Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[C:19](Cl)(=[O:21])[CH3:20].[Cl-].[NH4+]>C1COCC1>[C:19]([N:9]1[C@@H:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:12][O:11][C:10]1=[O:13])(=[O:21])[CH3:20]
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: CC(=O)Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reaction time: 0.17 h
Yield: 83.3 %

Procedure:
10 g (56.4 mmol) of (4S)-4-benzyl-2-oxazolidinone is dissolved under argon atmosphere in 100 ml of abs. THF and is mixed dropwise at -78° C. with 37 ml (59.3 mmol, 1.6M in hexane, 1.05 eq) of n-butyllithium. After 10 min., 4.1 ml (4.5 g, 57.5 mmol, 1.02 eq) of acetyl chloride is instilled. The solution is stirred for 15 more min. under cooling and then 3 hours at room temperature. For working up it is mixed with 50 ml of saturated ammonium chloride solution, the organic solvents are distilled off in a vacuum and the remaining residue is extracted several times with ethyl acetate. After drying on sodium sulfate and concentration by evaporation in a vacuum, the remaining solid is recrystallized in ethyl acetate/hexane. 10.3 g (83%) of colorless needles with melting point of 106° C. is formed.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)(C)C>[Br-:1].[CH2:2]([N+:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: c1ccncc1
Reactant: CCCCCCCCCCCCBr
Solvent: CC(C)O
Product: CCCCCCCCCCCC[n+]1ccccc1
Product: [Br-]

Procedure:
Equimolar amounts of 1-bromo-dodecane (249.2 g) and pyridine (79.1 g) are placed in a glass, three-necked, round bottom flask equipped with a heating means, a stirring means, and a condensing means. Then 82.1 g of isopropanol are added to the flask as a solvent. The contents of the vessel are heated to reflux with constant stirring. Reflux is maintained for six hours. Analysis of the reaction mixture indicates that the reaction is approximately 100 percent complete.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]([N:5]([CH2:15][C:16]1([C:22]([O:24][CH3:25])=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[C@H:6]1[CH2:8][C@@H:7]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:4].C=O.[C:30](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.CO>[CH3:30][N:19]1[CH2:20][CH2:21][C:16]([CH2:15][N:5]([C@@H:6]2[CH2:8][C@H:7]2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3](=[O:4])[C:2]([F:1])([F:26])[F:27])([C:22]([O:24][CH3:25])=[O:23])[CH2:17][CH2:18]1
Reactant: COC(=O)C1(CN(C(=O)C(F)(F)F)[C@H]2C[C@@H]2c2ccccc2)CCNCC1
Reactant: CC(=O)O
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCCl
Product: COC(=O)C1(CN(C(=O)C(F)(F)F)[C@@H]2C[C@H]2c2ccccc2)CCN(C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.7 %

Procedure:
To a solution of methyl 4-((2,2,2-trifluoro-N-((1S,2R)-2-phenylcyclopropyl)acetamido)methyl)piperidine-4-carboxylate (270 mg, 0.702 mmol) in 1,2-dichloroethane (DCE) (3 mL) and methanol (1.500 mL) were added formaldehyde (0.129 mL, 1.405 mmol) and acetic acid (0.060 mL, 1.054 mmol), and the mixture was stirred at room temperature for 1 h. Sodium triacetoxyborohydride (223 mg, 1.054 mmol) was added and the mixture was stirred at room temperature for 4 h. The mixture was quenched with 10% N NaHCO3 aqueous solution and extracted with DCM (3×). The extract was dried (Na2SO4) and concentrated. The residue was dried under vacuum to give 265 mg of product as pale yellow oil. MS: (M+H)+=399.2.
Reaction SMILES: Br[C:2]1[C:3]([CH2:22][OH:23])=[C:4]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([CH:18]4[CH2:20][CH2:19]4)[CH:14]=3)[C:9]2=[O:21])[CH:5]=[CH:6][CH:7]=1.[CH3:24][N:25]1[C:30]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]([N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)=[O:39])=[CH:34][CH:33]=2)=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][C:26]1=[O:55].C(Cl)(Cl)Cl.O1CCOCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.O>[CH:18]1([C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[C:9](=[O:21])[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([C:28]4[CH:29]=[C:30]([NH:31][C:32]5[CH:37]=[CH:36][C:35]([C:38]([N:40]6[CH2:41][CH2:42][O:43][CH2:44][CH2:45]6)=[O:39])=[CH:34][CH:33]=5)[N:25]([CH3:24])[C:26](=[O:55])[CH:27]=4)[C:3]=2[CH2:22][OH:23])[CH2:17][CH2:16]3)[CH2:20][CH2:19]1
Reactant: Cn1c(Nc2ccc(C(=O)N3CCOCC3)cc2)cc(B2OC(C)(C)C(C)(C)O2)cc1=O
Reactant: O=C1c2ccc(C3CC3)cc2CCN1c1cccc(Br)c1CO
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Solvent: O
Product: Cn1c(Nc2ccc(C(=O)N3CCOCC3)cc2)cc(-c2cccc(N3CCc4cc(C5CC5)ccc4C3=O)c2CO)cc1=O
Yield: 53.5 %

Procedure:
To a flask charged with 2-(3-bromo-2-hydroxymethyl-phenyl)-6-cyclopropyl-3,4-dihydro-2H-isoquinolin-1-one (3.70 g, 9.9 mmol), 1-Methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyridin-2-one (4.38 g, 9.9 mmol), Pd2 (dba)3.CHCl3 (229 mg, 0.25 mmol), 2-Dicyclohexylphosphino-2′,4′,6′-Tri-i-Propyl-1,1′-Biphenyl (238 mg, 0.50 mmol), and K3PO4 hexahydrate (7.5 g, 20 mmol) was added 40 mL of 4:1 dioxane:water and the mixture heated to reflux for 4 h, cooled and filtered over Solka-Floc®, rinsing with ethyl acetate. Partitioned and washed the organic phase with water and brine. Dried over sodium sulfate, filtered and concentrated to afford a dark oil. Purification by silica gel chromatography (methylene chloride/methanol) afforded 3.2 g of 6-Cyclopropyl-2-(2-hydroxymethyl-3-{1-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-2-oxo-1,2-dihydro-pyridin-4-yl}-phenyl)-3,4-dihydro-2H-isoquinolin-1-one as a colorless solid. MS (ESI) 606.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@H:16]([NH:18][C:19]([C:21]3[N:22]=[C:23]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[S:24][CH:25]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].N1C=CC=CC=1.[CH3:38][S:39](Cl)(=[O:41])=[O:40].O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@H:16]([NH:18][C:19]([C:21]3[N:22]=[C:23]([CH:26]4[CH2:31][CH2:30][N:29]([S:39]([CH3:38])(=[O:41])=[O:40])[CH2:28][CH2:27]4)[S:24][CH:25]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: C[C@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1csc(C2CCNCC2)n1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: C[C@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1csc(C2CCN(S(C)(=O)=O)CC2)n1
Reaction time: 8 h
Yield: 35.5 %

Procedure:
(R)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(piperidin-4-yl)thiazole-4-carboxamide (80 mg, 0.176 mmol) was added into a flask under nitrogen atmosphere. Dry pyridine was added along with methanesulfonyl chloride (20.14 mg, 0.176 mmol) and the mixture was stirred overnight. The reaction was stopped by adding water. The reaction mixture was diluted with DCM and washed with 1M Na2CO3 and water. The product was triturated using diethyl ether. Yield 35.5%. 1H-NMR (400 MHz; CDCl3): δ 1.29 (d, 3H), 1.92 (m, 2H), 2.18 (m, 2H), 2.81 (dd, 1H), 2.84 (s, 3H), 3.08 (m, 1H), 3.89 (m, 2H), 4.34 (dd, 1H), 4.42 (dd, 1H), 4.59 (m, 1H), 6.63 (d, 1H), 7.50 (d, 1H), 7.67 (d, 1H), 7.68 (d, 1H), 7.77 (dd, 1H), 7.98 (d, 1H), 8.01 (s, 1H).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:10]=3[C:11]=2[C:12](=[O:14])[CH3:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:20]=O.Cl.[CH3:23][NH:24][CH3:25]>C(O)(C)C>[C:1]1([C:7]2[O:8][C:9]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:10]=3[C:11]=2[C:12](=[O:14])[CH2:13][CH2:23][N:24]([CH3:20])[CH3:25])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CNC
Reactant: C=O
Reactant: CC(=O)c1c(-c2ccccc2)oc2ccc(Cl)cc12
Agent: Cl
Solvent: CC(C)O
Product: CN(C)CCC(=O)c1c(-c2ccccc2)oc2ccc(Cl)cc12

Procedure:
To a solution of 13.5 grams of the 2-phenyl-3-acetyl-5-chlorobenzofuran that was thus prepared in 35 milliliters of isopropanol were added 2.1 grams of paraformaldehyde and 5.7 grams of dimethylamine hydrochloride and the mixture was heated for 16 hours under reflux. The solvent was then evaporated therefrom under vacuum and the residue was taken up in a 5% aqueous solution of hydrochloric acid. The substances that remained undissolved in the hydrochloric acid were extracted therefrom with ethyl ether. The aqueous solution was then made alkaline by the addition of a 5% aqueous solution of sodium hydroxide, whereupon the oily base separated. The solution containing the oily base was then shaken with ethyl ether and the ethyl ether extract was separated therefrom, dried over anhydrous sodium sulfate, and a solution of hydrogen chloride in ethanol was added thereto, whereupon crystals of the hydrochloride of the compound named in the heading of this example separated. After recrystallization from ethanol, 8.1 grams of crystals, which had a melting point of 153°-155° C, was obtained.
Reaction SMILES: C([O:3][C:4](=[O:36])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[CH:15]=[CH:16][C:17]3[O:22][CH2:21][CH2:20][N:19]([S:23]([C:26]4[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=4[O:33][CH3:34])(=[O:25])=[O:24])[C:18]=3[CH:35]=2)=[O:13])=[CH:7][CH:6]=1)C.[OH-].[Na+].Cl>O1CCCC1.CO>[Cl:32][C:30]1[CH:29]=[CH:28][C:27]([O:33][CH3:34])=[C:26]([S:23]([N:19]2[C:18]3[CH:35]=[C:14]([C:12]([NH:11][C:8]4[CH:9]=[CH:10][C:5]([C:4]([OH:36])=[O:3])=[CH:6][CH:7]=4)=[O:13])[CH:15]=[CH:16][C:17]=3[O:22][CH2:21][CH2:20]2)(=[O:25])=[O:24])[CH:31]=1
Reactant: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(Cl)ccc2OC)CCO3)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(Cl)cc1S(=O)(=O)N1CCOc2ccc(C(=O)Nc3ccc(C(=O)O)cc3)cc21
Temperature: 45 °C

Procedure:
A solution of 4-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo-[1,4]oxazine-6-carbonyl]-amino}-benzoic acid ethyl ester (0.91 g, 1.72 mmol) in tetrahydrofuran (10 mL) and methanol (10 mL) was treated with 3N NaOH (5 mL, 15 mmol, 8.7 equiv.). The mixture was stirred at 45° C. for 30′. The mixture was then acidified with HCl 3N (5 mL) and the solid which precipitated was filtered, washing with water, and dried under high vacuum. 4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoic acid was obtained as a white solid, 0.85 g (98%). MS (ISP): m/e=501.0 (M−H); δH (300 MHz; d6-DMSO) 12.65 (1H, s), 10.35 (1H, s), 8.05 (1H, d), 7.81-7.88 (5H, m), 7.66-7.71 (2H, m), 7.19 (1H, d), 6.98 (1H, d), 3.96 (2H, m), 3.85 (2H, m), 3.53 (3H, s).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[F:23])[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=[N:17][O:18][CH3:19])[C:13]([NH:15][CH3:16])=[O:14].[CH3:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C(COC)OC.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>[F:23][C:22]1[C:2]([C:28]2[CH:29]=[CH:30][C:25]([CH3:24])=[CH:26][CH:27]=2)=[CH:3][C:4]([O:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:12](=[N:17][O:18][CH3:19])[C:13]([NH:15][CH3:16])=[O:14])=[CH:20][CH:21]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: CNC(=O)C(=NOC)c1ccccc1Oc1ccc(F)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CNC(=O)C(=NOC)c1ccccc1Oc1ccc(F)c(-c2ccc(C)cc2)c1
Yield: 97.1 %

Procedure:
A solution of 0.3 g of the product from Example 3 in 15 ml of dimethoxyethane was admixed with 0.2 g of 4-methylphenylboronic acid, 0.17 g of sodium carbonate, 2 ml of water and 40 mg of tetrakis(triphenylphosphine)palladium(0) and refluxed for 20 hours. The mixture was then poured into water and extracted with ethyl acetate, and the extract was washed with 1N aqueous sodium hydroxide solution and then with water and dried. Distillative removal of the solvent and silica gel chromatography (MtBE: cyclohexane=9:1) gave 0.3 g of the title compound.
Reaction SMILES: O[CH2:2][C@@H:3]([NH:5][C:6](=[O:9])[O:7][CH3:8])[CH3:4].C(N(CC)CC)C.CS(Cl)(=O)=O.[N-:22]=[N+:23]=[N-:24].[Na+]>ClCCl>[N:22]([CH2:2][C@@H:3]([NH:5][C:6](=[O:9])[O:7][CH3:8])[CH3:4])=[N+:23]=[N-:24]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)N[C@@H](C)CO
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)N[C@@H](C)CN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of Intermediate (S)-methyl 1-hydroxypropan-2-ylcarbamate (2.65 g, 20 mmol) and triethylamine (7.0 ml, 50 mmol) in anhydrous dichloromethane (100 mL) was added methanesulfonyl chloride (1.91 mL, 23.9 mmol). The mixture was stirred at rt for 3 h and was then extracted with ethyl acetate. The organic layer was washed with 1N sodium hydroxide solution and brine, and was then dried over sodium sulfate, filtered and concentrated. The crude mesylate product was then dissolved in dry DMF (70 mL) and sodium azide (5.2 g, 80 mmol) was added. The mixture was heated with stirring at 80° C. for 2 h. The cooled reaction mixture was concentrated and the residue was partitioned between ethyl acetate and brine. The organic layer was separated and washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (8:1 hexane/ethyl acetate eluant) to afford (S)-methyl 1-azidopropan-2-ylcarbamate. MS m/z 159.1 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12]([CH3:15])([CH3:14])[NH:11][C:10]([CH3:17])([CH3:16])[CH2:9]2)=[CH:4][CH:3]=1.O.[H][H]>C(O)C.[Ru]>[OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([CH:8]2[CH2:9][C:10]([CH3:17])([CH3:16])[NH:11][C:12]([CH3:15])([CH3:14])[CH2:13]2)[CH2:4][CH2:3]1
Reactant: [H][H]
Reactant: CC1(C)CC(c2ccc(O)cc2)CC(C)(C)N1
Agent: [Ru]
Solvent: O
Solvent: CCO
Product: CC1(C)CC(C2CCC(O)CC2)CC(C)(C)N1

Procedure:
10 parts of 4-(4'-hydroxyphenyl)-2,2,6,6-tetramethylpiperidine were dissolved in 150 parts of ethanol and treated with 30 parts of water, the mixture being warmed to maintain solution. The solution was then hydrogenated using 3 parts of ruthenium on carbon (5%) catalyst at 125° C and 100 atmospheres of hydrogen. The catalyst was separated and the solvent evaporated under reduced pressure. The residue was dissolved in chloroform, dried with magnesium sulphate and evaporated under reduced pressure. The residue was crystallised from petroleum (b.p. 80°-100° C) to yield the desired product melting at 145°-150° C and having the following elemental analysis.
Reaction SMILES: Br[C:2]1[O:3][C:4]([CH3:7])=[N:5][N:6]=1.C([Mg]Cl)(C)C.[CH3:13][C:14]([CH3:24])([CH3:23])/[CH:15]=[N:16]/[S:17]([C:19]([CH3:22])([CH3:21])[CH3:20])=[O:18]>C1COCC1.C1(C)C=CC=CC=1>[CH3:13][C:14]([CH3:24])([CH3:23])[CH:15]([NH:16][S:17]([C:19]([CH3:22])([CH3:21])[CH3:20])=[O:18])[C:2]1[O:3][C:4]([CH3:7])=[N:5][N:6]=1
Reactant: Cc1nnc(Br)o1
Reactant: CC(C)(C)/C=N/S(=O)C(C)(C)C
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1nnc(C(NS(=O)C(C)(C)C)C(C)(C)C)o1
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
To a solution of 2-bromo-5-methyl-1,3,4-oxadiazole (CAN 864750-58-3, 0.473 g, 2.91 mmol) in dry THF (8 ml) cooled down to −15° C. under an argon atmosphere was added isopropyl magnesium chloride, lithium chloride complex (2.23 ml, 2.91 mmol). (During the addition the temperature was kept below −12° C.). The reaction was then stirred at −15° C. for 30 minutes followed by slow addition of a solution of (NE)-N-(2,2-dimethylpropylidene)-2-methyl-propane-2-sulfinamide (CAN 917104-90-6, 500 mg, 2.64 mmol) in dry toluene (8 ml). The reaction was allowed to warm up to room temperature overnight. The reaction was quenched by addition of water. The reaction medium was diluted with ethylacetate and the organic phase was extracted with a saturated aqueous solution of ammonium chloride. The organic phase was collected and the aqueous phase was back-extracted with ethylacetate. The combined organic phases were dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a dichloromethane/methanol gradient to yield the title compound (462 mg, 64%). MS (ESI, m/z): 274.5 (M+H+).
Reaction SMILES: [CH:1]1([C:4](Cl)=O)[CH2:3][CH2:2]1.[NH2:7][C:8]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:9]=1[C:10](O)=[O:11].N1C=CC=CC=1.[NH2:27][NH2:28]>C1COCC1.C(OCC)(=O)C>[NH2:27][N:28]1[C:10](=[O:11])[C:9]2[C:8](=[CH:16][C:15]([C:17]([F:20])([F:19])[F:18])=[CH:14][CH:13]=2)[N:7]=[C:4]1[CH:1]1[CH2:2][CH2:3]1
Reactant: NN
Reactant: Nc1cc(C(F)(F)F)ccc1C(=O)O
Reactant: O=C(Cl)C1CC1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Nn1c(C2CC2)nc2cc(C(F)(F)F)ccc2c1=O
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Cyclopropanecarbonyl chloride (2.71 ml, 29.6 mmol) was added to a solution of 2-amino-4-(trifluoromethyl)benzoic acid (2.00 g, 9.75 mmol) in THF (50 mL) followed by pyridine (4.07 ml, 50.3 mmol). The mixture was stirred at 70° C. overnight. The mixture was cooled at 0° C., hydrazine was added, and the reaction was stirred at room temperature for 30 minutes and then at 75° C. for 24 hours. The reaction was cooled at 22° C., diluted with ethyl acetate, washed with aq. NaHCO3, dried with magnesium sulfate, filtered, and concentrated. The residue was suspended in toluene and concentrated again. The process was repeated to obtain the title compound.
Reaction SMILES: O[B:2]1[CH2:7][CH:6]=[CH:5][CH:4]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[O:3]1.C[C@@:17]1([OH:27])[C@H:22]([OH:23])[CH2:21][C@@H:20]2[CH2:24][C@H:18]1[C:19]2([CH3:26])[CH3:25].[CH2:28]1COCC1>>[OH:3][CH:4](/[CH:5]=[CH:6]\[CH2:7][B:2]1[O:23][C@:22]2([CH3:28])[C@@H:17]([C@@H:18]3[CH2:24][C@H:20]([CH2:21]2)[C:19]3([CH3:25])[CH3:26])[O:27]1)[CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]
Reactant: CC1(C)[C@@H]2C[C@@H](O)[C@@](C)(O)[C@H]1C2
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)CC1C=CCB(O)O1
Product: CC(C)(C)OC(=O)CC(O)/C=C\CB1O[C@@H]2[C@@H]3C[C@H](C[C@]2(C)O1)C3(C)C
Reaction time: 16 h
Yield: 59.9 %

Procedure:
To a stirred solution of tert-butyl 2-(2-hydroxy-3,6-dihydro-2H-1,2-oxaborinin-6-yl)acetate XLVII (770 mg, 4.58 mmol) in THF (25 mL) was added (1 S,2S,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]heptane-2,3-diol (980 mg, 4.58 mmol) at room temperature. The reaction mixture was stirred for 16 h and concentrated under vacuum. The residue was purified by column chromatography (100% hexane→30% EtOAc/hexane) on silica gel to give tert-butyl (4Z)-3-hydroxy-6-[(1R,2R,6S,8R)-6,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]decan-4-yl]hex-4-enoate LIV (1 g, 2.75 mmol, 59.9% yield).
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[O:14])[N:10]([NH:15][C:16](=[O:42])[C@@H:17]([C@@H:22]([C:32](=[O:41])[NH:33][O:34]C2CCCCO2)[CH2:23]/[CH:24]=[CH:25]/[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:18][CH:19]([CH3:21])[CH3:20])[C:9]1=[O:43])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.C(OCC)(=O)C>[CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[O:14])[N:10]([NH:15][C:16](=[O:42])[C@@H:17]([C@@H:22]([C:32](=[O:41])[NH:33][OH:34])[CH2:23]/[CH:24]=[CH:25]/[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:18][CH:19]([CH3:21])[CH3:20])[C:9]1=[O:43])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C[C@@H](C(=O)NN1C(=O)C(=O)N(Cc2ccccc2)C1=O)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)C[C@@H](C(=O)NN1C(=O)C(=O)N(Cc2ccccc2)C1=O)[C@H](C/C=C/c1ccccc1)C(=O)NO
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.9 %

Procedure:
A solution of 0.045 g of (E)-N-(3-benzyl-2,4,5-trioxo-1-imidazolidinyl]-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-4-methylvaleramide in 2 ml of methanol was treated with 0.010 g of p-toluenesulphonic acid monohydrate and stirred at room temperature for 2 hours. The mixture was diluted with ethyl acetate and washed in sequence with 5% aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride. The organic layer was dried over anhydrous magnesium sulphate and evaporated to give a residue which was triturated with diethyl ether to give 0.032 g of (E)-N-(3-benzyl-2,4,5-trioxo-1-imidazolidinyl]-2(R)-[1(S)-(hydroxycarbamoyl)-4-phenyl-3-butenyl]-4-methylvaleramide in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:8]2=CC=C[N:7]2[CH2:6][C:5]2[CH:12]=[CH:13][CH:14]=[CH:15][C:4]=2[N:3]=1.N1C=CC=CC=1C(NN)=O>C(O)C>[ClH:1].[NH:3]1[C:4]2[CH:15]=[CH:14][CH:13]=[CH:12][C:5]=2[CH:6]=[N:7][CH:8]=[CH:2]1
Reactant: ClC1=Nc2ccccc2Cn2cccc21
Agent: NNC(=O)c1ccccn1
Solvent: CCO
Product: C1=CNc2ccccc2C=N1
Product: Cl

Procedure:
Under an atmosphere of nitrogen, a slurry of 575 g of 11-chloro-5H-pyrrolo[2,1-c][1,4]benzodiazepine in 7.2 L of anhydrous ethanol is stirred while 364 g of pyridine-2-carboxylic acid hydrazide is added over a period of five minutes. The mixture is heated slowly to 65°. An exothermic reaction occurs and there is vigorous refluxing. When the refluxing subsides to a normal rate heating is continued and the mixture is stirred and refluxed for 21-22 hours. The product precipitates from the hot solution during the reflux period. The crystals are filtered off and washed on the filter with anhydrous ethanol. The product is air-dried overnight, then dried at high vacuum without heat for 2 days to yield 3-(2-pyridinyl)-9H-pyrrolo[2,1-c]-1,2,4-triazolo[4,3-a][1,4benzodiazepine hydrochloride, m.p. 265°-268° (d).
Reaction SMILES: [C:1]([NH:16][CH:17](O)[CH3:18])(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]1[C@@H:14]2[C@@H:9]([NH:10][C:11]([NH:13]2)=[O:12])[CH2:8][S:7]1.N1[C-]=NN=N1.C([NH2+]C(C)C)(C)C.[CH:32]([N:35]([CH:49]([CH3:51])[CH3:50])[P:36](N(C(C)C)C(C)C)[O:37][CH2:38][CH2:39][C:40]#[N:41])([CH3:34])[CH3:33].C(=O)(O)[O-:53].[Na+]>CN(C=O)C>[CH:32]([N:35]([CH:49]([CH3:51])[CH3:50])[P:36]([O:37][CH2:38][CH2:39][C:40]#[N:41])[O:53][CH2:18][CH2:17][NH:16][C:1](=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]1[C@@H:14]2[C@@H:9]([NH:10][C:11]([NH:13]2)=[O:12])[CH2:8][S:7]1)([CH3:34])[CH3:33]
Reactant: O=C([O-])O
Reactant: CC(C)N(C(C)C)P(OCCC#N)N(C(C)C)C(C)C
Reactant: CC(O)NC(=O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Agent: CC(C)[NH2+]C(C)C
Agent: [Na+]
Agent: [c-]1nnn[nH]1
Solvent: CN(C)C=O
Product: CC(C)N(C(C)C)P(OCCC#N)OCCNC(=O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
To a solution of 150 mg of N-biotinylaminoethanol (2a) in 5 ml of dry DMF was added 65 mg of diisopropylammonium tetrazolide and 0.300 ml of 2-cyanoethyl N,N,N',N'-tetraisopropylphosphorodiamidite. The resulting solution was stirred at room temperature for 1.25 hr and then poured onto 50 ml of 5% aqueous sodium bicarbonate. The mixture was extracted with two 50 ml portions of methylene chloride, and the combined extracts were washed with 5% sodium bicarbonate and brine, dried over sodium sulfate, and evaporated to afford the crude product as a thick oil. This was dissolved in 2 ml of dry methylene chloride, affording a solution that was added dropwise to 30 ml of rapidly stirring petroleum ether. The colorless precipitate that formed was collected by suction filtration under argon, affording after drying at room temperature under vacuum 109 mg (43%) of a colorless solid.