Yield: 66.4 %

Procedure:
A 100 mL, 3-neck round bottom flask, equipped with mechanical stirrer, temperature probe and nitrogen inlet was charged with cesium carbonate (654 mg, 2.01 mmol), N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-3-((3,3,3-trifluoropropyl)thio)propanamide (380 mg, 1.00 mmol) and N,N-dimethylformamide, (5 mL). Iodoethane (0.089 mL, 1.10 mmol) was added dropwise. The reaction was stirred at 40° C. for 2 hours, at which point thin layer chromatography analysis [((Eluent: ethyl acetate] indicated that only a trace of starting material remained. The reaction mixture was cooled to 20° C. and water (20 mL) was added. It was extracted with ethyl acetate (2×20 mL) and the combined organic layers were concentrated to dryness at <40° C. The residue was purified by flash column chromatography using 0-100% ethyl acetate/hexane as eluent. The fractions containing pure product were concentrated to dryness to afford a colorless oil (270 mg, 66%): 1H NMR (400 MHz, DMSO-d6) δ 9.11 (d, J=2.7 Hz, 1H), 8.97 (s, 1H), 8.60 (dd, J=4.8, 1.4 Hz, 1H), 8.24 (ddd, J=8.4, 2.8, 1.4 Hz, 1H), 7.60 (ddd, J=8.4, 4.7, 0.8 Hz, 1H), 3.62 (q, J=7.1 Hz, 2H), 2.75 (t, J=7.0 Hz, 2H), 2.66-2.57 (m, 2H), 2.57-2.44 (m, 2H), 2.41 (t, J=7.0 Hz, 2H), 1.08 (t, J=7.1 Hz, 3H); EIMS m/z 406 ([M]+).
Reaction SMILES: C(N(CC)CC)C.O[CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=[O:15].[C:16](#[N:20])[CH2:17][C:18]#[N:19]>CO>[NH2:20][C:16]1[O:15][C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C:9]=2[C:17]=1[C:18]#[N:19]
Reactant: O=C1CCCCC1O
Reactant: N#CCC#N
Solvent: CCN(CC)CC
Solvent: CO
Product: N#Cc1c(N)oc2c1CCCC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.9 %

Procedure:
2.1 4.8 ml of triethylamine are added dropwise to a solution of 11.0 g of 2-hydroxycyclohexanone and 9.6 g of malononitrile in 25 ml of methanol, and the mixture is stirred at room temperature for a further 4 hours. The crystals which deposit are separated off and washed with methanol, giving 12.8 g of 2-amino-4,5,6,7-tetrahydrobenzofuran-3-carbonitrile (“BA”), m.p. 179°.
Reaction SMILES: [Cl-].[NH4+:2].C[Al](C)C.[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:9]=1[C:15]1[N:19]([CH3:20])[N:18]=[C:17]([C:21](OCC)=O)[CH:16]=1>C1(C)C=CC=CC=1>[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:9]=1[C:15]1[N:19]([CH3:20])[N:18]=[C:17]([C:21]#[N:2])[CH:16]=1
Reactant: [NH4+]
Reactant: CCOC(=O)c1cc(-c2c(F)cccc2F)n(C)n1
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: Cn1nc(C#N)cc1-c1c(F)cccc1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of ammonium chloride (0.42 g, 7.52 mmol) in toluene (10 mL) at 0° C. was added dropwise trimethyl aluminum (2 M in toluene, 3.76 mL, 7.52 mmol). After the addition was complete, the reaction mixture was stirred at 0° C. for 1 h, warmed to room temperature, and then a mixture of ethyl 5-(2,6-difluorophenyl)-1-methyl-1H-pyrazole-3-carboxylate (i.e. the product of Step A) (1 g, 3.76 mmol) in toluene (5 mL) was added and the mixture was heated at 110° C. for 4 h. The reaction mixture was allowed to cool to room temperature, partitioned between aqueous hydrochloric acid (1 N) and diethyl ether (about 20 mL) and the organic phase was separated. The aqueous phase was extracted with diethyl ether and the combined organic layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting material was purified by silica gel column chromatography (10 to 20% gradient of ethyl acetate in hexanes) to provide the title compound as a solid (0.4 g).
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([NH:23]C(=O)OC(C)(C)C)[CH:9]([N:12]([CH3:22])[C:13]([O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])=[O:14])[CH2:10][CH3:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>CCOCC.CCO>[NH2:23][C@H:8]([CH:9]([N:12]([CH3:22])[C:13](=[O:14])[O:15][CH2:16][CH2:17][Si:18]([CH3:20])([CH3:19])[CH3:21])[CH2:10][CH3:11])[CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCC([C@H](CC1CCCCC1)NC(=O)OC(C)(C)C)N(C)C(=O)OCC[Si](C)(C)C
Solvent: CCOCC
Solvent: CCO
Product: CCC([C@@H](N)CC1CCCCC1)N(C)C(=O)OCC[Si](C)(C)C

Procedure:
The (2S)-tert-butyl 1-cyclohexyl-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)pentan-2-ylcarbamate (137 mg, 0.14 mmol) was dissolved in Et2O (5 mL), anhydrous TSA (24 mg, 0.14 mmol) dissolved in EtOH was added. The solvent was removed in vacuo using a hot bath at 60° C. for 30 min to give (S)-2-(trimethylsilyl)ethyl 2-amino-1-cyclohexylpentan-3-yl(methyl)carbamate. MS ESI +ve m/z 343 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C@@H:7]2[CH2:11][NH:10][C@H:9]([C:12]([OH:14])=[O:13])[CH2:8]2)=[CH:4][CH:3]=1.S(Cl)([Cl:19])=O.[CH3:21]O>>[ClH:19].[F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C@@H:7]2[CH2:11][NH:10][C@H:9]([C:12]([O:14][CH3:21])=[O:13])[CH2:8]2)=[CH:4][CH:3]=1
Reactant: CO
Reactant: O=C(O)[C@@H]1C[C@H](Oc2ccc(F)cc2)CN1
Reactant: O=S(Cl)Cl
Product: COC(=O)[C@@H]1C[C@H](Oc2ccc(F)cc2)CN1
Product: Cl
Reaction time: 2 h

Procedure:
To a stirred suspension of cis-4-(4-fluorophenoxy)-L-proline (which can be prepared as set forth by Ondetti et al. in Example 36 of U.K. patent application No. 2,028,327) (250 mg., 11 mmole) in 70 ml. of methanol at -30° under argon, there is added 8.09 ml. (10 eq.) of thionyl chloride. After stirring at -20° for 2 hours, the cold bath is removed and the mixture is stirred at room temperature for 16 hours. The solvent is removed at reduced pressure and the residue is dissolved in 150 ml. of dichloromethane. The resulting solution is washed with 1N sodium bicarbonate (twice) and water. After drying (MgSO4), the solution is treated with excess hydrochloric acid and then concentrated at reduced pressure. Recrystallization from methanol/ether gives 1.49 g. of product. The mother liquors yield an additional 0.5 g. of product so that a total of 1.99 g. of cis-4-(4-fluorophenoxy)-L-proline, methyl ester, hydrochloride is obtained; m.p. 147°-148° (s. 144°); [α]D20 =+6.96° (c=1.55, methanol).
Reaction SMILES: [P:1]([Cl:4])(Cl)[Cl:2].[CH3:5][CH:6]1[CH2:10][CH2:9][CH:8]([CH3:11])[N:7]1[C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1>N1C=CC=CC=1>[CH3:5][CH:6]1[CH2:10][CH2:9][CH:8]([CH3:11])[N:7]1[C:12]1[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][C:17]=1[P:1]([Cl:4])[Cl:2]
Reactant: Cc1ccc(N2C(C)CCC2C)cc1
Reactant: ClP(Cl)Cl
Solvent: c1ccncc1
Product: Cc1ccc(N2C(C)CCC2C)c(P(Cl)Cl)c1

Procedure:
A solution of PCl3 (36.3 g, 264.3 mm) in 200 mL of pyridine was treated with (+/−)-2,5-dimethyl-1-N(4′-methylphenyl)pyrrolidine (10.0 g, 52.8 mm) over a period of 5 min. The resulting mixture was then refluxed for 2 days to give the crude (+/−)-2,5-dimethyl-1-N(2′-dichlorophosphino-4′-methylphenyl)pyrrolidine (31P NMR: δ164.7 (s), 159.9 (s) ppm). After precipitates (Py.HCl) were filtered off, the excess PCl3 and pyridine solvent were removed from filtrates, a mixture of 100 mL of pyridine and 300 mL of THF was added to the resulting residue. Next, polymer-supported secondary amines (15.0 g, 1.1 mmol/g, 16.5 mmol) was slowly added into the mixture above while stirring at room temperature for a period of 10 min. The resulting suspension was refluxed overnight before the solution was filtered off. The resin was washed with THF (2×50 mL), hexane (3×50 mL), CH2Cl2 (4×50 mL), and hexane (2×50 mL). The resulting resin was dried in vacuum overnight to yield the polymer-supported (+/−)-2,5-dimethyl-1-N(1-N(2′-chlorophosphino-4′-methylphenyl)pyrrolidine. 31P NMR (122 MHz, CDCl3): δ145.1, 136.0 ppm.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:40][C:41]([CH3:63])([CH3:62])[C@H:42]([N:46]1[CH2:50][CH2:49][N:48]([CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[C:54]([N+:58]([O-:60])=[O:59])[CH:53]=2)[C:47]1=[O:61])[C:43](O)=[O:44].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:40][C:41]([CH3:63])([CH3:62])[C@H:42]([N:46]1[CH2:50][CH2:49][N:48]([CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[C:54]([N+:58]([O-:60])=[O:59])[CH:53]=2)[C:47]1=[O:61])[C:43]([NH:1][C@@H:2]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1)=[O:44]
Reactant: CC(C)(C)[C@@H](C(=O)O)N1CCN(Cc2cccc([N+](=O)[O-])c2)C1=O
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2cccc([N+](=O)[O-])c2)C1=O)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.6 %

Procedure:
A solution containing the product from Example 2C (0.065 g, 0.123 mmol) in THF (1 mL) was treated with the product from Example 125B (0.049 g, 0.147 mmol), DEPBT (0.055 g, 0.185 mmol), and N,N-diisopropylethylamine (0.102 mL, 0.615 mmol), stirred at 25° C. for 16 hours, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-100% ethyl acetate/dichloromethane, followed by 0-5% methanol in ethyl acetate to give the title compound (0.077 g, 74% yield).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:33])=[C:4]([C:16]([NH:18][C@@H:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][C@@H:20]2[F:32])=[O:17])[N:5](COCC[Si](C)(C)C)[C:6]=1[CH3:7].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(N)CN>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([F:33])=[C:4]([C:16]([NH:18][C@@H:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])[CH2:21][C@@H:20]2[F:32])=[O:17])[NH:5][C:6]=1[CH3:7]
Reactant: Cc1c(Cl)c(F)c(C(=O)N[C@@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2F)n1COCC[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: NCCN
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1[nH]c(C(=O)N[C@@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2F)c(F)c1Cl
Temperature: 50 °C
Yield: 91 %

Procedure:
tert-butyl (3S,4R)-4-{[(4-chloro-3-fluoro-5-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrol-2-yl)carbonyl]amino}-3-fluoropiperidine-1-carboxylate (Intermediate 259, 80 mg, 0.16 mmol) was dissolved in anhydrous THF (6 ml), followed by the addition of tetra-butyl ammonium fluoride (1 ml, 1M in THF) and ethylene diamine (1 mmol), the mixture was then stirred at 50° C. over night. After cooling down to room temperature, the reaction mixture was diluted with ethyl acetate (20 ml) and washed with saturated aqueous sodium bicarbonate (10 ml) and brine (10 ml), dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (100%˜70% hexanes/ethyl acetate) to give the desired product (55 mg).
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:7][CH:8]([O:10][C@H:11]([CH3:16])[C:12](OC)=[O:13])[CH3:9])[CH:4]([CH3:6])[CH3:5].CO.O>C1(C)C=CC=CC=1>[CH2:3]([O:7][CH:8]([O:10][C@H:11]([CH3:16])[CH2:12][OH:13])[CH3:9])[CH:4]([CH3:6])[CH3:5]
Reactant: COC(=O)[C@@H](C)OC(C)OCC(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: Cc1ccccc1
Product: CC(C)COC(C)O[C@H](C)CO
Yield: 96.5 %

Procedure:
8.4 g (0.204 mole) of sodium borohydride was suspended at room temperature in a solution of 35.8 g (0.17 mole) of the methyl (R)-(+)-2-(1-isobutoxyethoxy)propionate (obtained in Reference Example 5) dissolved in 170 ml of toluene. Thereto was dropwise added slowly 40.8 ml (1.02 mole) of methanol with stirring, so that the internal temperature of the reaction system could be kept at 40° C. After the completion of the dropwise addition, the mixture was stirred at room temperature for 4 hours to give rise to a reaction. To the reaction mixture was added 50 ml of water, followed by stirring for 0.5 hour. The organic layer was separated. The water layer was subjected to re-extraction with 50 ml of toluene. The two organic layers were combined and washed with 50 ml of water and 50 ml of a saturated aqueous sodium chloride solution in this order. The washed solution was dried over anhydrous sodium sulfate and then subjected to vacuum distillation to remove the solvent. The resulting concentrate was subjected to distillation to obtain 28.9 g (yield: 98.0%) of an oily title compound (diastereomixture).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.[C:27]([NH:34][C@H:35]([CH2:37]O)[CH3:36])([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28]>C(Cl)Cl>[I:25][CH2:37][C@@H:35]([NH:34][C:27](=[O:28])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH3:36]
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C[C@@H](CI)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
PS-triphenylphosphine (2.5 mmol/g, 1.3 g, 3.3 mmol) was suspended in methylene chloride (12 mL). Imidazole (225 mg, 3.3 mmol) was added and the mixture was cooled to 0° C. in an ice-water bath. To the cooled mixture was added iodine (838 mg, 3.3 mmol), and the resulting mixture was warmed to room temperature, stirred 10 minutes and recooled to 0° C. Boc-L-alaninol (463 mg, 2.64 mmol) in methylene chloride (3 mL) was added over several minutes. The resulting mixture was stirred at 0° C. for 1 hour, warmed to room temperature and stirred 2 h. The mixture was filtered. The solids collected were washed thoroughly with ethyl acetate. The filtrate washed with dilute aqueous HCl (3%), sodium thiosulfate (1 M), saturated aqueous sodium bicarbonate and brine. The extracts were then dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude tert-butyl [(1S)-2-iodo-1-methylethyl]carbamate (xxvii) was obtained as a yellow oil and used without further purification. 1H NMR (300 MHz, CDCl3): δ 3.34-3.56 (m, 2H), 3.27 (dd, J=3.7, 9.8 Hz, 1H), 1.43 (s, 9H), 1.18 (d, J=6.7 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[C:11]([CH2:13][C:14]([OH:16])=O)[N:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:17][CH:18]([P:27](=[O:34])([O:31][CH2:32][CH3:33])[O:28][CH2:29][CH3:30])[P:19](=[O:26])([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22].Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH:12]=[C:11]([CH2:13][C:14]([NH:17][CH:18]([P:19](=[O:26])([O:20][CH2:21][CH3:22])[O:23][CH2:24][CH3:25])[P:27](=[O:34])([O:31][CH2:32][CH3:33])[O:28][CH2:29][CH3:30])=[O:16])[N:10]=[CH:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)n1cnc(CC(=O)O)c1
Reactant: CCOP(=O)(OCC)C(N)P(=O)(OCC)OCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCOP(=O)(OCC)C(NC(=O)Cc1cn(C(=O)OC(C)(C)C)cn1)P(=O)(OCC)OCC
Yield: 65.9 %

Procedure:
To a solution of 2-[1-(tert-butoxycarbonyl)imidazol-4-yl]acetic acid (45 mg) and tetraethyl (aminomethylene)bis(phosphonate) (91 mg) in N,N-dimethylformamide (1 ml) was added N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (42 mg) with stirring on ice-sodium chloride bath under nitrogen atmosphere. After stirring for 36 hours at 5° C., the mixture was diluted with chloroform (10 ml) and washed with cold 1N aqueous solution of citric acid (10 ml). The aqueous layer was extracted with chloroform (10 ml) twice and the combined organic layers were dried over sodium sulfate and evaporated in vacuo. The residue was dissolved in ethyl acetate (10 ml) and the solution was washed with water (10 ml), dried over sodium sulfate and evaporated in vacuo to give a colorless syrup of tetraethyl [[2-{1-(tert-butoxycarbonyl)imidazol-4-yl}acetamido]methylene]bis(phosphonate) (67 mg).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH:6]=[CH2:7])=[O:3].[CH3:8][N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.O.[OH-].[Na+]>ClCCl>[CH2:5]([O:4][C:2]([N:12]1[CH2:13][CH2:14][N:9]([CH3:8])[CH2:10][CH2:11]1)=[O:3])[CH:6]=[CH2:7]
Reactant: CN1CCNCC1
Reactant: C=CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: C=CCOC(=O)N1CCN(C)CC1
Reaction time: 0.5 h

Procedure:
A solution of allyl chloroformate (15 ml) in dry dichloromethane was added at -20° C. under stirring to a solution of N-methylpiperazine (10 g) in the same solvent. After 30 minutes the temperature was let rise to +15° C. and the reaction mixture was poured into water. The organic layer was discarded, 1N NaOH was added to a pH≥7, and the mixture was extracted with dichloromethane. The CH2Cl2 extracts were dried (MgSO4), evaporated, and the resulting oil distilled 118° C. (at 18 mmHg) to yield 4-allyloxycarbonyl-1-methylpiperazine (15.3 g).
Reaction SMILES: [C@H:1]([O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][C:11](=[O:38])[N:12]([C:23]3[CH:28]=[CH:27][C:26]([N:29]([CH3:37])[CH2:30][CH:31]4[CH2:36][CH2:35][CH2:34][NH:33][CH2:32]4)=[CH:25][CH:24]=3)[CH:13]2[C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[CH:8][C:7]=1[O:39][CH3:40])([CH2:3][CH3:4])[CH3:2].[CH3:41]C(O)=O.C=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C@H:1]([O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][C:11](=[O:38])[N:12]([C:23]3[CH:28]=[CH:27][C:26]([N:29]([CH3:37])[CH2:30][CH:31]4[CH2:36][CH2:35][CH2:34][N:33]([CH3:41])[CH2:32]4)=[CH:25][CH:24]=3)[CH:13]2[C:16]2[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=2)=[CH:8][C:7]=1[O:39][CH3:40])([CH2:3][CH3:4])[CH3:2]
Reactant: CC(=O)O
Reactant: CC[C@@H](C)Oc1cc2c(cc1OC)CC(=O)N(c1ccc(N(C)CC3CCCNC3)cc1)C2c1ccc(Cl)cc1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC[C@@H](C)Oc1cc2c(cc1OC)CC(=O)N(c1ccc(N(C)CC3CCCN(C)C3)cc1)C2c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of Example 45 (TFA salt, 7 mg, 0.01 mmol) in DCM (0.5 ml) were successively added AcOH (0.001 ml, 0.021 mmol), formaldehyde (37% in water, 0.002 ml, 0.021 mmol) and NaBH(OAc)3 (4.4 mg, 0.021 mmol) at RT. The reaction mixture was stirred at RT for 1 h, then diluted into DCM and washed with a 2M aqueous Na2CO3 solution. The organic phase was dried over Na2SO4, filtered and evaporated to dryness. The crude material was purified by reverse phase prep-HPLC (Waters system) to yield the title compound (TFA salt, 7.4 mg, 0.01 mmol, quant.) as a colorless solid. HPLC: AtRet=2.11 min; LC-MS: m/z 576.3 [M+H]+; 1H NMR (500 MHz, DMSO-d6): 0.83-0.92 (2t, J=7.5, 3H, mixture of diastereoisomers), 1.10-1.20 (2t, J=6.1, 3H, mixture of diastereoisomers), 1.44-1.67 (m, 4H), 1.69-1.87 (m, 2H), 2.04-2.19 (m, 1H), 2.65-2.81 (m, 5H), 2.84-2.93 (m, 3H), 3.08-3.19 (m, 1H), 3.22-3.41 (m, 3H), 3.56 (d, J=20.0, 1H), 3.72 (s, 3H), 3.91 (d, J=20.0, 1H), 4.17-4.27 (m, 1H), 5.91-5.96 (m, 1H), 6.58-6.63 (m, 2H), 6.83 (s, 1H), 6.88-6.94 (m, 2H), 6.98-7.02 (m, 1H), 7.32-7.37 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[C:8](=[O:9])[C:7]2[N:10]3[C@@:14]([O:21][CH3:22])([C@H:15]([CH2:16][O:17][C:18]([NH2:20])=[O:19])[C:6]=2[C:4](=[O:5])[C:3]=1OC)[C@H:13]1[NH:23][C@H:12]1[CH2:11]3.[C:26]1([CH2:32][CH2:33][NH2:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CO>[C:18](=[O:17])([OH:19])[NH2:20].[OH:17][CH2:16][CH:15]1[C:6]2[C:4](=[O:5])[C:3]([NH:34][CH2:33][CH2:32][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[C:2]([CH3:1])[C:8](=[O:9])[C:7]=2[N:10]2[CH2:11][CH:12]3[NH:23][CH:13]3[C:14]12[O:21][CH3:22]
Reactant: NCCc1ccccc1
Reactant: COC1=C(C)C(=O)C2=C(C1=O)[C@@H](COC(N)=O)[C@@]1(OC)[C@H]3N[C@H]3CN21
Solvent: CO
Product: COC12C(CO)C3=C(C(=O)C(C)=C(NCCc4ccccc4)C3=O)N1CC1NC12
Product: NC(=O)O
Reaction time: 18 h
Yield: 112.9 %

Procedure:
To a solution of 115 mg of mitomycin A (0.33 mmol) in 4 ml of anydrous methanol was added with stirring 80 mg of phenylethylamine (0.66 mmol) in 2 ml of anhydrous methanol. After 18 hours, the solvent was removed by evaporation under reduced pressure. The residue was dissolved in 15 ml of ethyl acetate, and then washed with five 15 ml portions of pH 4 buffer solution. The solvent was removed under reduced pressure and the residue was chromatographed using silica gel as adsorbent and ethyl acetate as solvent. Recrystallization of the product from ethyl acetate-ether gave 85 mg (58.7% yield) of purple solid having a melting point of 94°-96° C. and providing the following analysis: