Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH2:12][CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.C([O-])([O-])=O.[K+].[K+].C(O)(=O)C>CN(C=O)C.O>[Cl:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([NH:12][CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH:10]=1
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Reactant: NCc1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1ccc(Cl)cc1NCc1cccnc1
Temperature: 150 °C
Yield: 29.9 %

Procedure:
A mixture of 2,4-dichlorobenzoic acid (10 g, 53 mmol), 3-aminomethylpyridine (4.5 ml, 44 mmol), K2CO3 (7.8g, 56 mmol) and CuBr (80 mg, cat) in DMF (20 ml) was heated at 150° C. for 1 hour, cooled to 0° C., diluted with water (80 ml) and carefully acidified with glacial acetic acid. The resulting solid was collected by filtration, washed with water, acetone and ether to give the pure product (>99% by HPLC) as a bluish white solid (3.46 g, 30%), m.p. 235°-236° C.; 1H NMR d (DMSO, 360 MHz, 353 K) 8.60 (bs, 1H, aromatic), 8.49 (bs, 1H, aromatic), 7.79 (d, J=8.5 Hz, 1H, aromatic), 7.72 (d, J=7.8 Hz, 1H, aromatic), 7.35 (dd, J=4.8, 7.6 Hz, 1H, aromatic), 6.74 (d, J=1.8 Hz, 1H, aromatic), 6.59 (dd, J=2.0, 8.4 Hz, 1H, aromatic), 4.51 (s, 2H, CH2); HRMS [M-2H]- calcd for C13 H9N2O2Cl: 260.0353. Found: 260.0348. Anal. calcd for C13H11ClN2O2.1/4H2O: C, 58.44; H, 4.33; N, 10.48. Found: C, 58.30; H, 4.10; N, 10.25.
Reaction SMILES: [F:1][CH:2]([F:11])[C@@H:3]([C@H:5]1[CH2:9][O:8][C:7](=[O:10])[NH:6]1)[CH3:4].[F:12][C:13]1[N:18]=[C:17](F)[CH:16]=[CH:15][N:14]=1.[H-].[Na+]>CN(C=O)C.C(OC(=O)C)C.[Cl-].[Na+].O.O>[F:11][CH:2]([F:1])[C@@H:3]([C@H:5]1[CH2:9][O:8][C:7](=[O:10])[N:6]1[C:15]1[CH:16]=[CH:17][N:18]=[C:13]([F:12])[N:14]=1)[CH3:4]
Reactant: C[C@@H](C(F)F)[C@H]1COC(=O)N1
Reactant: Fc1ccnc(F)n1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H](C(F)F)[C@H]1COC(=O)N1c1ccnc(F)n1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 58.7 %

Procedure:
To a solution of (S)-4-((R)-1,1-difluoropropan-2-yl)oxazolidin-2-one (223 mg, 1.35 mmol) and 2,4-difluoropyrimidine (157 mg, 1.35 mmol) in DMF (4.09 mL) was added sodium hydride (60% wt.; 70.2 mg) in three portions at <0° C. (sodium chloride/ice). After the first portion of sodium hydride the mixture was stirred for ˜5 min. The remaining two portions of sodium hydride were added over ˜5 min and stirring was continued for 30 min. The mixture was diluted with ethylacetate (10 mL), stirred for 5 min and further slowly diluted with brine/water (1/1; 10 mL). The mixture was allowed to warm to 5° C. and poured into a mixture of brine/water (1/1; 20 mL) and ethylacetate (20 mL). The aqueous layer was separated and extracted with ethylacetate (25 mL). The combined organic layers were washed with brine (40 mL), dried over sodium sulfate, filtered off and concentrated under reduced pressure. The residue was purified by column chromatography [SiO2, 12 g, EtOAc/heptane] to provide (S)-4-((R)-1,1-difluoropropan-2-yl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one (207 mg) as a white solid.
Reaction SMILES: [C:1]([C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([C@@H:10]1[C@H:15]2[CH2:16][C@H:12]([C@H:13]([OH:17])[CH2:14]2)[N:11]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:9])#[N:2].C(=O)([O-])O.[Na+].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[C:1]([C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([C@@H:10]1[C@H:15]2[CH2:16][C@H:12]([C:13](=[O:17])[CH2:14]2)[N:11]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:9])#[N:2]
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H](C[C@H]2O)[C@H]1C(=O)N1CCC[C@H]1C#N
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H](CC2=O)[C@H]1C(=O)N1CCC[C@H]1C#N
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of tert-butyl (1R,3S,4S,6R)-3-{[(2S)-2-cyano-1-pyrrolidinyl]carbonyl}-6-hydroxy-2-azabicyclo[2.2.1]heptane-2-carboxylate obtained in Example 5-7 (353 mg) in dichloromethane (10 mL), were added sodium hydrogencarbonate (177 mg) and Dess-Martin periodinane (692 mg). The mixture was stirred at room temperature for 4 hrs.
Reaction SMILES: [C:1]([C:3]1[CH:26]=[CH:25][C:6]([CH2:7][CH:8]2[CH:13]=[CH:12][N:11](C(OC3C=CC=CC=3)=O)[CH:10]=[C:9]2[CH:23]=[O:24])=[CH:5][CH:4]=1)#[N:2].[S]>C1C2C(CCCC2)CCC1>[CH:23]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:8]=1[CH2:7][C:6]1[CH:25]=[CH:26][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)=[O:24]
Reactant: N#Cc1ccc(CC2C=CN(C(=O)Oc3ccccc3)C=C2C=O)cc1
Agent: [S]
Solvent: C1CCC2CCCCC2C1
Product: N#Cc1ccc(Cc2ccncc2C=O)cc1
Temperature: 145 °C

Procedure:
The product obtained in Step A (2 g/0.0058 mol) is brought to solution in 80 ml of Decalin, and then 0.336 g (0.010 mol) of sulphur is added, and the whole is heated at 140-150° C. for 24 hours. The reaction mixture is filtered and then concentrated. A brown oil is obtained, which is purified by chromatography over silica gel (heptane, 10% AcOEt 10%) to yield the title product.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[C:4]([C:9]2[CH:10]=[N:11][N:12]3[CH:17]=[CH:16][N:15]=[CH:14][C:13]=23)[N:3]=1.[F:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25][NH2:26])=[N:23][CH:24]=1.C(N(C(C)C)CC)(C)C>O1CCCC1>[Cl:8][C:7]1[C:2]([NH:26][CH2:25][C:22]2[CH:21]=[CH:20][C:19]([F:18])=[CH:24][N:23]=2)=[N:3][C:4]([C:9]2[CH:10]=[N:11][N:12]3[CH:17]=[CH:16][N:15]=[CH:14][C:13]=23)=[N:5][CH:6]=1
Reactant: NCc1ccc(F)cn1
Reactant: Clc1cnc(-c2cnn3ccncc23)nc1Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc(CNc2nc(-c3cnn4ccncc34)ncc2Cl)nc1
Yield: 40 %

Procedure:
A mixture of 3-(4,5-dichloropyrimidin-2-yl)pyrazolo[1,5-a]pyrazine (Preparation 32, 75 mg, 0.26 mmol), (5-fluoropyridin-2-yl)methanamine (33 mg, 0.26 mmol) and diisopropylethylamine (52 μL, 30 mmol) in tetrahydrofuran (3 mL) was heated to reflux for 72 h. The solvent was then evaporated under reduced pressure and the crude product was purified by reverse phase chromatography (C-18 silica from Waters©, water/acetonitrile/methanol as eluents [0.1% v/v formic acid buffered] 0% to 100%) to give the title compound (37 mg, 39%).
Reaction SMILES: Cl[C:2]1[C:7]([Br:8])=[CH:6][N:5]=[CH:4][N:3]=1.[SH:9][CH2:10][C:11]([O:13][CH3:14])=[O:12].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[Br:8][C:7]1[C:2]([S:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[N:3][CH:4]=[N:5][CH:6]=1
Reactant: COC(=O)CS
Reactant: Clc1ncncc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CSc1ncncc1Br
Temperature: 150 °C
Yield: 83.6 %

Procedure:
A mixture of 4-chloro-5-bromopyrimidine (0.193 g, 1.0 mmol), methyl 2-mercaptoacetate (0.116 g, 1.1 mmol) and sodium carbonate (0.159 g, 1.5 mmol) in DMF (0.7 mL) was heated under microwave irradiation to 150° C. for 20 minutes. The mixture was washed with water, extracted with ethyl acetate and purified by chromatography to yield methyl 2-(5-bromopyrimidin-4-ylthio)acetate (0.22 g, 84%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14]([O:19][CH3:20])[CH:13]=[C:12]([O:21][CH3:22])[C:11]=2[C@@H:23]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[C@H:24]1[CH2:36][O:37]C(=O)C.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14]([O:19][CH3:20])[CH:13]=[C:12]([O:21][CH3:22])[C:11]=2[C@@H:23]1[CH2:27][CH2:26][N:25]([C:28]2[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=2)[C@H:24]1[CH2:36][OH:37]
Reactant: COc1ccc(N2CC[C@@H](c3c(OC)cc(OC)c4c(=O)cc(-c5ccccc5Cl)oc34)[C@@H]2COC(C)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(N2CC[C@@H](c3c(OC)cc(OC)c4c(=O)cc(-c5ccccc5Cl)oc34)[C@@H]2CO)cc1

Procedure:
Compound of example 123 (1.1 g, 1.94 mmol) in MeOH (5 mL) was hydrolyzed using 5% methanolic NaOH (5 mL) at 50° C. as described in example 4 to get the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1)([O-:3])=[O:2].I[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].OO>CS(C)=O.O>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1-n1cccc1
Reactant: CCOC(=O)CI
Agent: OO
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)Cc1cccn1-c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 10.9 %

Procedure:
To a stirred mixture of 1.88 g of 1-(2-nitrophenyl)pyrrole, 4.80 g of ethyl iodoacetate and 2.22 g of FeSO4.7H2O in 40 ml of dimethyl sulfoxide is added dropwise 10 ml of 30% hydrogen peroxide while keeping the reaction mixture at room temperature with a cold water bath. The mixture is stirred at room temperature for one day. An additional 2.4 g of ethyl iodoacetate, 1.1 g of FeSO4.7H2O and 5 ml of 30% hydrogen peroxide is added and the mixture stirred at room temperature for 1 day. The mixture is diluted with water and extracted with diethyl ether. The organic extract is washed with water, brine and dried (Na2SO4). The solvent is removed and the residue (2.12 g) chromatographed on silica gel with ethyl acetate-hexane (1:4) as solvent to give 0.30 g of product as a brown gum.
Reaction SMILES: C(OC(NC[C@H]1CC[C@H]([C:16]([NH:18][C:19](=[O:29])[C@H:20]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[NH2:21])=O)CC1)=O)(C)(C)C.[ClH:30].O1CCOC[CH2:32]1>>[ClH:30].[CH3:32][N:18]([CH3:16])[C:19](=[O:29])[C@H:20]([CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[NH2:21]
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](C(=O)NC(=O)[C@@H](N)Cc2ccccc2)CC1
Reactant: C1COCCO1
Agent: Cl
Product: CN(C)C(=O)[C@@H](N)Cc1ccccc1
Reaction time: 0.5 h

Procedure:
To the compound (I) (19.00 g), 4 N hydrogen chloride/1,4-dioxane solution (325 ml) was added under room temperature, and the mixture was stirred at the same temperature for 30 minutes. The mixture was concentrated under a reduced pressure, and L-phenylalanine dimethylamide hydrochloride (II) was obtained quantitatively as a white powder. Subsequently, to a solution of the compound (II), trans-4-(t-butoxycarbonylaminomethyl)cyclohexylcarboxylic acid (16.70 g) and triethylamine (9.75 ml) in dry dichloromethane (200 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (13.69 g) was added under ice-cooling, the mixture was stirred for 2 hours, and again stirred at room temperature for 2 hours. To the reaction water was added to obtain an organic layer, which was washed with 10% aqueous citric acid, water, 5% aqueous sodium hydrogen carbonate, and water, in this order, followed by drying over anhydrous sodium sulfate. The solids were filtered off, the filtrate concentrated under a reduced pressure and the residue was washed with diethyl ether, followed by filtration to give N-[trans-4-(t-butoxycarbonylaminomethyl)cyclohexylcarbonyl]-L-phenylalanine dimethylamide (III) (21.90 g). The structure was confirmed by NMR.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14](=[O:30])[CH2:15][NH:16][CH:17]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:3].[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.COC1C=CC=CC=1C(Cl)=O>>[CH3:3][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:11])[CH3:12])[C:5]=1[NH:13][C:14](=[O:30])[CH2:15][N:16]([CH:17]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=2[C:19]2[C:18]1=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:31](=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH3:1]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)CNC(c1ccccc1)c1ccccc1
Agent: COc1ccccc1C(=O)Cl
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CN(C(=O)c1ccccc1)C1c2ccccc2-c2ccccc21

Procedure:
When in the procedure of Example 94 an appropriate amount of product of Example 77 was substituted for the product of Example 4 and an appropriate amount of benzoyl chloride was substituted for 2-methoxybenzoyl chloride and the general procedure of Example 94 was followed the title compound was obtained. Total yield, 0.56 g (76%).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]([N:28]1[CH:31]([S:32][CH2:33][C:34](=O)[CH2:35][C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)[CH:30]([NH:44][C:45]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:29]1=[O:64])=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>O1CCOCC1>[F:42][C:39]1[CH:40]=[CH:41][C:36]([CH2:35][C:34]2[CH2:33][S:32][C@@H:31]3[CH:30]([NH:44][C:45]([C:58]4[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=4)([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)[C:29](=[O:64])[N:28]3[C:8]=2[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[CH:37][CH:38]=1
Reactant: CC(C)(C)OC(=O)C(N1C(=O)C(NC(c2ccccc2)(c2ccccc2)c2ccccc2)C1SCC(=O)Cc1ccc(F)cc1)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)C1=C(Cc2ccc(F)cc2)CS[C@@H]2C(NC(c3ccccc3)(c3ccccc3)c3ccccc3)C(=O)N12
Yield: 75.5 %

Procedure:
1-(1-t-butoxycarbonyl-1-triphenylphosphoranylidenemethyl)-3-(triphenylmethylamino)-4-(3-p-fluorophenyl-2-oxopropylthio)azetidin-2-one (253 mg) was refluxed in dry dioxan (25 ml) under nitrogen for 24 hours. Evaporation of the solvent and chromatography of the residue on silica gave (IX) as a white solid (131 mg). νmax (CHCl3) 1775, 1715 cm-1 δ ppm (CDCl3) 1.52 (s, 3H), 3.01 (q, J = 17 Hz, 2H), 2.66- 3.12 (1H, exchange, D2O, 3.63 (q, J = 15Hz, 2H). 4.28 (d, J = 4.5Hz, 1H), 4.71 (multiplet collapsing to d, J = 4.5Hz on D2O exchange, 1H), 6.77-7.58 (m, aromatic).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][C:9]#[N:10])[C:5]([N+:11]([O-:13])=[O:12])=[CH:4][N:3]=1.Cl.[Br:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][NH2:19].C(N(CC)CC)C>CCO>[Br:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][NH:19][C:2]1[N:7]=[C:6]([S:8][C:9]#[N:10])[C:5]([N+:11]([O-:13])=[O:12])=[CH:4][N:3]=1
Reactant: N#CSc1nc(Cl)ncc1[N+](=O)[O-]
Reactant: NCc1ccccc1Br
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: N#CSc1nc(NCc2ccccc2Br)ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.7 %

Procedure:
2-Chloro-5-nitro-4-thiocyanatopyrimidine (100 mg, 0.46 mmol) was suspended in 1 mL absolute EtOH. o-Bromobenzylamine hydrochloride (103 mg, 0.46 mmol) was dissolved in 1 mL absolute EtOH and added to the reaction quickly at ambient temperature. Then triethylamine (129 μL, 0.92 mmol) was added dropwise via syringe. The reaction was stirred 16 h at ambient temperature. The resulting precipitate was filtered providing 136 mg of the desired (2-bromo-benzyl)-(5-nitro-4-thiocyanato-pyrimidin-2-yl)-amine as a white solid.
Reaction SMILES: [C:1]([NH:18][C@H:19]([C:30]([OH:32])=[O:31])[CH2:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23][CH:22]=1)([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].[N+:33]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[S:42]Cl)([O-:35])=[O:34].C(OCC)C.O>O1CCOCC1.CC#N>[NH:18]([C:1]([O:3][CH2:4][CH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:12]2[C:17]1=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:2])[C@H:19]([C:30]([OH:32])=[O:31])[CH2:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23][C:22]=1[S:42][C:37]1[C:36]([N+:33]([O-:35])=[O:34])=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=[N+]([O-])c1ccccc1SCl
Reactant: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O)OCC1c2ccccc2-c2ccccc21
Solvent: C1COCCO1
Solvent: O
Solvent: CCOCC
Product: O=C(N[C@@H](Cc1c(Sc2ccccc2[N+](=O)[O-])[nH]c2ccccc12)C(=O)O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 2.0 g (4.7 mmole) Fmoc-L-tryptophan in 12 ml dioxane, 0.87 g (4.6 mmole) of 2-nitrophenyl-sulfenylchloride (2-Nps-Cl) in 25 ml dioxane was added under stirring at room temperature. After standing for 3 days, 50 ml ethyl ether was added to the reaction mixture and the solvent was evaporated. The product was purified by chromatography on silica gel in solvent A (Solvent A=Chloroform:Ethanol:Neptane—1:1:1). Rf 0.43. After purification the product was obtained as a yellow-brown crystalline compound. The yield was 2.5 g (89%). HPLC (C18): tR 8.3 min, 85-100% B in 20 min. (A: H2O+0.1% TFA; B: CH3CN+0.1% TFA).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:3][C@H:4]([OH:32])[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][O:41][C:42]([NH:44][C@@H:45]([C:49]([CH3:53])([S:51][CH3:52])[CH3:50])[C:46](O)=[O:47])=[O:43].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:40][O:41][C:42](=[O:43])[NH:44][C@@H:45]([C:49]([CH3:50])([S:51][CH3:52])[CH3:53])[C:46](=[O:47])[NH:1][C@@H:2]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH2:3][C@H:4]([OH:32])[C@H:5]([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)[NH:19][C:20](=[O:21])[C@H:22]([C:23]([CH3:25])([CH3:26])[CH3:24])[NH:27][C:28](=[O:31])[O:29][CH3:30]
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)[C@@H](O)C[C@@H](N)Cc1ccccc1)C(C)(C)C
Reactant: COC(=O)N[C@H](C(=O)O)C(C)(C)SC
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@@H](O)C[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)SC)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.4 %

Procedure:
A solution containing the product from Example 23S (0.025 g, 0.047 mmol) in THF (0.5 mL) was treated with the product from Example 30A (0.0125 g, 0.056 mmol), DEPBT (0.021 g, 0.070 mmol), and N,N-diisopropylethylamine (0.040 mL, 0.230 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 to give the title compound (0.024 g, 69% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.84 (s, 9 H), 1.08 (s, 3 H), 1.11 (s, 3 H), 1.50 (m, 2 H), 1.93 (s, 3 H), 2.45 (m, 1 H), 2.75 (m, 3 H), 3.51 (s, 3 H), 3.56 (s, 3 H), 3.67 (m, 1 H), 394 (d, J=9.5 Hz, 1 H), 4.10 (d, J=10.30 Hz, 3 H), 4.84 (d, J=5.88 Hz, 1 H), 6.79 (dd, J=15.81, 9.93 Hz, 2 H), 7.09 (m, 5 H), 7.30 (d, J=7.35 Hz, 3 H), 7.57 (s, 1 H), 7.87 (m, 5 H), 8.63 (d, J=4.41 Hz, 1 H).
Reaction SMILES: [OH:1][NH:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:6][CH:5]=1.[OH-].[Na+].Br[CH2:20][CH2:21][OH:22]>C(O)C.O>[OH:22][CH2:21][CH2:20][O:1][NH:2][C:3](=[O:16])[C:4]1[CH:5]=[CH:6][C:7]([C:10](=[O:15])[C:11]([CH3:13])([CH3:12])[CH3:14])=[CH:8][CH:9]=1
Reactant: CC(C)(C)C(=O)c1ccc(C(=O)NO)cc1
Reactant: OCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)C(=O)c1ccc(C(=O)NOCCO)cc1
Temperature: 55 °C

Procedure:
To a solution of 4.0 grams (18.1 mmol) of N-hydroxy-4-pivaloylbenzamide in 10 milliliters of ethanol is added an aqueous solution of 725 milligrams (18.1 mmol) of sodium hydroxide in 1 milliliter of water. To this is added 1.67 milliliters (23.6 mmol) of 2-bromoethanol; and the resulting mixture is heated at 55° C. for 24 hours. The mixture is cooled to 20° C., concentrated, and extracted 3 times with 10 milliliters of chloroform. The combined extracts are washed with 15 milliliters of water and then 15 milliliters of brine, dried over magnesium sulfate and concentrated. The residue is recrystallized from methylene chloride/hexane (1:4) to yield N-(2-hydroxyethoxy)-4-pivaloylbenzamide.
Reaction SMILES: [Br:1][C:2]1[C:14]([F:15])=[CH:13][C:5]([C:6]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=O)=[C:4]([Cl:16])[CH:3]=1.B.C1COCC1>C1COCC1>[Br:1][C:2]1[C:14]([F:15])=[CH:13][C:5]([CH2:6][N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[C:4]([Cl:16])[CH:3]=1
Reactant: O=C(c1cc(F)c(Br)cc1Cl)N1CCCC1
Agent: B
Solvent: C1CCOC1
Product: Fc1cc(CN2CCCC2)c(Cl)cc1Br
Temperature: 65 °C
Yield: 93.9 %

Procedure:
To Intermediate 10, 1-(4-bromo-2-chloro-5-fluorobenzoyl)pyrrolidine (48.0 g, 156.5 mmol) in THF (200 mL) at rt was slowly added a solution of BH3·THF complex (400 mL, 400 mmol, 1M THF). The resulting reaction was heated to 65° C. (oil bath) for 16 hr, and then the reaction was cooled to rt and slowly quenched with MeOH (dropwise addition). The reaction mixture was heated to reflux for 2 hr, cooled to rt, and concentrated under reduced pressure. This material was taken up in EtOAc and further quenched slowly with 6N HCl, then neutralized with aqueous NaOH (15%). The layers were separated and the aqueous layer was back extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. Purification of this material was accomplished by flash column chromatography using a Biotage™ 75 L column, eluting with a gradient of 5%, 10% MeOH/CH2Cl2. The product containing fractions were collected and concentrated to give the title compound (43 g, 94% yield) as a light yellow oil: Rf=0.6 (10% MeOH/CH2Cl2); LRMS m/z Calcd for C11H12BrClFN, 292.6, found, 292 294, 296 (M+1) APCI; 1H NMR (300 MHz, CDCl3): δ 7.51 (d, J=6.6 Hz, 1H), 7.33 (d, J=9.5 Hz, 1H), 3.66 (s, 2H), 2.59-2.55 (m, 4H), 1.82-1.79 (m, 4H); 100 MHz 13C NMR (CDCl3) δ 158.3 (d, JC-F=247.2 Hz), 139.3, 133.3, 128.9, 117.8 (d, JC-F=24.9 Hz), 107.3 (d, JC-F=22.6 Hz), 56.7, 54.4, 23.9.
Reaction SMILES: [C:1]([C:3]1[CH:17]=[CH:16][C:6]2[N:7]=[C:8]([NH:10][C:11]([NH:13][CH2:14][CH3:15])=[O:12])[S:9][C:5]=2[CH:4]=1)#[N:2].Cl.NO.C(=O)([O-])[O-:22].[Na+].[Na+]>>[CH2:14]([NH:13][C:11]([NH:10][C:8]1[S:9][C:5]2[CH:4]=[C:3]([C:1]([NH2:2])=[O:22])[CH:17]=[CH:16][C:6]=2[N:7]=1)=[O:12])[CH3:15]
Reactant: CCNC(=O)Nc1nc2ccc(C#N)cc2s1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: NO
Agent: [Na+]
Product: CCNC(=O)Nc1nc2ccc(C(N)=O)cc2s1
Temperature: 25 °C

Procedure:
About 1 g of N-(6-cyano-1,3-benzothiazol-2-yl)-N′-ethylurea was charged into about 30 mL of aqueous alkanol. Added about 0.6 g hydroxylamine hydrochloride and about 0.45 g sodium carbonate then heated to reflux. The solution was refluxed for about 4–8 hours then cooled to room temperature. The precipitate was recovered by filtration and washed well with water. LC/MS indicated a mixture of two products identified as the following after further purification by preparative HPLC:
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][NH:5][C@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.C([O-])(O)=O.[Na+].Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].C(=O)=O>O.C1(C)C=CC=CC=1>[C:16]([N:5]1[CH2:6][C@H:2]([OH:1])[CH2:3][C@H:4]1[C:7]([OH:9])=[O:8])([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: O=C=O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98 %

Procedure:
N-Benzyloxycarbonyl)-trans-4-hydroxy-L-proline. Trans-4-hydroxy-L-proline 1 (10.0 g, 76.3 mmol) and NaHCO3 (16.0 g, 190 mmol) were dissolved in H2O (165 mL), then a solution of benzyl chloroformate (12.5 mL, 15.0 g, 87.7 mmol) in toluene (40 mL) was added over a period of 15 minutes. After stirring at room temperature for 16 h, CO2 evolution had ceased and the two phases were separated. Excess benzyl chloroformate was removed from the aqueous phase by washing with ether (4×50 mL). Cooling of the aqueous phase in an ice bath, followed by acidification to pH 2 with concentrated HCl, caused the oily product to precipitate. This oil was extracted into ethyl acetate by repeated washings (5×50 mL) of the aqueous layer. Further acidification of the aqueous layer produced no more precipitate, indicating thorough removal of the product. The combined organic extracts were dried (MgSO4) and concentrated to a viscous oil, which crystallized upon standing at room temperature to provide 19.9 g (98%) of N-CBZ-trans-4-hydroxy-L-proline: mp 106°-107° C. (lit.19 mp 106°-107° C.); [α]24D-77.5° (c 1.03, CHCl3) [lit.19 [α]20D-72° (c 1.0 CHCl3)].