Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC(C(F)(F)F)=O.OC(C(F)(F)F)=O.[CH2:15]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[C:16]#[CH:17].C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][CH2:32][CH2:33][O:34][C:35]1[CH:44]=[C:43]2[C:38]([C:39]([O:45][C:46]3[C:47]([F:56])=[C:48]4[C:52](=[CH:53][CH:54]=3)[NH:51][C:50]([CH3:55])=[CH:49]4)=[N:40][CH:41]=[N:42]2)=[CH:37][C:36]=1[O:57][CH3:58]>CC(N(C)C)=O>[F:56][C:47]1[C:46]([O:45][C:39]2[C:38]3[C:43](=[CH:44][C:35]([O:34][CH2:33][CH2:32][CH2:31][N:21]4[CH2:22][CH2:23][N:18]([CH2:15][C:16]#[CH:17])[CH2:19][CH2:20]4)=[C:36]([O:57][CH3:58])[CH:37]=3)[N:42]=[CH:41][N:40]=2)=[CH:54][CH:53]=[C:52]2[C:48]=1[CH:49]=[C:50]([CH3:55])[NH:51]2
Reactant: C#CCN1CCNCC1
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O=C(O)C(F)(F)F
Product: C#CCN1CCN(CCCOc2cc3ncnc(Oc4ccc5[nH]c(C)cc5c4F)c3cc2OC)CC1
Temperature: 85 °C
Reaction time: 8 h
Yield: 73.7 %

Procedure:
1-Prop-2-ynylpiperazine diTFA salt (329 mg, 0.94 mmol) and potassium carbonate (258 mg, 1.87 mmol) were added to a solution of 7-(3-bromopropoxy)-4-[(4-fluoro-2-methylindol-5-yl)oxy]-6-methoxyquinazoline (144 mg, 0.31 mmol), (prepared as described for the starting material in Example 7), in DMA (3.6 ml). The reaction mixture was stirred at 85° C. overnight before being filtered. The filtrate was concentrated under vacuum and the crude product was purified by column chromatography eluting with increasingly polar mixtures of ammonia/methanol in methylene chloride (1 to 7%). A second purification by column chromatography eluting with a mixture of methanol in methylene chloride (1/9) gave 4-[(4-fluoro-2-methylindol-5-yl)oxy]-6-methoxy-7-{3-[4-(2-propynyl)piperazin-1-yl]propoxy}quinazoline as a white solid (115 mg, 73%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][C:7]1([CH:14]=[CH:13][CH:12]=[CH:11][CH2:10]1)C#N.[CH:15]([N-:18]C(C)C)(C)C.[Li+].[C:23]1(=[O:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.O>O1CCCC1.C(OCC)(=O)C>[OH:29][C:23]1([CH:6]([C:7]2[CH:10]=[CH:11][C:12]([C:15]#[N:18])=[CH:13][CH:14]=2)[C:2]2[NH:1][CH:5]=[CH:4][N:3]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C1CCCCC1
Reactant: N#CC1(Cc2ncc[nH]2)C=CC=CC1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(C(c2ncc[nH]2)C2(O)CCCCC2)cc1
Reaction time: 0.5 h

Procedure:
1.83 g of 4-[1-(imidazolyl)methylbenzonitrile is dissolved in 50 ml of tetrahydrofuran and combined at -50° with 7.3 ml of 1.5-molar solution of lithium diisopropylamide in tetrahydrofuran; the mixture is stirred for 0.5 hour, further stirred with 1.05 g of cyclohexanone for 1 hour at -60°, and heated to 25°. Then water is added, the mixture is diluted with ethyl acetate, washed neutral with water, dried over sodium sulfate, and concentrated to dryness under vacuum, yielding 2.7 g of crude 4-[1-hydroxycyclohex-1-yl-1-(imidazolyl)methyl]benzonitrile.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH3:4].[CH:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>>[CH2:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([CH2:3][CH3:4])[CH3:1]
Reactant: C=CCC
Reactant: c1ccccc1
Product: CCC(C)c1ccccc1
Product: CCCCc1ccccc1

Procedure:
When benzene is alkylated with butenes, e.g., n-butene, to produce butylbenzene, e.g. sec-butylbenzene, the reaction may also take place under at least partially liquid phase conditions including a temperature of up to about 250° C., preferably up to about 150° C., e.g., from about 10° C. to about 125° C.; a pressure of about 25,000 kPa-a or less, e.g., from about 100 kPa-a to about 3,000 kPa-a; a weight hourly space velocity (WHSV) based on butenes alkylating agent of from about 0.1 hr−1 to about 250 hr−1, preferably from about 1 hr−1 to about 50 hr−1; and a ratio of benzene to butenes in the alkylation reactor of from about 0.5:1 to about 30:1 molar, more preferably from about 1:1 to about 10:1 molar.
Reaction SMILES: [OH-].[Na+].C(O)C.[F:6][C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:9][C:8]=1[NH:20]C(=O)OC>O>[F:6][C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:9][C:8]=1[NH2:20]
Reactant: COC(=O)Nc1cc(OC2CCCC2)c(Cl)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1cc(OC2CCCC2)c(Cl)cc1F
Temperature: 25 °C
Yield: 99.6 %

Procedure:
2N sodium hydroxide aqueous solution (3.5 ml) was added to an ethanol solution (1.5 ml) of methyl N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)carbamate (1.507 g, 5.24 mmol), and the mixture was heated under reflux for 2 hours. After reaction, the reaction liquid was cooled to room temperature, water was added thereto, and this was extracted with ethyl acetate (20 ml ×2). The organic layer was washed with water and saturated brine and then dried over anhydrous magnesium sulfate. The drying agent was taken out by filtration, and the solvent was removed by distillation under reduced pressure, to obtain 2-fluoro-4-chloro-5-cyclopentyloxyaniline (1.20 g, 5.22 mmol). Yield: ~100 %.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.Cl[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15].O>CN1CCCC1=O>[CH2:17]([O:16][C:14]([N:8]([C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=1)[CH2:9][C:10]([OH:12])=[O:11])=[O:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)CNc1ccc(O)cc1
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C(O)CN(C(=O)OCc1ccccc1)c1ccc(O)cc1
Reaction time: 0.67 h
Yield: 75 %

Procedure:
N-(4-hydroxyphenyl)glycine (55.0 g, 0.330 mol) was dissolved in 275 mL of N-methylpyrrolidone in a 1 L round-bottomed flask. Benzyl chloroformate (50.1 mL, 0.352 mol) was added with stirring over a 40 min period and then stirred at ambient conditions for 18 h. Deionized water was added until slightly turbid and then stored at 4° C. for 24 h. The product was isolated and recrystallized in warm ethanol, dried in vacuum oven at 40° C. overnight (yield 75%, mp=196-198° C.). 1H-NMR (500 MHz, DMSO-d6) δ 12.80 (s, 1H, COOH), 9.50 (s, 1H, phenol), 7.58-6.95 (m, 7H, aryl), 6.74 (s, 2H, aryl), 5.10 (d, J=21.9, 2H, —CH2-benzyl), 4.22 (d, J=21.7, 2H, N—CH2-).
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH:14]=[O:15])=[CH:10][NH:11]2)=[CH:7][CH:6]=1)[CH3:4].ClS([N:20]=[C:21]=[O:22])(=O)=O.C(O)(=O)C>C1COCC1.O>[CH2:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH:14]=[O:15])=[CH:10][N:11]2[C:21]([NH2:20])=[O:22])=[CH:7][CH:6]=1)[CH3:4]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CCc1ccc2c(C=O)c[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: CCc1ccc2c(C=O)cn(C(N)=O)c2c1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
To a solution of NaH (60% in mineral oil, 259 mg, 6.47 mmol) in THF (10 mL) cooled to 5° C. under nitrogen a solution of 6-ethyl-1H-indole-3-carbaldehyde (1.12 g, 6.47 mmol) in THF (20 mL) was slowly added and the mixture was stirred at 5° C. for 30 min. While maintaining the internal temperature between 5° C. and 10° C., chlorosulfonyl isocyanate (1.12 mL, 12.9 mmol) was added dropwise and the solution was further stirred at RT overnight. Acetic acid (15 mL) was added (slightly exothermic) and the solution was stirred at RT for 1.5 h. Ice cubes and water (25 mL) were added, and the solution was further stirred at RT for 30 min. Water was added and the mixture was extracted with EtOAc. The aqueous layer was back-extracted twice with EtOAc. The combined organic layers were dried (Na2SO4), filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane to EtOAc) to give the desired compound. LC/MS: 290.0 [M+H]+, 312.0 [M+Na]+; tR (HPLC conditions a): 3.02 min.
Reaction SMILES: [CH2:1]1[CH:9]2[N:4]([CH2:5][CH:6]=[C:7]([C:10]3[C:18]4[C:13](=[N:14][CH:15]=[CH:16][CH:17]=4)[NH:12][CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1.[C:19]1([S:29](Cl)(=[O:31])=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[CH2:1]1[CH:9]2[N:4]([CH2:5][CH:6]=[C:7]([C:10]3[C:18]4[C:13](=[N:14][CH:15]=[CH:16][CH:17]=4)[N:12]([S:29]([C:19]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[CH:22]=[CH:21][CH:20]=4)(=[O:31])=[O:30])[CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1
Reactant: C1=C(c2c[nH]c3ncccc23)CC2CCCN2C1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1cccc2ccccc12)n1cc(C2=CCN3CCCC3C2)c2cccnc21

Procedure:
from 3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-1H-7-Azaindole (10 mg, 0.0418 mmol), 1-naphthalenesulfonyl chloride (20 mg, 0.088 mmol) and 1M NaN(TMS)2 (100 μL, 0.10 mmol) in THF (0.5 mL) at RT.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[C:5]([C:25]2[CH:30]=[CH:29][C:28]([CH:31]([OH:33])[CH3:32])=[CH:27][CH:26]=2)=[CH:6][C:7]2[N:11]=[C:10]([O:12][C:13]3[CH:14]=[CH:15][C:16]([CH3:23])=[C:17]([CH:22]=3)[C:18]([O:20]C)=[O:19])[NH:9][C:8]=2[CH:24]=1>CO.CCOCC>[Cl:3][C:4]1[C:5]([C:25]2[CH:30]=[CH:29][C:28]([CH:31]([OH:33])[CH3:32])=[CH:27][CH:26]=2)=[CH:6][C:7]2[N:11]=[C:10]([O:12][C:13]3[CH:14]=[CH:15][C:16]([CH3:23])=[C:17]([CH:22]=3)[C:18]([OH:20])=[O:19])[NH:9][C:8]=2[CH:24]=1
Reactant: COC(=O)c1cc(Oc2nc3cc(-c4ccc(C(C)O)cc4)c(Cl)cc3[nH]2)ccc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Product: Cc1ccc(Oc2nc3cc(-c4ccc(C(C)O)cc4)c(Cl)cc3[nH]2)cc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.5 M NaOH (0.2 mL, 0.500 mmol) was added to a solution of methyl 5-({6-chloro-5-[4-(1-hydroxyethyl)phenyl]-1H-benzimidazol-2-yl}oxy)-2-methylbenzoate in MeOH (2.5 mL). Additional 2.5 M NaOH (0.250 mL, 0.625 mmol) was added and the reaction was stirred at rt overnight. The reaction mixture was diluted with Et2O (50 mL) and washed with 10 mL of 1 M aqueous HCl. The aqueous phase was extracted with Et2O. The combined organics were washed with brine, dried (MgSO4), filtered, and concentrated to afford the desired product. LC-MS: calculated for C23H19ClN2O4 422.86, observed m/e 423.8 (M+H)+ (Rt: 1.74 min). 1H NMR (500 MHz, CD3OD): δ 7.85 (d, 1H), 7.47 (s, 1H), 7.44-7.36 (m, 6H), 7.30 (s, 1H), 4.87 (m, 1H), 2.61 (s, 3H), 1.48 (d, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[S:12][C:13]=1[C:14]#[N:15].S(=O)(=O)(O)[OH:23]>O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([N:16]2[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)[S:12][C:13]=1[C:14]([NH2:15])=[O:23]
Reactant: O=S(=O)(O)O
Reactant: N#Cc1sc(N2CCOCC2)nc1-c1ccc(Cl)cc1Cl
Solvent: O
Product: NC(=O)c1sc(N2CCOCC2)nc1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.6 %

Procedure:
4-(2,4-dichlorophenyl)-2-morpholin-4-yl-1,3-thiazole-5-carbonitrile (30 mg, 0.088 mmol) was dissolved in sulfuric acid (0.200 mL, 3.75 mmol) and the mixture was stirred at rt for 1 hour. Water (1 mL) was added and the mixture was quenched with an excess of saturated NaHCO3. Precipitate was filtered off, washed with water and dried to afford the title compound (27 mg, 80%). LCMS: (FA) ES+, 358. 1H NMR (400 MHz, d6-DMSO) δ: 7.67 (d, 1H), 7.47 (d, 1H), 7.43 (dd, 1H), 3.72-3.69 (m, 4H), 3.44-3.42 (m, 4H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:9]2[N:10]([N:16]=[CH:17][CH:18]=2)[C:11]([C:14]#[N:15])=[CH:12][CH:13]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1[C:9]2[N:10]([N:16]=[CH:17][CH:18]=2)[C:11]([C:14]#[N:15])=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#N)n2nccc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(N)c2ccnn12
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.3 %

Procedure:
To a clear solution of (7-cyano-pyrazolo[1,5-a]pyridin-4-yl)-carbamic acid tert-butyl ester (3 g, 11.6 mmol) in methylene chloride (40 mL) was added TFA (8 mL). The mixture was stirred at rt for 3 h, and then concentrated under reduced pressure. The residue was partitioned between EtOAc (100 mL) and sat. NaHCO3 solution (50 mL). The aqueous solution was separated and extracted with EtOAc (2×50 mL). The combined organic solutions were dried over Na2SO4, filtered though SiO2 pad, and concentrated under reduced pressure. Crystallization in EtOAc and 95% EtOH gave compound 777F (1.07 g, 58%) as a dark yellow solid. HPLC: 97% at 1.96 min (retention time) (YMC S5 ODS-A column 4.6×50 mm eluting with 1090% aqueous methanol over 4 mincontaining 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 159 [M+H]+.
Reaction SMILES: [CH3:1][C@@H:2]([O:9][C:10]([CH:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([OH:22])[CH:18]=2)[CH2:13]1)=[O:11])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].FC(F)(F)[C@H:25]([OH:32])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].[CH2:35]([C:43]1[CH:48]=[CH:47][C:46](C2C=CC(C(O)=O)=CC=2)=[CH:45][CH:44]=1)[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH3:1][C@@H:2]([O:9][C:10]([CH:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:22][C:25]([C:26]3[C:27]([C:46]4[CH:45]=[CH:44][C:43]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:48][CH:47]=4)=[CH:28][CH:29]=[CH:30][CH:31]=3)=[O:32])[CH:18]=2)[CH2:13]1)=[O:11])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCc1ccc(-c2ccc(C(=O)O)cc2)cc1
Reactant: CCCCCC[C@@H](O)C(F)(F)F
Reactant: CCCCCC[C@@H](C)OC(=O)C1CCc2cc(O)ccc2C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCCCCCc1ccc(-c2ccccc2C(=O)Oc2ccc3c(c2)CCC(C(=O)O[C@H](C)CCCCCC)C3)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 0.31 g (1 mmol) of 1,2,3,4-tetrahydro-6-hydroxynaphthalene-2-carboxylic acid (R)-1-methylheptyl ester obtained as in the fourth stage of Example 23 where R-1-methyl heputanol was used in stead of (R)-1-trifluoromethylheptanol, 0.31 g (1 mmol) of 4'-octylbiphenyl-4-carboxylic acid (FK-1124-8 from Teikoku Kagaku Sangyo K.K.), 0.02 g (0.16 mmol) of 4-N,N-dimethylaminopyridine and 15 ml of methylene chloride was added dropwise 3 ml of a methylene chloride solution containing 0.27 g (1.3 mmol) of N,N'-dicyclohexylcarbodiimide with stirring at room temperature over a period of 3 hours.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([N:24]([C:32]2[N:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[CH:34][N:33]=2)C(=O)OC(C)(C)C)[CH:8]=[C:9]([C:11]2[S:15][C:14]([N:16]3[CH2:22][CH2:21][CH2:20][NH:19][C:18](=[O:23])[CH2:17]3)=[N:13][CH:12]=2)[CH:10]=1)(=[O:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[O:23]=[C:18]1[NH:19][CH2:20][CH2:21][CH2:22][N:16]([C:14]2[S:15][C:11]([C:9]3[CH:10]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:6]=[C:7]([NH:24][C:32]4[N:37]=[C:36]([C:38]([F:39])([F:41])[F:40])[CH:35]=[CH:34][N:33]=4)[CH:8]=3)=[CH:12][N:13]=2)[CH2:17]1
Reactant: CC(=O)Nc1cc(-c2cnc(N3CCCNC(=O)C3)s2)cc(N(C(=O)OC(C)(C)C)c2nccc(C(F)(F)F)n2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(N3CCCNC(=O)C3)s2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.1 %

Procedure:
To a solution of tert-butyl {3-(acetylamino)-5-[2-(3-oxo-1,4-diazepan-1-yl)-1,3-thiazol-5-yl]phenyl}[4-(trifluoromethyl)pyrimidin-2-yl]carbamate (79 mg, 0.134 mmol) in dichloromethane (1 mL) at room temperatrue, under nitrogen, was added trifluoroacetic acid (1 mL, 13 mmol). The mixture was stirred at room temperature for 1 h and concentrated to dryness. The residue was partitioned between ethyl acetate and 5% aqueous sodium bicarbonate. The solid product precipitated in the two phases. The organic layer was concentrated to dryness and the residue was transferred into the aqueous with a small amount of EtOH. The resulting aqueous suspension was filtered, the solids collected, and washed with water, a small amount of ethanol, then hexane, and dried to afford 48 mg (0.098 mmol, 73% yield) of N-(3-[2-(3-oxo-1,4-diazepan-1-yl)-1,3-thiazol-5-yl]-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)acetamide as an off-white solid. MS APCI: [M+H]+ m/z 492.1. 1H NMR (400 MHz, d6-dmso): δ 10.25 (s, 1H); 9.98 (s, 1H); 8.82 (d, J=4.9 Hz, 1H); 7.75 (m, 2H); 7.61 (br t, J=5.0 Hz, 1H); 7.43-7.37 (m, 2H); 7.28 (d, J=4.9 Hz, 1H); 4.19 (s, 2H); 3.81 (m, 2H); 3.24 (m, 2H); 2.05 (s, 3H); 1.80 (m, 2H). rhSyk=+++.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH:25][CH2:26][C:27]1[N:28]=[C:29]([C:33]2[CH:41]=[CH:40][C:36]([C:37]([OH:39])=O)=[CH:35][CH:34]=2)[O:30][C:31]=1[CH3:32].C(N(C(C)C)CC)(C)C.[N:51]1[CH:56]=[CH:55][CH:54]=[C:53]([CH2:57][NH2:58])[CH:52]=1>CN(C=O)C.C(Cl)Cl>[OH:25][CH2:26][C:27]1[N:28]=[C:29]([C:33]2[CH:34]=[CH:35][C:36]([C:37]([NH:58][CH2:57][C:53]3[CH:52]=[N:51][CH:56]=[CH:55][CH:54]=3)=[O:39])=[CH:40][CH:41]=2)[O:30][C:31]=1[CH3:32]
Reactant: NCc1cccnc1
Reactant: Cc1oc(-c2ccc(C(=O)O)cc2)nc1CO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1oc(-c2ccc(C(=O)NCc3cccnc3)cc2)nc1CO
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 59.1 %

Procedure:
HBTU (170 mg, 0.45 mmol) was added to a solution of acid 55 (80 mg, 0.34 mmol) and diisopropylethylamine (0.13 mL, 0.69 mmol) in anhydrous DMF (7 mL). The solution was stirred at 20° C. for 10 min. 3-Pyridinylmethanamine (0.14 mL, 1.4 mmol) was then added and the reaction mixture was stirred at 20° C. for 1 h. It was the diluted with DCM (300 mL) and washed with H2O (3×50 mL) and then washed with brine (50 mL). The combined organic phase was dried, filtered and the solvent evaporated. The residue was purified by column chromatography, eluting with 10% MeOH/DCM, to give amide 56 (65 mg, 59%) as a cream powder: mp (MeOH/DCM) 182-184° C.; 1H NMR δ 9.19 (t, J=5.7 Hz, 1H, NH), 8.57 (br s, 1H, H-2′), 8.46 (br d, J=4.6 Hz, 1H, H-6′), 8.00 (s, 4H, H-2, H-3, H-5, H-6), 7.74 (br d, J=7.8 Hz, 1H, H-4′), 7.36 (dd, J=7.8, 4.8 Hz, 1H, H-5′), 5.06 (t, J=5.6 Hz, 1H, OH), 4.51 (d, J=5.8 Hz, 2H, CH2N), 4.39 (d, J=5.6 Hz, 2H, CH2O), 2.41 (s, 3H, CH3); MS m/z 324.8 (MH+, 100%); Anal. calcd for C18H17N3O3.⅓H2O: C, 65.94; H, 5.38; N, 12.82. Found: C, 66.06; H, 5.20; N, 12.85.
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([N:10]2[CH2:14][CH2:13][C@@H:12]([N:15]([CH3:23])[C:16]3[CH:21]=[CH:20][N:19]=[C:18](Cl)[N:17]=3)[CH2:11]2)=[N:3][CH:2]=1.[CH3:24][NH2:25]>>[N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([N:10]2[CH2:14][CH2:13][C@@H:12]([N:15]([CH3:23])[C:16]3[CH:21]=[CH:20][N:19]=[C:18]([NH:25][CH3:24])[N:17]=3)[CH2:11]2)=[N:3][CH:2]=1
Reactant: CN
Reactant: CN(c1ccnc(Cl)n1)[C@@H]1CCN(c2ncnc3[nH]ccc23)C1
Product: CNc1nccc(N(C)[C@@H]2CCN(c3ncnc4[nH]ccc34)C2)n1
Temperature: 110 °C
Reaction time: 0.75 h

Procedure:
A mixture of (R)—N-(1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)-2-chloro-N-methylpyrimidin-4-amine (26.0 mg, 0.08 mmol) and methylamine (in THF, 2.0 M, 5.0 mL, 10.0 mmol) was stirred at 110° C. for 45 min in an Initator™ Biotage microwave reactor. The volatiles were removed under reduced pressure and the residue was purified by chromatography on silica gel to give the title compound. MS (m/z): 325 (M+H)+.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][S:6][S:7][CH2:8][CH2:9][NH2:10].[N+:11]([C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1F)([O-:13])=[O:12].C([O-])([O-])=O.[K+].[K+]>O>[N+:11]([C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1[NH:3][CH2:4][CH2:5][S:6][S:7][CH2:8][CH2:9][NH:10][C:15]1[CH:16]=[CH:17][C:18]([N+:20]([O-:22])=[O:21])=[CH:19][C:14]=1[N+:11]([O-:13])=[O:12])([O-:13])=[O:12]
Reactant: NCCSSCCN
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=[N+]([O-])c1ccc(NCCSSCCNc2ccc([N+](=O)[O-])cc2[N+](=O)[O-])c([N+](=O)[O-])c1
Temperature: 75 °C
Reaction time: 18 h

Procedure:
A 25 mL round-bottom flask fitted with a magnetic stirrer was charged with 225 mg (1.0 mmol) of cystamine dihydrochloride, 409 mg (2.2 mmol) 2,4-dinitrofluorobenzene, 25 mg of K2CO3, and 10 mL of H2O. The mixture then stirred in a 75° C. oil bath for 18 h. After cooling, the solvent was decanted from a yellow insoluble sludge. The sludge crystallized on trituration with 10 mL of CH2Cl2. The yellow crystals were washed with additional CH2Cl2 and recrystallized from 0.5 mL of 15:85 H2O/DMF. The isolated product was washed with 1:1 H2O/DMF affording 77 mg of N,N'-bis-(2,4-dinitrophenyl) cystamine, mp 175°-176° C. Calcd for C16H16N6O8S2:C, 39.67; H, 3.31; N, 17.36; S, 13.22. Found: C, 39.74; H, 3.38; N, 17.26; S, 13.48. 200 MHz NMR (DMSO-d6): 3.08 (t, J =6.6, 4H), 3.80 (4 lines, 4H), 7.27 (d, J =9.6, 2H), 8.25 (dd, J =2.8, 9.6, 2H), 8.84 (dd, J =2.8, 0.8, 2H), 8.93 (t, J=5.6, 2H).
Reaction SMILES: C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([N:39]2[CH:43]=[N:42][N:41]=[N:40]2)=[C:28]([CH:38]=1)[CH2:29][NH:30][C:31](=[O:37])[C@@H:32]1[CH2:36][CH2:35][CH2:34][NH:33]1.[C:44]([O:48][C:49]([N:51]1[CH2:54][CH2:53][C:52]1([CH3:58])[C:55](O)=[O:56])=[O:50])([CH3:47])([CH3:46])[CH3:45]>CN(C=O)C>[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([N:39]2[CH:43]=[N:42][N:41]=[N:40]2)=[C:28]([CH:38]=1)[CH2:29][NH:30][C:31](=[O:37])[C@@H:32]1[CH2:36][CH2:35][CH2:34][N:33]1[C:55]([C:52]1([CH3:58])[CH2:53][CH2:54][N:51]1[C:49]([O:48][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:50])=[O:56]
Reactant: O=C(NCc1cc(Cl)ccc1-n1cnnn1)[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)N1CCC1(C)C(=O)O
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC1(C)C(=O)N1CCC[C@H]1C(=O)NCc1cc(Cl)ccc1-n1cnnn1

Procedure:
EDC (0.104 g, 0.54 mmol), HOAt (24.6 mg, 0.18 mmol), NMM (0.079 mL, 0.72 mmol), and N-[5-chloro-2-(1H-tetraazol-1-yl)benzyl]-L-prolinamide hydrochloride (Example 26, Step B, 0.143 g, 0.42 mmol) were added to a stirred solution of racemic 1-(tert-butoxycarbonyl)-2-methylazetidine-2-carboxylic acid (0.143 g, 0.36 mmol in DMF (1.1 mL). After 3 h at room temperature the reaction was partitioned between EtOAc and water. The organic layer was washed with brine, dried (Na2SO4) and concentrated in vacuo. The two diastereomers were separated and purified by reverse phase HPLC. The more polar diastereomer was concentrated in vacuo. N-[5-chloro-2-(1H-tetraazol-1-yl)benzyl]-1-[(1-tert-butoxycarbonyl-2-methylazetidin-2-yl)carbonyl]-L-prolinamide (diastereomer A) was obtained as a glass. MS m/z=404.6).
Reaction SMILES: B.C1COCC1.[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:24])[CH2:22][Br:23])=[CH:17][C:16]=1[N+:25]([O-:27])=[O:26])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CO>C1(C)C=CC=CC=1.C1COCC1>[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][C:18]([C@@H:21]([OH:24])[CH2:22][Br:23])=[CH:17][C:16]=1[N+:25]([O-:27])=[O:26])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(CBr)c1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Agent: B
Solvent: C1CCOC1
Solvent: CO
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cc([C@@H](O)CBr)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of BH3.THF in THF (1 M, 108.00 mL, 108.00 mmol) was added to a solution of 1-(4-benzyloxy-3-nitrophenyl)-2-bromoethanone (3) (63.30 g, 180.00 mmol) and R-methyl-CBS-oxazoborolidine (1 M in toluene, 36.00 mL, 36.00 mmol) in anhydrous THF (500 mL). The resulting reaction mixture was stirred at rt for 16 h. Methanol (250 mL) was then slowly added to quench the reaction. After removal of solvent by rotary evaporation, the resulting residue was purified by column chromatography (silica gel, a gradient of 70:30 to 100:0 dichloromethane/hexanes) to give the desired bromo alcohol 4 as a yellow, viscous oil (36.80 g, 75% yield): 1H NMR (500 MHz, CDCl3) δ 2.72 (d, 1H), 3.48 (dd, 1H), 3.59 (dd, 1H), 4.89 (m, 1H), 5.21 (s, 2H), 7.11 (d, 1H), 7.39 (m, 5H), 7.50 (dd, 1H), 7.87 (d, 1H).