Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]([CH:16]=[C:17]([CH2:19][O:20][CH2:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[CH:18]=2)[C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:7][CH:8]=1)#[N:2].C(N(CC)CC)C.[C:35](Cl)(=[O:37])[CH3:36].S([O-])(O)(=O)=O.[Na+]>ClCCl>[C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]([CH:16]=[C:17]([CH2:19][O:20][CH2:21][CH:22]3[CH2:27][CH2:26][N:25]([C:35](=[O:37])[CH3:36])[CH2:24][CH2:23]3)[CH:18]=2)[C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: COC(=O)c1cc(COCC2CCNCC2)cc(-c2cccc(C#N)c2)c1
Reactant: CC(=O)Cl
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cc(COCC2CCN(C(C)=O)CC2)cc(-c2cccc(C#N)c2)c1
Yield: 78 %

Procedure:
In 20 ml of dichloromethane, was dissolved 298 mg of the compound obtained in Example 16. To the resulting solution, was added 3.0 ml of triethylamine. To the obtained mixture, 0.46 ml of acetyl chloride was added under cooling with ice and stirring. The mixture was stirred at 0° C. to room temperature for 18 hours. The obtained mixture was poured into a saturated aqueous solution of sodium hydrogensulfate and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated brine and subsequently dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained crude product was purified by silica gel column chromatography to afford 260 mg (78%) of the title compound.
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]2([C:18]3=[CH:19][C:20]4[O:24][CH2:23][O:22][C:21]=4[CH:25]=[C:17]3[O:16][CH2:15]2)[C:7]1=[O:26])C.O.[OH-].[Li+].Cl>C1COCC1.O>[O:26]=[C:7]1[C:8]2([C:18]3=[CH:19][C:20]4[O:24][CH2:23][O:22][C:21]=4[CH:25]=[C:17]3[O:16][CH2:15]2)[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:6]1[CH2:5][C:4]([OH:27])=[O:3]
Reactant: CCOC(=O)CN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21
Temperature: 0 °C
Reaction time: 17 h
Yield: 102 %

Procedure:
To a suspension of ethyl(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetate (10.5 g, 24.5 mmol) in THF (200 mL) and water (100 mL) was added lithium hydroxide monohydrate (3.98 g, 95.0 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 30 min and at ambient temperature for 17 h. The mixture was neutralized with of 4 M HCl (15.0 mL). The residue obtained upon removing the solvent was acidified by the addition of 4 M HCl (6.2 mL) to pH 3. The solid was filtered, washed with water and hexane, and dried under the reduced pressure to give the title compound (8.48 g, 87%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 7.32-7.06 (m, 4H), 6.79 (d, 1H), 6.49 (s, 1H), 6.23 (s, 1H), 5.84 (m, 2H), 4.92 (m, 1H), 4.69-4.63 (m, 2H), 4.45 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 177.8, 171.8, 155.8, 149.0, 142.4, 141.2, 132.0, 129.0, 124.1, 124.0, 119.2, 108.3, 103.4, 101.5, 93.5, 80.2, 58.2, 41.1; MS (ES−) m/z 338.2 (M−1).
Reaction SMILES: [NH2:1][C@@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][S:5][CH3:6].[S:10](Cl)([C:13]1[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=1)(=[O:12])=[O:11]>[OH-].[Na+]>[S:10]([NH:1][C@@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][S:5][CH3:6])([C:13]1[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=1)(=[O:12])=[O:11]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CSCC[C@@H](N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: CSCC[C@@H](NS(=O)(=O)c1ccc(C)cc1)C(=O)O

Procedure:
In Scheme 2, preparing enantiomerically pure (R)-azetidine alcohol 1 (R=Cbz) from D-methionine is as described in Abreo, et al., op. cit. First, D-methionine in aqueous sodium hydroxide solution is treated with tosyl chloride to form N-tosyl-D-methionine, which is treated with MeI followed by 1N sodium hydroxide to afford α-(N-p-tosyl-amino)-γ-butyrolactone according to the method of Sugano and Miyoshi, Bull. Chem. Soc. Japan, 1973, 46, 669. Further conversion to azetidine-2-carboxylic acid is carried out by the procedure of Miyoshi, et al., Chem. Lett. 1973, 5-6. The lactone in ethanol is treated with gaseous HBr to form N-tosyl-g-bromonorvaline ethyl ester. The bromoester in DMF solution with about four equivalents of H2O is treated with NaOH to form (R)-N-tosyl-azetidine-2-carboxylic acid (may be contaminated by the (S)-enantiomer as determined by 1H-NMR analysis of the amide derivative with α-methylbenzylamine)(Abreo, et al., op. cit.) Treating the N-tosylazetidine-2-carboxylic acid with sodium in liquid ammonia affords azetidine-2-carboxylic acid, which is subsequently treated with N-(benzyloxycarbonyl)oxy succinimide according to Abreo, et al., to afford N-Cbz-azetidine-2-carboxylic acid. To remove contaminating (S)-enantiomer, the N-Cbz derivative in MeOH is treated with D-tyrosine hydrazide to form an insoluble salt of the (R)-enantiomer, which is collected by filtration. The optical rotation of the subsequently liberated free acid is [α]D =+105.4 (c 4.0, CHCl3). Treating the free acid with borane.THF affords 1 (R=Cbz). The S-enantiomer ((S)-1) may be synthesized analogously starting from L-methionine. If needed for enantiomeric enrichment, the product may be optically resolved with D-tyrosine-hydrazide in analogy to the procedure described above. Other protecting groups, for example Boc, are readily incorporated by standard methods, e.g. by reacting the intermediate or Cbz deprotected azetidine-2-carboxylic acid with an appropriate standard reagent under prescribed conditions (Greene and Wuts, see above.).
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:6][OH:7])[CH2:4][OH:5].Cl[C:9]([O:11][CH3:12])=[O:10]>ClCCl.N1C=CC=CC=1>[CH3:12][O:11][C:9]([O:1][CH2:2][CH:3]([CH2:6][OH:7])[CH2:4][OH:5])=[O:10]
Reactant: COC(=O)Cl
Reactant: OCC(CO)CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)OCC(CO)CO
Temperature: 25 °C
Reaction time: 16 h
Yield: 42.1 %

Procedure:
To a solution of 2-(hydroxymethyl)-1,3-propanediol (9.4 mmol) in dichloromethane (20 mL) and pyridine (7.5 mL) at 0° C. was added methyl chloroformate (9.4 mmol) slowly. The resulting solution was warmed to room temperature and stirred for 16 h. The reaction was concentrated under reduced pressure and chromatographed by eluting with methanol-dichloromethane (1:4) to give 650 mg of 2-(methoxycarbonyloxymethyl)-1,3-propanediol.
Reaction SMILES: CCCCCC.C([Li])CCC.Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:15][CH:14]=1.[C:25]1([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[CH:30]=[CH:29][C:28]([C:31]2[N:36]=[C:35]([C:37]3[CH:42]=[CH:41][C:40]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)=[CH:39][CH:38]=3)[N:34]=[C:33]([C:49]3[CH:54]=[CH:53][C:52](Br)=[CH:51][CH:50]=3)[N:32]=2)=[CH:27][CH:26]=1>O1CCCC1.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>[C:25]1([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[CH:30]=[CH:29][C:28]([C:31]2[N:36]=[C:35]([C:37]3[CH:42]=[CH:41][C:40]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)=[CH:39][CH:38]=3)[N:34]=[C:33]([C:49]3[CH:54]=[CH:53][C:52]([C:22]4[CH:23]=[CH:24][C:19]([C:16]5[CH:17]=[CH:18][CH:13]=[CH:14][CH:15]=5)=[CH:20][CH:21]=4)=[CH:51][CH:50]=3)[N:32]=2)=[CH:27][CH:26]=1
Reactant: Brc1ccc(-c2ccccc2)cc1
Reactant: Brc1ccc(-c2nc(-c3ccc(-c4ccccc4)cc3)nc(-c3ccc(-c4ccccc4)cc3)n2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: c1ccc(-c2ccc(-c3ccc(-c4nc(-c5ccc(-c6ccccc6)cc5)nc(-c5ccc(-c6ccccc6)cc5)n4)cc3)cc2)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 71 %

Procedure:
Under a stream of argon, 2.1 ml of a hexane solution containing 3.3 mmol of butyl lithium was slowly added to 30 ml of tetrahydrofuran cooled to −78° C. in which prepared by dissolving 0.69 g of 4-bromobiphenyl. After stirring at −78° C. for 15 minutes, 0.91 g of dichloro(tetramethylethylenediamine)zinc(II) was added thereto and stirred at −78° C. for 10 minutes and then at room temperature for 2.5 hours. A 1.35 g portion of 2,4-bis(4-biphenylyl)-6-(4-bromophenyl)-1,3,5-triazine prepared in Reference Example 3 and 0.12 g of tetrakis(triphenylphosphine)palladium(0) were dissolved in 60 ml of tetrahydrofuran and added to this solution, followed by stirring under heating reflux for 2 hours. The reaction solution was concentrated under a reduced pressure, and the thus obtained solid was purified by a silica gel column chromatography (developing solvent hexane:chloroform=2:1 to chloroform) and then recrystallized from dichloromethane-methanol to obtain a white solid of the intended 2,4-bis(4-biphenylyl)-6-[1,1′:4′,1″]terphenyl-4-yl-1,3,5-triazine (1.09 g, yield 71%).
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6](=[O:23])[NH:7][C:8]2[CH:22]=[CH:21][C:11]([C:12]([N:14]([CH3:20])[CH:15]3[CH2:19][CH2:18][NH:17][CH2:16]3)=[O:13])=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.Br[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([OH:41])([C:37]([F:40])([F:39])[F:38])[C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH:1]1([CH2:4][NH:5][C:6](=[O:23])[NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:12]([N:14]([CH:15]3[CH2:19][CH2:18][N:17]([CH2:25][C:26]4[CH:27]=[CH:28][C:29]([C:32]([OH:41])([C:33]([F:34])([F:35])[F:36])[C:37]([F:38])([F:39])[F:40])=[CH:30][CH:31]=4)[CH2:16]3)[CH3:20])=[O:13])=[CH:21][CH:22]=2)[CH2:2][CH2:3]1
Reactant: OC(c1ccc(CBr)cc1)(C(F)(F)F)C(F)(F)F
Reactant: CN(C(=O)c1ccc(NC(=O)NCC2CC2)cc1)C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(C(=O)c1ccc(NC(=O)NCC2CC2)cc1)C1CCN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)C1
Yield: 14.7 %

Procedure:
A mixture of 4-(3-(cyclopropylmethyl)ureido)-N-methyl-N-(pyrrolidin-3-yl)benzamide (4.74 mmol, 1.5 g), 2-(4-(bromomethyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (4.74 mmol, 1.598 g) and potassium carbonate (7.11 mmol, 0.983 g) in acetonitrile (40 mL) was refluxed for 5 hours. The reaction was concentrated under reduced pressure and dichloromethane/methanol was added. The suspension was filtered and the filtrate was concentrated under reduced pressure. Chromatography on silica eluting with a gradient of dichloromethane/methanol gave the title compound (400 mg). MS (ESI) m/z 573.2 [M+H]+
Reaction SMILES: [I:1][C:2]1[CH:15]=[CH:14][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]([NH:11][O:12][CH3:13])[C:4]=2[CH:3]=1.C(N(CC)CC)C.[CH3:23][N:24]1[CH:28]=[C:27]([C:29](Cl)=[O:30])[C:26]([C:32](F)([F:34])[F:33])=[N:25]1>ClCCl>[I:1][C:2]1[CH:15]=[CH:14][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]([N:11]([O:12][CH3:13])[C:29]([C:27]3[C:26]([CH:32]([F:34])[F:33])=[N:25][N:24]([CH3:23])[CH:28]=3)=[O:30])[C:4]=2[CH:3]=1
Reactant: CONC1CCCCc2ccc(I)cc21
Reactant: Cn1cc(C(=O)Cl)c(C(F)(F)F)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C(=O)c1cn(C)nc1C(F)F)C1CCCCc2ccc(I)cc21
Temperature: 24 °C
Reaction time: 3 h
Yield: 88.5 %

Procedure:
To a stirred solution of N-(3-iodo-6,7,8,9-tetrahydro-5-H-benzocyclohepten-5-yl)-O-methyl-hydroxylamine (77 mg; 0.24 mmol), prepared as described in example P3c and triethylamine (0.037 ml; 0.26 mmol) in dichloromethane (1.6 ml) under nitrogen at 4° C. was added dropwise 1-methyl-3-trifluoromethyl-1H-pyrazole-4-carbonyl chloride (47 mg; 0.24 mmol). The reaction mixture was stirred at 24° C. for 3 h under nitrogen. The mixture diluted with dichloromethane (10 ml), washed with 1M sodium hydroxide (1 ml), 1M hydrochloric acid (1 ml) and brine (1 ml). Organics were dried over sodium sulfate. The solvent was removed in vacuo. The crude (190 mg) was subject to flash chromatography (eluant: c-hexane/ethyl acetate 90:10 to 50:50) to afford 0.101 g (88% of theory) of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid (3-iodo-6,7,8,9-tetrahydro-5-H-benzocyclohepten-5-yl)-methoxy-amide as a yellow solid oil.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[S:34](=[O:37])(=[O:36])[NH2:35])=[CH:24][CH:23]=2)[C:7](=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])[N:9]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].[N:40]1([C:46](Cl)=[O:47])[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1>C1COCC1>[CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[S:34](=[O:37])(=[O:36])[NH:35][C:46]([N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)=[O:47])=[CH:24][CH:23]=2)[C:7](=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(Cl)N1CCOCC1
Reactant: CCCCc1nn(-c2ccccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCc1nn(-c2ccccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 25.9 %

Procedure:
To a solution of 51.1 mg (0.0964 mmole) of 5-n-butyl-2,4-dihydro-4-[(2'-sulfamoylbiphenyl-4-yl)methyl]- 2-[2-(trifluoromethyl)phenyl]-3H-1,2,4-triazol-3-one (from Example 16, Step C) in 0.2 ml of dry THF was added 4.6 mg (0.116 mmole) of sodium hydride (60% in oil), and the mixture was allowed to stir at room temperature under N2 for 4 hours. Next, 17 μl (21.6 mg, 0.145 mmole) of 4-morpholinecarbonyl chloride was added, and the solution was stirred under N2 at room temperature overnight. The reaction was quenched by addition of 2 ml of H2O followed by extraction with 3×5 ml of ethyl acetate. The combined organic extracts were washed with 2×5 ml of H2O and then with 5 ml of brine. After co-evaporation twice from toluene, the crude product was flash chromatographed on silica gel (gradient elution with 0.3-10% MeOH in CH2Cl2) to give 16.1 mg of the title compound as a whitish glass; satisfactory purity by TLC in 19:1 and 9:1 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 682 (M+K)+.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:17])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH2:15][OH:16])([CH3:14])[CH2:6][CH2:5]2.[H-].[Na+].[CH3:20][O:21][CH2:22]Cl>CN(C)C=O.C1C=CC=CC=1>[CH3:20][O:21][CH2:22][O:1][C:2]1[C:3]([CH3:17])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH2:15][OH:16])([CH3:14])[CH2:6][CH2:5]2
Reactant: COCCl
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(CO)O2
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: COCOc1c(C)c(C)c2c(c1C)CCC(C)(CO)O2
Temperature: 0 °C

Procedure:
16.1 g of 6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethanol were dissolved in 70 ml of dry dimethylformamide. 3.0 g of a 50% w/w suspension of sodium hydride in oil (which had been washed with cyclohexane 3 times) were added gradually to the resulting solution at 5°-10° C., with stirring and under a nitrogen stream. The mixture was reacted for 1 hour at room temperature, and then the solution was ice-cooled to 3°-5° C., and 5.5 g of chloromethyl methyl ether dissolved in 40 ml of dry benzene were added dropwise. After the whole of this had been added, the solution was reacted for 1 hour at room temperature. The reaction mixture was then poured into ice-water and extracted with cyclohexane. The extract was washed four times with a 5% w/v aqueous solution of sodium hydroxide, and then with water. It was then dried and the solvent was distilled off under reduced pressure, giving the desired 6-(methoxymethoxy)-2,5,7,8-tetramethylchroman-2-ylmethanol. On thin layer chromatography, the Rf value was 0.45 [silica gel; developing solvent:benzene:ethyl acetate=4:1 by volume].
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O:19][C:20](=O)[C:21](OCC)=[O:22])C.CC(C)([O-])C.[K+]>O>[OH:22][C:21]1[C:20](=[O:19])[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8](=[O:16])[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: O=C(Cc1ccccc1)Nc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Product: O=C1C(O)=C(c2ccccc2)C(=O)N1c1ccccc1
Reaction time: 3 h

Procedure:
After the addition of anhydride THF (20 ml) to compound 5a (1.55 g, 7.34 mmol), the temperature was adjusted to 0° C. Diethyloxalate (1.45 g, 9.50 mmol) and potassium t-butoxide (1.35 g, 11.9 mmol) were added thereto and the agitation for 3 hours was carried out. After the identification of the reaction progress with TLC, the solution was poured into the distilled water and acidified with 1N HCL aqueous solution. Three times extractions were carried out with EA and three times washings were carried out with brine. Water was removed by using Na2SO4, solvents were removed and then, the suspension was carried out by HX.
Reaction SMILES: [CH3:1][C:2]([CH3:6])([CH3:5])[CH:3]=O.[CH3:7][O:8][C:9](=[O:13])[CH2:10][CH2:11][NH2:12].[BH3-]C#N.[Na+]>CO>[CH3:7][O:8][C:9](=[O:13])[CH2:10][CH2:11][NH:12][CH2:3][C:2]([CH3:6])([CH3:5])[CH3:1]
Reactant: CC(C)(C)C=O
Reactant: COC(=O)CCN
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COC(=O)CCNCC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1.5 g 2,2-Dimethyl-propionaldehyde, 2.18 g 3-Amino-propionic acid methyl ester and 50 ml MeOH was stirred at room temperature for 30 min. 1.5 g NaCNBH3 was added in small portion. The mixture was stirred for another 3 hrs. The solvent was removed in vacuum. 50 mL Water was added to the residue and the mixture was basified to PH10 by 1N NaOH. The solution was extracted by EtOAc (30 mL×3). The organic phase was washed by 20 mL water, dried over Na2SO4. Removed the solvent gave 0.66 g target molecule as clear oil.
Reaction SMILES: [OH:1][CH:2]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:3](OCCCl)=[O:4].[C:16]([O:20][CH:21]([CH3:23])[CH3:22])(=[O:19])[CH2:17][OH:18].C(C1C=CC=CC=1)(C)(C)C>C(OCC)C>[OH:1][CH:2]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:3]([O:18][CH2:17][C:16]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])=[O:4]
Reactant: CC(C)OC(=O)CO
Reactant: O=C(OCCCl)C(O)Cc1ccccc1
Solvent: CC(C)(C)c1ccccc1
Solvent: CCOCC
Product: CC(C)OC(=O)COC(=O)C(O)Cc1ccccc1

Procedure:
A 6 mL aliquot of an ethyl ether solution containing 0.25 M 2-chloroethyl 2-hydroxy-3-phenylpropionate, 0.25 M isopropyl glycolate, and 1.0% tert-butylbenzene was added to 0.43 g Lipase AK. After mixing for 2 d at room temperature, the conversion of 2-chloroethyl 2-hydroxy-3-phenylpropionate to the title compound was estimated (by GC, Method B) to be approximately 28%. The GC peak assigned to the title compound was confirmed by HRMS: calcd for C13H14O5Tms (M--CH3) 323.1314, obsd 323.1290. In identical reactions substituting Lipase P30, Lipase G, Lipase MAP10, porcine pancreatic lipase, Lipase AP12 or Protease M for Lipase AK, the relative values for conversions at 2 d (Lipase AK=100) were 88, 85, 76, 51, 7, and 7%, respectively.
Reaction SMILES: [C:1]([C:4]1[C:5]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]3)=[CH:23][CH:22]=2)=[N:6][C:7]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)=[CH:8][N:9]=1)(=[O:3])[NH2:2].[Cl:40]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[C:1]([C:4]1[C:5]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([N:27]3[CH2:28][CH2:29][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:31][CH2:32]3)=[C:25]([Cl:40])[CH:26]=2)=[N:6][C:7]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)=[CH:8][N:9]=1)(=[O:3])[NH2:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3nc(Oc4cccc([N+](=O)[O-])c4)cnc3C(N)=O)cc2)CC1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3nc(Oc4cccc([N+](=O)[O-])c4)cnc3C(N)=O)cc2Cl)CC1
Temperature: 50 °C
Reaction time: 15 h
Yield: 98.7 %

Procedure:
To a mixture of tert-butyl 4-(4-{[3-carbamoyl-6-(3-nitrophenoxy)pyrazin-2-yl]amino}phenyl)piperazine-1-carboxylate (1 g) and chloroform (30 mL) was added N-chlorosuccinimide (262 mg), and the reaction mixture was stirred at 50° C. for 15 hours and further, at 60° C. for 24 hours. To the reaction mixture was added silica gel, and the solvent was evaporated under reduced pressure and then purified by silica gel column chromatography (eluent; chloroform) to obtain tert-butyl 4-(4-{[3-carbamoyl-6-(3-nitrophenoxy)pyrazin-2-yl]amino}-2-chlorophenyl)piperazine-1-carboxylate (1.05 g) as a yellow solid.
Reaction SMILES: [OH-].[K+].Cl[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[CH2:21][C:22]#[N:23].C1C=CC=CC=1>N1C=CC=CC=1>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[CH:21]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1)[C:22]#[N:23]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: N#CCc1ccc(Cl)cc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: N#CC(c1ccc([N+](=O)[O-])cc1)c1ccc(Cl)cc1Cl
Temperature: -5 °C
Reaction time: 10 h

Procedure:
To a solution of 39 parts of potassium hydroxide in 39 parts of pyridine is added a solution of 17 parts of 1-chloro-4-nitrobenzene in 46 parts of pyridine. The whole is cooled to -5° C and there is added dropwise a solution of 22 parts of 2,4-dichlorobenzeneacetonitrile in pyridine, while still cooling at -5° C. Upon completion, stirring is continued for 10 hours at 0° C. After the addition of 90 parts of benzene, the product is precipitated. It is filtered off, washed on the filter with benzene and taken up in water. The aqueous mixture is treated with acetic acid, whereupon the product is separated as an oil. The latter is extracted with methylbenzene. The extract is dried, filtered and evaporated. The residue is crystallized from a mixture of methanol, 2,2' -oxybispropane, petroleumether and trichloromethane, yielding 2,4-dichloro-α-(4-nitrophenyl)benzeneacetonitrile; mp. 81°- 82.5° C.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH2:3][NH:4][C:5](=[O:15])[C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]([NH2:13])[C:7]=1[OH:14].C(N(CC)CC)C.[C:25]([O:28][CH2:29][C:30](Cl)=[O:31])(=[O:27])[CH3:26]>C1COCC1>[F:17][C:2]([F:1])([F:16])[CH2:3][NH:4][C:5](=[O:15])[C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]([NH:13][C:30](=[O:31])[CH2:29][O:28][C:25](=[O:27])[CH3:26])[C:7]=1[OH:14]
Reactant: CC(=O)OCC(=O)Cl
Reactant: Nc1cc(F)cc(C(=O)NCC(F)(F)F)c1O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)OCC(=O)Nc1cc(F)cc(C(=O)NCC(F)(F)F)c1O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
6.3 (25 mmol) of crude 3-amino-5-fluoro-2-hydroxybenzoic acid-(2,2,2,-trifluoro-ethyl)amide is dissolved in 30 ml of THF, 3.04 g (30 mmol) of triethylamine as well as 4.1 g (30 mmol) of acetoxyacetylchloride are added and stirred for 12 hours at room temperature. The reaction solution is then concentrated by evaporation in a vacuum and the residue is chromatographed on silica gel 60 with ethyl acetate/hexane. 5.52 g=62.7% of the theoretical yield is obtained as an amorphous solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]2[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8]2)=[CH:5][CH:4]=[N:3]1.C1C(=O)N([Br:26])C(=O)C1>C1COCC1>[Br:26][C:5]1[CH:4]=[N:3][N:2]([CH3:1])[C:6]=1[CH:7]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8]1
Reactant: Cn1nccc1C1CCN(C(=O)OC(C)(C)C)C1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: Cn1ncc(Br)c1C1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.6 %

Procedure:
A mixture of tert-butyl 3-(1-methyl-1H-pyrazol-5-yl)-pyrrolidine-1-carboxylate (2.3 g, 7.0 mmol) and NBS (1.48 g, 8.39 mmol) in THF (50 mL) was stirred at room temperature for 1 h. Solvent was removed to afford the crude product, which was purified by reverse phase Combiflash eluting with a 0-70% gradient of CH3CN in 0.3% NH4HCO3 to give tert-butyl 3-(4-bromo-1-methyl-1H-pyrazol-5-yl)pyrrolidine-1-carboxylate (2.28 g, 75% yield) as white solid. LCMS (ESI) m/z: 332.1 [M+H+]. 1H-NMR (500 MHz, CDCl3) δ 7.38 (s, 1H), 3.88 (s, 3H), 3.75-3.61 (m, 3H), 3.52 (s, 1H), 3.38 (s, 1H), 2.48 (s, 1H), 2.15 (s, 1H), 1.48 (s, 9H).