Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C:4]12[CH2:10][CH:7]([CH:8]=[CH:9]1)[C:6](=[O:11])[NH:5]2)(=O)C.[BH4-].[Na+].[CH2:14]([OH:18])[CH2:15]CC.CCCCCC>O.CC(O)CC.CO>[C:14]([NH:5][C@@H:4]1[CH2:10][C@H:7]([CH2:6][OH:11])[CH:8]=[CH:9]1)(=[O:18])[CH3:15]
Reactant: CC(=O)C12C=CC(C1)C(=O)N2
Reactant: CCCCO
Agent: [BH4-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CO
Solvent: CCC(C)O
Product: CC(=O)N[C@H]1C=C[C@@H](CO)C1
Temperature: 1 °C
Reaction time: 1.5 h
Yield: 85 %

Procedure:
1.3.2 287.4 g (−)-acetyl-2-azabicyclo[2.2.1]hept-5-ene-3-one (100%==>−255 ml, 97%; 1.9 moles) were dissolved in 380 ml water and 1217 ml 2-butanol. The solution was cooled to 0 to 2° C. 45 g NaBH4 (1.188 moles, 1.25 eq.) were suspended in 304 ml fresh 2 butanol in another stirring device. The NaBH4 suspension as added to the solution during 1-2 hours. The reaction was exothermic, and the temperature was not allowed to exceed 5° C. The temperature had to be at 0° C. before a portion was added. The reaction was followed by DC (thin-layer chromatography) (hexane/etrol/MeOH: 551). The reaction was allowed to continue for 1 to 2 hours after the addition. When the reaction as complete (educt concentration had to be at <1.0%), the pH was adjusted to 2 with ca. 135 g concentrated hydrochloric acid. The temperature as maintained below 10° C. The pH was then adjusted immediately to 9 with ca. 85 ml 30% sodium hydroxide solution. The precipitated salts were filtered and washed with 127 ml fresh 2-butanol. The filtrate and the “2-butanol wash” were combined, and the phases separated. The aqueous phase as extracted twice with 380 ml fresh 2-butanol each time. The 2-butanol phases were combined. Ca. 2450 g of a 10% solution of the product (1R,4S)-1-acetylamino-4-(hydroxymethyl)-2-cyclopentene, were obtained in 2-butanol. This corresponded to ca. 250 g of 100% product, (1R,4S)-1-acetylamino-4-(hydroxymethyl)-2-cyclopentene, corresponding to a yield of 85%.
Reaction SMILES: O[C@H:2]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][N:11]=1)[C:7]#[N:8])[CH3:3].C1C(=O)N([Cl:19])C(=O)C1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>>[Cl:19][C@@H:2]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][N:11]=1)[C:7]#[N:8])[CH3:3]
Reactant: C[C@H](O)c1cc(C#N)ccn1
Reactant: O=C1CCC(=O)N1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: C[C@@H](Cl)c1cc(C#N)ccn1
Temperature: 30 °C
Yield: 7 %

Procedure:
The title compound was prepared from 2-((S)-1-hydroxy-ethyl)-isonicotinonitrile (620 mg, 4.18 mmol) according to General Method C, except that 1.0 equiv. NCS and 1.0 equiv. PPh3 were used. After 24 hrs reaction time another 0.2 equiv. each of NCS and PPh3 were added and the temperature was increased to 30° C. for 12 h. Workup and purification by flash column chromatography yielded the title compound (46 mg, 7% yield) with 82% ee. 1H NMR (CDCl3) δ 8.74 (d, 1H), 7.76 (s, 1H), 7.46 (dd, 1H), 5.16 (q, 1H), 1.88 (d, 3H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([NH:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)=[CH:9][CH:10]=2)[CH:5]=[N:4][C:3]=1[C:22]([NH:24][CH2:25][C:26]([CH3:32])([CH3:31])[C:27]([O:29]C)=[O:28])=[O:23].O.CCOC(C)=O.Cl>CO.[OH-].[Na+]>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([NH:12][CH2:13][C:14]3[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)=[CH:9][CH:10]=2)[CH:5]=[N:4][C:3]=1[C:22]([NH:24][CH2:25][C:26]([CH3:32])([CH3:31])[C:27]([OH:29])=[O:28])=[O:23]
Reactant: COC(=O)C(C)(C)CNC(=O)c1ncc2cc(NCc3ccc(OC)cc3)ccc2c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc(CNc2ccc3c(O)c(C(=O)NCC(C)(C)C(=O)O)ncc3c2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Methyl 3-(4-hydroxy-7-(4-methoxybenzylamino)isoquinoline-3-carboxamido)-2,2-dimethylpropanoate (15 mg, 0.03 mmol) was dissolved in MeOH (2 mL) and 2 N NaOH (2 mL). After stirring for 5 hours at room temperature, H2O (15 mL) and EtOAc (15 mL) were added. To the stirred mixture was added 1 N hydrochloric acid until pH was 1. The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO4, concentrated, and purified by flash chromatography (0-20% MeOH/CH2Cl2) to give the title compound in 13 mg. MS: (−) m/z 422.13 (M−1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=1B1OC(C)(C)C(C)(C)O1>>[Cl:1][C:2]1[N:7]=[C:6]([C:11]2[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:10]=2[F:9])[CH:5]=[CH:4][N:3]=1
Reactant: CC1(C)OB(c2cc([N+](=O)[O-])ccc2F)OC1(C)C
Reactant: Clc1ccnc(Cl)n1
Product: O=[N+]([O-])c1ccc(F)c(-c2ccnc(Cl)n2)c1

Procedure:
2,4-Dichloropyrimidine (2.0 g, 13 mmol) was coupled to 2-(2-fluoro-5-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (3.9 g, 15 mmol) using the method in Example 14 part a). Purification by chromatography on silica gel eluting with dichloromethane containing 20% isohexane gave 2-chloro-4-(2-fluoro-5-nitro-phenyl)pyrimidine as a white solid: δH (400 MHz, CDCl3) 7.40 (1H, dd, J 10 and 9), 7.85 (1H, dd, J 5 and 2), 8.38-8.43 (1H, m), 8.77 (1H, d, J 6), 9.16 (1H, q, J 3).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=[O:7])=[CH:2]1.S(=O)(=O)(O)O.[OH-].[Na+].[N+:16]([O-])([OH:18])=[O:17]>>[N+:16]([C:5]1[S:1][CH:2]=[C:3]([C:6]([OH:8])=[O:7])[CH:4]=1)([O-:18])=[O:17]
Reactant: O=C(O)c1ccsc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1csc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
3-Thiophenecarboxylic acid (5.12 g) was added portionwise to a mixture of nitric acid (20 ml) and sulfuric acid (11.5 ml) below 5° C. The mixture was stirred at the same temperature for 30 minutes, and poured into ice water. The mixture was alkalified with 1N sodium hydroxide and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give 5-nitro-3-thiophenecarboxylic acid (4.45 g) as crystals.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH:6]=O)=[N:2]1.[CH3:8][C:9]([S:12]([NH2:14])=[O:13])([CH3:11])[CH3:10]>C1COCC1.C(OCC)(=O)C.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[O:1]1[CH:5]=[CH:4][C:3](/[CH:6]=[N:14]/[S:12]([C:9]([CH3:11])([CH3:10])[CH3:8])=[O:13])=[N:2]1
Reactant: CC(C)(C)S(N)=O
Reactant: O=Cc1ccon1
Agent: [Ti+4]
Agent: CC[O-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)/N=C/c1ccon1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.5 %

Procedure:
In a round-bottomed flask, isoxazole-3-carbaldehyde (300 mg, 3.09 mmol) was dissolved in THF (7 ml) and 2-methylpropane-2-sulfinamide (450 mg, 3.71 mmol) and titanium(IV) ethoxide (1.3 ml, 6.18 mmol) were added. The reaction mixture was stirred at room temperature overnight then slowly quenched by dropwise addition of brine (2 ml) which resulted in the formation of a thick yellow precipitate. The reaction mixture was diluted with ethyl acetate and stirred vigorously at room temperature for 10 min. The suspension was filtered over Celite and rinsed with ethyl acetate. The filtrate was concentrated and the residue was chromatographed over silica gel with EtOAc/hexanes (gradient 0-20% EtOAc) to afford 585 mg (95%) of 2-methyl-propane-2-sulfinic acid 1-isoxazol-3-yl-meth-(E)-ylideneamide as a colorless oil.
Reaction SMILES: C([C:4]1([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:20]([C:22]4[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=4)=[O:21])[CH:17]=3)[NH:12][N:11]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH2:5]1)(=O)C.Cl>N.CO>[NH2:28][C:25]1[CH:24]=[CH:23][C:22]([C:20]([NH:19][C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[NH:12][N:11]=[C:10]3[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[O:21])=[CH:27][CH:26]=1
Reactant: CC(=O)C1(c2n[nH]c3ccc(NC(=O)c4ccc(N)cc4)cc23)C=CC=CC1
Agent: Cl
Agent: N
Solvent: CO
Product: Nc1ccc(C(=O)Nc2ccc3[nH]nc(-c4ccccc4)c3c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.7 %

Procedure:
To a solution of N-(1-acetyl-3-phenyl(1H-indazol-5-yl))(4-aminophenyl)carboxamide (200 mg, 0.664 mmol) in 0.3% ammonia in methanol (12 mL). After the reaction mixture was stirred at room temperature for 3 hours, the mixture was acidified with 5% HCl. The resulting precipitate was filtered and dried to give the title compound (200 mg, 92% yield). 1H NMR (DMSO-d6) δ 13.14 (br s, 1H), 9.84 (s, 1H), 8.52 (s, 1H), 7.95 (d, 2H), 7.75 (m, 3H), 7.54 (m, 3H), 7.39 (t, 1H), 5.74 (br, 2H); ES-MS (m/z) 329 [M+1]+.
Reaction SMILES: C(O)(=O)C.[CH:5]([NH2:7])=[NH:6].O=[C:9]([CH2:15][CH3:16])[CH2:10][C:11](OC)=[O:12].C[O-].[Na+].O>CO.C(OCC)(=O)C.C(O)(=O)C>[CH2:15]([C:9]1[CH:10]=[C:11]([OH:12])[N:7]=[CH:5][N:6]=1)[CH3:16]
Reactant: N=CN
Reactant: CCC(=O)CC(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: CCc1cc(O)ncn1
Reaction time: 15 h
Yield: 38.4 %

Procedure:
Formamidine acetate (500 g) and methyl 3-oxopentanoate (500 g) were added to a solution of sodium methoxide (500 g) in methanol (4 L) at 20° C. and the mixture stirred for 15 hours. Water (1 L) and acetic acid (500 ml) were added to give a pH of 7. The solvent was removed by evaporation under reduced pressure and the aqueous residue was diluted with water (1 L) and extracted with methyl ethyl ketone (4×2.5 L). The organic phases were combined and concentrated by evaporation under reduced pressure to give an orange syrup. The syrup was dissolved in ethyl acetate (1 L) and the solution stirred for 15 hours to give a solid. The solid was collected by filtration, washed with ethyl acetate (200 ml, at 10° C.) and dried at 50° C. under reduced pressure to provide the title compound (183 g). After concentrating the mother liquors under reduced pressure, diethyl ether (3 L) was added to provide a solid. This was solid was collected by filtration, washed with tert-butyl methyl ether (200 ml) and dried at 50° C. under reduced pressure to provide a second crop of the title compound (195 g). The total yield of the title compound was approximately 79%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:18])[C:8]([CH3:17])=[C:9]([C:12]([O:14]CC)=[O:13])[C:10]=1[CH3:11])=[O:5])[CH3:2]>S(=O)(=O)(O)O>[CH3:18][N:7]1[C:8]([CH3:17])=[C:9]([C:12]([OH:14])=[O:13])[C:10]([CH3:11])=[C:6]1[C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCOC(=O)c1c(C)c(C(=O)OCC)n(C)c1C
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1c(C)c(C(=O)O)c(C)n1C

Procedure:
The starting material is prepared as follows: The mixture of 11.9 g of 1,3,5-trimethylpyrrole-2,4-dicarboxylic acid diethyl ester and 50 ml of concentrated sulfuric acid is heated on the steam cone for 1 hour. The resulting solution is poured on to ice, the precipitate collected and washed with water. It it taken up in aqueous sodium carbonate, the solution filtered and the filtrate acidified with 5 N hydrochloric acid. The precipitate formed is collected, washed with water, dried and recrystallized from ethanol, to yield the 1,3,5-trimethyl-2-carbethoxypyrrole-4-carboxylic acid melting at 197°-198° with decomposition.
Reaction SMILES: [C:1]([C:5]1[CH:29]=[CH:28][C:8]([O:9][CH2:10][C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[C:17]([O:26]C)[CH:16]=2)=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl.B(Br)(Br)Br>C(OCC)(=O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH2:10][C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][S:22]([CH3:25])(=[O:23])=[O:24])=[C:17]([OH:26])[CH:16]=2)=[O:12])=[CH:28][CH:29]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc(CNC(=O)COc2ccc(C(C)(C)C)cc2)ccc1NS(C)(=O)=O
Agent: BrB(Br)Br
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)c1ccc(OCC(=O)NCc2ccc(NS(C)(=O)=O)c(O)c2)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 68 %

Procedure:
To a solution of 2-(4-tert-butylphenoxy)-N-{3-methoxy-4-[(methylsulfonyl)amino]benzyl}acetamide (Example 11) (446 mg, 1.06 mmol) in methylene dichrolide (20 ml) was added 1.0 M methylene dichloride solution of boron(III)bromide (5.3 ml, 5.3 mmol) at 0° C. After being stirred for 1.5 hours at 0° C., the mixture was quenched with water and crude residue was extracted with methylene dichloride. The organic layer was separated, then washed with brine, dried over magnesium sulfate. Then, filtration to remove magnesium sulfate, evaporation under removed pressure gave the residue, which was applied to a silica gel chromatography column and eluted with a volume mixture of hexane : ethyl acetate (2/3) to furnish 293 mg (55% yield) of the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:7][CH2:6][C:5](=[O:8])[C:4]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][CH:10]=2)=[CH:3]1.[BH4-].[Na+].[Cl-].[NH4+]>CO>[CH3:1][C:2]1([CH3:15])[CH2:7][CH2:6][CH:5]([OH:8])[CH:4]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][CH:10]=2)[CH2:3]1
Reactant: Cn1nccc1C1=CC(C)(C)CCC1=O
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: Cn1nccc1C1CC(C)(C)CCC1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the 4,4-dimethyl-2-(1-methyl-1H-pyrazol-5-yl)cyclohex-2-en-1-one (432 mg, 2.12 mmol) prepared in Example 67c in methanol (6.0 mL), sodium borohydride (200 mg, 5.29 mmol) was added with cooling on ice, and the reaction solution was stirred at room temperature for 1 hour. To the reaction solution, a saturated aqueous solution of ammonium chloride (20 mL) was added, followed by extraction with dichloromethane (50 mL). The thus obtained organic layer was dried over anhydrous sodium sulfate and vacuum concentrated to yield a mixture of the title compound and an allyl alcohol derivative.
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]([NH2:6])=[NH:5].Cl[C:8]1[N:13]=[C:12]([CH2:14][C:15]2[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:22])[N:11]=[C:10]([NH:23][C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=2)[N:9]=1>O1CCOCC1>[C:28]([C:27]1[CH:30]=[CH:31][C:24]([NH:23][C:10]2[N:11]=[C:12]([CH2:14][C:15]3[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:22])[N:13]=[C:8]([NH:5][C:4]([NH2:6])=[NH:3])[N:9]=2)=[CH:25][CH:26]=1)#[N:29]
Reactant: N#Cc1ccc(Nc2nc(Cl)nc(Cc3c(Cl)cccc3Cl)n2)cc1
Reactant: N=C(N)N
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: N#Cc1ccc(Nc2nc(Cc3c(Cl)cccc3Cl)nc(NC(=N)N)n2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 64.3 %

Procedure:
NaOH (0.0128 mol), 1,4-dioxane (5 ml), and guanidine (0.0128 mol) were combined and stirred at RT for 5 minutes under argon. Then, intermediate (27) (0.00128 mol) was added and the reaction mixture was stirred at RT for 16 hours. The reaction mixture was quenched with H2O, and stirred. The resulting precipitate was filtered off and the residue was stirred in refluxing methanol, cooled, and filtered, yielding 0.34 g (64.3%) of N-[4-[(4-cyanophenyl)amino]-6-[(2,6-dichlorophenyl)methyl]-1,3,5-triazin-2-yl]-guanidine (compound 20).
Reaction SMILES: C(OC(C1CCNCC1)=O)C.C([O:14][C:15]([CH:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:33][C@H:32]([CH2:34][NH:35][C:36](=[O:38])[CH3:37])[O:31][C:30]3=[O:39])=[CH:25][C:24]=2[F:40])[CH2:19][CH2:18]1)=O)C.[Cl-].[Li+].[BH4-].[Na+].[Cl-].[NH4+]>C(O)C.C1COCC1>[F:40][C:24]1[CH:25]=[C:26]([N:29]2[CH2:33][C@H:32]([CH2:34][NH:35][C:36](=[O:38])[CH3:37])[O:31][C:30]2=[O:39])[CH:27]=[CH:28][C:23]=1[N:20]1[CH2:21][CH2:22][CH:17]([CH2:15][OH:14])[CH2:18][CH2:19]1
Reactant: CCOC(=O)C1CCN(c2ccc(N3C[C@H](CNC(C)=O)OC3=O)cc2F)CC1
Agent: CCOC(=O)C1CCNCC1
Agent: [BH4-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(CO)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 14 h
Yield: 68 %

Procedure:
Using a commercially available piperidine-4-carboxylic acid ethyl ester, (S)-1-{4-[5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenyl}-piperidine-4-carboxylic acid ethyl ester (Compound No. 1) was synthesized by the same method as in Example 1. To a THF solution (6.6 ml) of this compound (661 mg), lithium chloride (275 mg), sodium borohydride (245 mg) and ethanol (4.5 ml) were added successively and the mixture was stirred at room temperature for 14 h. A saturated aqueous ammonium chloride solution was added to the reaction solution and the reaction mixture was extracted with methylene chloride; the organic layer was washed with water and brine, dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography (solvent: chloroform/methanol=25/1-15/1) to afford the title compound (402 mg) in a yield of 68%.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:26])[C@@H:10]([CH2:24][OH:25])[NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27](=O)=O.CC(C)=O.B(F)(F)F.CCOCC.[N+](=C)=[N-]>ClCCl>[CH2:1]([O:8][C:9](=[O:26])[C@@H:10]([CH2:24][O:25][CH3:27])[NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C=O
Reactant: COc1ccc(COC(=O)N[C@H](CO)C(=O)OCc2ccccc2)cc1
Agent: C=[N+]=[N-]
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Solvent: CC(C)=O
Product: COC[C@@H](NC(=O)OCc1ccc(OC)cc1)C(=O)OCc1ccccc1
Yield: 70 %

Procedure:
The N-p-methoxybenzyloxycarbonyl-D-serine benzyl ester (720 mg, 2.00 mmol) is dissolved in dry dichloromethane (20 ml) and the solution cooled to dry ice/acetone. Boron trifluoride etherate (100 μl) is added followed by the portionwise addition of diazomethane (30 mmol in 20 ml CH2Cl2). After about 30 minutes the solution is filtered and washed once with water (10 ml), then dried (MgSO4) and evaporated to dryness. The resulting residue is chromatographed on silica gel using chloroform as eluant to give the pure title compound as an oil (520 mg, 70%) which crystallises on standing to give a colourless solid of m.p. 68°-69° C.; [α]D20 -1.3° (c 4.0, CHCl3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2([N+:16]([O-])=O)[CH2:13][N:12]([CH3:14])[C:11](=[O:15])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1>O1CCOCC1.[Zn]>[NH2:16][C:8]1([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH2:13][N:12]([CH3:14])[C:11](=[O:15])[CH2:10][CH2:9]1
Reactant: CN1CC(c2cccc(Cl)c2)([N+](=O)[O-])CCC1=O
Agent: [Zn]
Solvent: C1COCCO1
Product: CN1CC(N)(c2cccc(Cl)c2)CCC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.1 %

Procedure:
To a solution of 115 mg (0.428 mmol) 5-(3-chloro-phenyl)-1-methyl-5-nitro-piperidin-2-one in 0.5 ml dioxane was added 2 ml 3NHCl and 280 mg (4.28 mmol) zinc dust. The mixture was stirred at room temperature for 30 minutes. The mixture was filtered and the filtrate was basified with a 5N NaOH solution. Ethyl acetate was added. The mixture was filtered through a pad of dicalite. The organic layer was separated and the aqueous layer was extracted twice with ethyl acetate. The combined extracts were dried over sodium sulfate, filtered and concentrated in vacuo to provide 88 mg (86%) of the title compound as a light yellow oil. MS (m/e): 239.0 (MH+).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C@H:10]1[O:15][C@@H:14]([CH3:16])[CH2:13][N:12]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[CH:27]=[CH:26][O:25][C:24]=3[CH3:28])[CH:18]=2)[CH2:11]1>C(Cl)(Cl)Cl>[Br:1][C:20]1[CH:21]=[CH:22][C:17]([N:12]2[CH2:11][C@H:10]([CH3:9])[O:15][C@H:14]([CH3:16])[CH2:13]2)=[CH:18][C:19]=1[C:23]1[CH:27]=[CH:26][O:25][C:24]=1[CH3:28]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1occc1-c1cccc(N2C[C@@H](C)O[C@@H](C)C2)c1
Solvent: ClC(Cl)Cl
Product: Cc1occc1-c1cc(N2C[C@@H](C)O[C@@H](C)C2)ccc1Br
Temperature: 0 °C
Reaction time: 1 h

Procedure:
N-Bromosuccinimide (380 mg, 2.137 mmol) was added portionwise to a solution of cis-2,6-dimethyl-4-[3-(2-methyl-3-furanyl)phenyl]morpholine (580 mg, 2.137 mmol) in chloroform (10 mL) at 0° C. The reaction was stirred at 0° C. for 1 hour. Crude LC/MS showed desired product can be seen and no starting material left, so the reaction mixture was diluted with ethyl acetate and washed with water, brine, water and brine. The organic layer was dried (sodium sulfate), filtered and concentrated under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20]([C:21](O)=[O:22])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.O[NH:25][C:26]([C:28]1[S:29][C:30]([S:33](=[O:36])(=[O:35])[NH2:34])=[CH:31][CH:32]=1)=[NH:27]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:16])([F:15])[F:17])[N:11]3[N:18]=[CH:19][C:20]([C:21]4[O:22][N:27]=[C:26]([C:28]5[S:29][C:30]([S:33]([NH2:34])(=[O:36])=[O:35])=[CH:31][CH:32]=5)[N:25]=4)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: N=C(NO)c1ccc(S(N)(=O)=O)s1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)cc3)nc12
Product: NS(=O)(=O)c1ccc(-c2noc(-c3cnn4c(C(F)(F)F)cc(-c5ccc(Cl)cc5)nc34)n2)s1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.4) (171 mg, 0.5 mmol) and N-hydroxy-5-sulfamoyl-thiophene-2-carboxamidine (example B.2) (166 mg, 0.75 mmol) according to general procedure II. Obtained after purification by flash chromatography (ethyl acetate/heptane) and crystallization (dichloromethane) as a yellow solid (180 mg, 68%). MS (ISN) 525.0 [(M−H)−]; mp 294° C.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]([NH:12][C:13]3[CH:14]=[N:15][N:16]([CH2:22][CH2:23][O:24]C4CCCCO4)[C:17]=3[C:18](=[O:21])[NH:19][CH3:20])=[O:11])[C:7]([NH:31][C:32]3[CH:33]=[N:34][CH:35]=[N:36][CH:37]=3)=[N:6][CH:5]=2)[CH2:3][CH2:2]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[OH:24][CH2:23][CH2:22][N:16]1[C:17]([C:18](=[O:21])[NH:19][CH3:20])=[C:13]([NH:12][C:10]([C:8]2[C:7]([NH:31][C:32]3[CH:33]=[N:34][CH:35]=[N:36][CH:37]=3)=[N:6][CH:5]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[N:9]=2)=[O:11])[CH:14]=[N:15]1
Reactant: CNC(=O)c1c(NC(=O)c2nc(C3CC3)cnc2Nc2cncnc2)cnn1CCOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: CNC(=O)c1c(NC(=O)c2nc(C3CC3)cnc2Nc2cncnc2)cnn1CCO
Reaction time: 1 h
Yield: 90.7 %

Procedure:
To a suspension of 6-cyclopropyl-N-(5-(methylcarbamoyl)-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-pyrazol-4-yl)-3-(pyrimidin-5-ylamino)pyrazine-2-carboxamide (0.07 g, 138 μmol, Eq: 1.00) at r.t under Ar in MeOH (2.7 ml) was added a amount catalytic amount of para-toluene sulfonic acid. The mixture was stirred at 70° for 1 hr. The solvent was evaporated. The residue was dissolved in dichloromethane, then washed with water. The organic was dried over MgSO4, filtered and evaporated. The crude product was purified by silica gel chromatography using a dichloromethane/MeOH gradient to obtain the tile compound (53 mg, 91%) as yellow solid.
Reaction SMILES: [CH:1]1([C:4]2[C:12]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:11][C:10]3[C:6](=[C:7]([C:32]([NH:34][CH3:35])=[O:33])[N:8]([C:18]4[CH:23]=[CH:22][C:21]([O:24][C:25]5[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=5)=[CH:20][CH:19]=4)[N:9]=3)[CH:5]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:43][CH2:44][OH:45]>C(#N)C.CCOC(C)=O>[CH:1]1([C:4]2[C:12]([N:13]([CH2:43][CH2:44][OH:45])[S:14]([CH3:17])(=[O:16])=[O:15])=[CH:11][C:10]3[C:6](=[C:7]([C:32]([NH:34][CH3:35])=[O:33])[N:8]([C:18]4[CH:19]=[CH:20][C:21]([O:24][C:25]5[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=5)=[CH:22][CH:23]=4)[N:9]=3)[CH:5]=2)[CH2:2][CH2:3]1
Reactant: OCCBr
Reactant: CNC(=O)c1c2cc(C3CC3)c(NS(C)(=O)=O)cc2nn1-c1ccc(Oc2ccc(F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CNC(=O)c1c2cc(C3CC3)c(N(CCO)S(C)(=O)=O)cc2nn1-c1ccc(Oc2ccc(F)cc2)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 34.7 %

Procedure:
To a solution of Compound (2) (13 mg, 26 μmol) in ACN (1 mL) was added potassium carbonate (7.3 mg, 52 μmol) followed by 2-bromoethanol (5.6 μL, 79 μmol). The mixture was then stirred at 80° C. for 16 h (monitored by LCMS). The mixture was cooled to RT, diluted with EtOAc (3 mL), washed with water (1 mL) and brine (2 mL). The organic phase was dried (MgSO4) and the solvent was removed in vacuo. The crude mixture was purified by preparative HPLC to give Compound (3) (4.86 mg, 34%) as a white powder. ESI-MS m/z calculated for [M+H]+: 539.18; found: 539.12; 1H NMR (400 MHz, CDCl3) δ 7.80 (s, 1H), 7.52 (brd, J=9.0 Hz, 2H), 7.47 (s, 1H), 7.12-7.02 (m, 6H), 5.79 (brd, J=4.3 Hz, 1H), 4.21-4.00 (m, 1H), 3.85-3.62 (m, 3H), 3.18 (s, 3H), 2.99 (d, J=4.9 Hz, 3H), 2.51-2.27 (m, 1H), 1.06 (ddd, J=11.3, 6.9, 3.1 Hz, 3H), 0.62-0.44 (m, 1H).